WO2025235862A1 - A modified immune cell receptor comprising a target-binding domain and the extracellular domain of cd16a - Google Patents

Abstract

The present disclosure relates to novel constructs, particularly modified immune cell receptor proteins and polynucleotides encoding said modified immune cell receptor proteins, and uses of said constructs. Said modified immune cell receptor protein is designated Engineered Valency-Enhanced CD16A (EVE16), which is intended for expression on the surface of various immune cells, including but not limited to Natural Killer (NK) cells, Natural Killer T (NKT) cells, T cells, monocytes, and others. EVE16 is a chimeric protein receptor designed to exploit the endogenous signal transduction pathways inherent to immune cells, notably NK cells, NKT cells, T cells, monocytes, and others, thereby facilitating the modulation of cellular signaling, particularly to initiate activating signaling. The present disclosure describes constructs comprising optimized leader peptides, target-binding domains, linker domains as well as cytoplasmic domains that demonstrate improved surface expression and activation signaling of EVE16, resulting in more potent cytotoxicity and other effector functions of immune cells. Additionally, this disclosure encompasses vectors harboring the aforementioned constructs (including expression constructs), cells, such as human immune cells, specifically NK cells, NKT cells, T cells, or monocytes expressing said constructs, and their use in disease treatment, particularly cancer and autoimmune diseases.

Description

CONSTRUCT FIELD OF THE INVENTION The present disclosure relates to novel constructs, particularly modified immune cell receptor proteins and polynucleotides encoding said modified immune cell receptor proteins, and uses of said constructs. BACKGROUND OF THE INVENTION The ability of cytotoxic and phagocytic lymphocytes to eliminate diseased cells is essential for the proper physiological functioning and overall health of an organism^1,2. For example, during a viral infection, cytotoxic lymphocytes, including various subsets of T cells, Natural Killer (NK) cells, NKT cells, and others, play a pivotal role in identifying and killing diseased cells that have been infected by a virus. Concurrently, phagocytes such as monocytes and macrophages, are tasked with engulfing infected and apoptotic cells, effectively facilitating their removal from the body. These essential functions extend beyond viral infections to encompass other infectious diseases, cancer, and autoimmune disorders, where the complete elimination of diseased cells is essential for resolving the pathology^3,4,5. While the mechanisms by which cytotoxic and phagocytic cells discern the diseased target cell and trigger their functionality vary across cell types, they share certain fundamental features. All cytotoxic and phagocytic cells express surface receptors that serve as sensors for markers indicative of a diseased state^6,7. Upon binding to their ligands, these receptors initiate an intracellular signaling cascade that activates the immune cell and initiates its effector functions. For instance, T cells express a T-cell receptor (TCR) that recognizes foreign antigens in the context of the major histocompatibility complex (MHC), thereby sensing foreign peptides expressed by virally infected cells or cancer cells harboring oncogenic mutations. Similarly, NK cells express germline-encoded receptors such as CD16A, NKG2D, NKp30, NKp44, and NKp46, which recognize bound antibodies or stress ligands on the surface of senescent, virus-infected, or cancer cells. Monocytes and macrophages express CD16A and CD64, which recognize antibody-opsonized targets, along with other surface receptors recognizing damage-associated molecular patterns such as CD91, TIM4, and others⁸. The goal of precision medicine has long aimed to achieve the safe and precise removal of targeted cell types from the human body. A significant step towards this objective was realized through the development of chimeric antigen receptor (CAR)-T, CAR-NK, and CAR-macrophage cell therapies, leveraging the evolved functionalities of these cells to selectively kill or phagocytose specific target cells^9,10,11,12. The chimeric antigen receptor (CAR) was engineered as a surface receptor with the capacity to target a particular cell type via single-chain fragment variable (scFv) binding to a cognate surface antigen, concurrently delivering activating signal through fused domains derived from naturally occurring stimulatory or co-stimulatory receptors. A typical CAR construct thus comprises a scFv antigen-binding domain, a hinge domain, a transmembrane domain and intracellular stimulatory or costimulatory domains derived from 4-1BB, CD28 and CD3ζ signaling proteins. The development of CAR-engineered cytotoxic and phagocytic cells marked a pivotal advancement in human medicine, demonstrating the feasibility of artificially redirecting these immune cells to eliminate desired cell types from the body. This approach proved effective in treating various conditions, including leukemias, lymphoma, multiple myeloma, and autoimmune diseases^13,14,15,16. Despite its clinical success, the CAR construct presents significant limitations. Notably, CAR exhibits propensity for trogocytosis, wherein it extracts the bound cognate antigen from the target cell membrane, leading to prolonged activation, exhaustion and the potential risk of fratricide^17,18 or activation-induced cell death (AICD). Strategies addressing CAR trogocytosis involve the development of fast-off scFv's and enhanced CAR recycling rates^19,20. Additionally, tonic signaling poses a challenge, whereby CAR initiates signal activation even in the absence of antigen binding. Different CAR modalities, such as 4-1BB versus CD28 co-stimulation, and diverse scFv's, like anti-CD19 versus anti-GD2, exhibit varying propensities for tonic signaling^21,22. Tonic signaling has been associated with early T cell exhaustion and premature differentiation, though some reports suggest that 4-1BB-containing CAR tonic signaling may improve CAR-T cell survival and proliferation²³. Finally, the CAR construct is limited to targeting only one or two antigens simultaneously, which poses a challenge for targeting solid tumors that are characterized by the absence of homogeneously expressed tumor-associated markers. These limitations underscore ongoing efforts to enhance the precision, safety, and versatility of CAR-based cell therapies for a broader range of clinical applications. SUMMARY OF THE INVENTION Among activating receptors expressed on the surface of NK cells, CD16A is unique in its ability to transmit strong activating signals through high-affinity interactions with the F_C domain of target-bound IgG1, IgG3, and to a lesser extent IgG4 antibodies²⁴. Despite being classified as the low-affinity Ig receptor, CD16A exhibits binding to the antibody F_C domain with the dissociation constant in the nanomolar range²⁵. Notably, the naturally occurring F176V CD16A allele demonstrates even stronger binding affinity for F_C domains of antibodies, with dissociation constant in the low nanomolar range²⁶. The high-affinity interactions exhibited by CD16A suggest the existence of evolutionary adaptations to mitigate the issue of trogocytosis, particularly in the case of viral infections that can lead to uptake of viral particles. Activation-induced shedding of CD16A, via the metalloprotease enzyme ADAM17, is presumed to contribute to target antigen disengagement, presenting a plausible mechanism to counteract trogocytosis^27,28. Furthermore, CD16A, lacking its own signaling domain, forms a multimeric complex with endogenously expressed signaling adaptor proteins FcεRIγ (FCER1G) and CD3ζ (CD247)^29,30. These signaling adaptor proteins contain conserved domains known as immunoreceptor tyrosine-based activation motifs (ITAMs), which mediate downstream signaling upon CD16A binding. Multi-chain activating complexes, such as these, have been previously demonstrated to lack appreciable tonic signaling activity³¹. Finally, the ability of CD16A to interact with the constant domain of IgG1 and IgG3 antibodies offers versatile targeting capabilities. These inherent characteristics position CD16A as a potentially superior framework for an engineered activating immune receptor compared to the conventional CAR construct. CD16A is dependent upon CD3ζ and/or FCER1G for the surface expression³². Furthermore, it has been shown that CD3ζ can be downregulated in several immune effector cells, including tumor-infiltrating lymphocytes, T cells, NK cells and macrophages, in diseases including cancer and autoimmunity^33-36. In the context of cellular immunotherapy, the chimeric antigen receptor construct has demonstrated considerable efficacy in redirecting effector functionality of T cells, NK cells, and macrophages. However, inherent limitations, including trogocytosis, tonic signaling, exhaustion, AICD and restricted targeting versatility, persist. Using as the framework the potent activating receptor CD16A, which has evolved to engage in high- affinity interactions and is integrated into the cellular signaling network through FCER1G and CD3ζ, the inventors have introduced a novel engineered activating immunoreceptor, termed Engineered Valency-Enhanced CD16A (EVE16). EVE16 exhibits the capacity to redirect cytotoxic and phagocytic immune cells towards a desired target cell, mitigating trogocytosis and tonic signaling, while simultaneously facilitating versatile targeting via binding to antibody FC domain. EVE16 has a dual mechanism of action, via scFv-mediated antigen-specific targeting, and via F_C-mediated targeting (antibody-dependent cellular cytotoxicity or ADCC). The signaling capacity of the EVE16 construct is contingent upon precise target engagement facilitated by its target-binding domain and FC-binding domain (see Figure 1A). Optimal EVE16 functionality requires its correct folding, high expression levels, and efficient trafficking of the full construct to the cell surface, while avoiding steric hindrances between different EVE16 domains. Additionally, robust signaling capacity that promotes cytotoxicity, cytokine secretion, and effector cell proliferation is essential for therapeutic intervention. The presence of high concentration of serum antibodies, including afucosylated antibodies, poses potential challenges, as they may bind to EVE16, resulting in steric occlusions that impede proper target engagement through the target-binding domain. Unknown surface receptors interacting with EVE16 can further contribute to steric occlusions. Notably, like CD16A, EVE16 relies on endogenous CD3ζ for trafficking to the cell surface, necessitating competition with other CD3ζ binders. Unexpectedly, the inventors discovered that varying the length and amino acid sequence of the linker domain that connects the target-binding domain and FC-binding domain significantly influenced EVE16 surface expression and target engagement. While the precise mechanism remains unclear, it is postulated that the linker domain folds beneath the V-shaped ectodomain of CD16A, extending into the extracellular space from one of the sides of CD16A (see Figure 2). For optimal target binding, this requires a minimum length linker with sufficient flexibility. Consequently, specific requirements regarding linker domain length and sequence are imperative to ensure proper target engagement and immune effector functions. Suitable flexibility of the linker can be achieved through the optimal incorporation of certain amino acids including glycine, serine and by reducing the content of cysteine and proline. Furthermore, for therapeutic applications, the linker domain should exhibit minimal immunogenicity. To this end, linker sequences derived from human proteins are preferred. The inventors have identified human-derived linker domains of sufficient length and flexibility that support high-level EVE16 surface expression and functional activity. Furthermore, the inventors discovered that both the choice of leader peptide and the orientation of the single-chain variable fragment (scFv) affect the expression and surface localization of the EVE16 construct. Although the underlying mechanisms are not fully elucidated, it is believed that the rate of translation relative to CD3ζ, as well as the intrinsic stability of the various EVE16 domains, contribute to the overall stability and expression of the receptor. A panel of leader peptides derived from human type I transmembrane proteins was screened, and specific peptides were identified that enhance EVE16 surface expression. In addition, it was found that the orientation of the scFv—whether VH-VL or VL-VH— influences expression levels. Based on these findings, the inventors further optimized EVE16 expression through selection of leader peptides and scFv configurations. Furthermore, the inventors have introduced multiple co-stimulatory domains to the original EVE16 construct, augmenting cellular signaling and effector functions. These innovations collectively contribute to the enhanced efficacy and versatility of EVE16-based cellular immunotherapies, marking a notable advancement in the field. Unexpectedly, the inventors discovered that the surface expression of EVE16 constructs was consistently lower than that of CAR constructs containing the same scFv, potentially because of competition for CD3ζ binding between various surface receptors, including endogenous CD16A, NKp30, NKp46 and TCR. Co-expression of EVE16 with the full- length CD3ζ protein significantly improved the surface expression of EVE16 confirming that CD3ζ is limiting for EVE16 plasma membrane trafficking. Therefore, the present invention encompasses: A modified immune cell receptor protein comprising: - a target-binding domain, - the extracellular domain of CD16A, wherein the extracellular domain comprises the FC-binding domain and the hinge domain of CD16A, and - a transmembrane domain, wherein the modified immune cell receptor protein also comprises a flexible linker positioned between the target-binding domain and the extracellular domain of CD16A, wherein the linker is at least 10 amino acids in length. The invention also encompasses: - A nucleic acid encoding the protein of the invention. - An immune cell or population of immune cells comprising the protein of the invention or the nucleic acid of the invention. - A pharmaceutical composition comprising a therapeutically effective amount of the nucleic acid of the invention or the immune cell(s) of the invention. - The immune cell of the invention, or the pharmaceutical composition of the invention, for use in therapy. - A method of treating a subject with cancer, comprising administering to the subject the immune cell of the invention or the pharmaceutical composition of the invention. - A method of treating a subject with autoimmune disease, comprising administering to the subject the immune cell of the invention or the pharmaceutical composition of the invention. - A method of treating a subject with a transplant, comprising administering to the subject the immune cell of the invention or the pharmaceutical composition of the invention. - A method of treating a subject with graft versus host disease (GVHD), comprising administering to the subject the immune cell of the invention or the pharmaceutical composition of the invention. BRIEF DESCRIPTION OF THE SEQUENCE LISTING SEQ ID NO: 1 - loncastuximab heavy chain SEQ ID NO: 2 - loncastuximab light chain SEQ ID NO: 3 - tafasitamab heavy chain SEQ ID NO: 4 - tafasitamab light chain SEQ ID NO: 5 - denintuzumab heavy chain SEQ ID NO: 6 - denintuzumab light chain SEQ ID NO: 7 - inebilizumab heavy chain SEQ ID NO: 8- inebilizumab light chain SEQ ID NO: 9 - obexelimab heavy chain SEQ ID NO: 10 - obexelimab light chain SEQ ID NO: 11 - ofatumumab heavy chain SEQ ID NO: 12 - ofatumumab light chain SEQ ID NO: 13 - veltuzumab heavy chain SEQ ID NO: 14 - veltuzumab light chain SEQ ID NO: 15- tositumomab heavy chain SEQ ID NO: 16 – tositumomab light chain SEQ ID NO: 17 – rituximab heavy chain SEQ ID NO: 18 - rituximab light chain SEQ ID NO: 19 - atezolizumab heavy chain SEQ ID NO: 20 - atezolizumab light chain SEQ ID NO: 21 - avelumab heavy chain SEQ ID NO: 22 – avelumab light chain SEQ ID NO: 23 - durvalumab heavy chain SEQ ID NO: 24 - durvalumab light chain SEQ ID NO: 25 -CD27 ectodomain SEQ ID NO: 27- FMC63 light chain SEQ ID NO: 28- Gemtuzumab heavy chain SEQ ID NO: 29- Gemtuzumab light chain SEQ ID NO:30 – GGGGSGGGGS SEQ ID NO:31 - GGGGSGGGGSGGGGS SEQ ID NO:32- GGGGSGGGGSGGGGSGGGGS SEQ ID NO:33- GSTSGSGKPGSGEGSTKG SEQ ID NO:34- KESGSVSSEQLAQFRSLD SEQ ID NO:35 - EGKSSGSGSESKST SEQ ID NO:36- GSAGSAAGSGEF SEQ ID NO: 37- delta CD8a linker SEQ ID NO: 38 - NKp44 long linker SEQ ID NO: 39 - NKp44 short linker SEQ ID NO: 40 - NKp46 long linker SEQ ID NO: 41 - KIR2DS1 linker SEQ ID NO: 42 - KIR3DS1 linker SEQ ID NO: 43 - CD27 short linker SEQ ID NO: 44 - CD27 long linker SEQ ID NO: 45 – AVSTI SEQ ID NO: 46 – extracellular domain of CD16A SEQ ID NO: 47 – CD3ζ TM domain SEQ ID NO: 48- CD4 TM domain SEQ ID NO: 49- CD8α TM domain SEQ ID NO: 50 – CD28 TM domain SEQ ID NO: 51 - CD137 (4-1BB) TM domain SEQ ID NO: 52 – CD16A TM domain SEQ ID NO: 53 – CD16A cytoplasmic domain SEQ ID NO: 54 - CD3ζ co-stimulatory signaling domain SEQ ID NO: 55 - CD3ζ variant co-stimulatory signaling domain SEQ ID NO: 56 - CD3ε co-stimulatory signaling domain SEQ ID NO: 57 – CD4 co-stimulatory signaling domain SEQ ID NO: 58 – CD27 co-stimulatory signaling domain SEQ ID NO: 59 – CD28 co-stimulatory signaling domain SEQ ID NO: 60 – CD40 co-stimulatory signaling domain SEQ ID NO: 61 – CD80 co-stimulatory signaling domain SEQ ID NO: 62 – CD86 co-stimulatory signaling domain SEQ ID NO: 63 – CD137 (4-1BB) co-stimulatory signaling domain SEQ ID NO: 64 – DAP10 co-stimulatory signaling domain SEQ ID NO: 65 – DAP12 co-stimulatory signaling domain SEQ ID NO: 66 – FcεRI co-stimulatory signaling domain SEQ ID NO: 67 – ICOS co-stimulatory signaling domain SEQ ID NO: 68 – KIR2DS2 co-stimulatory signaling domain SEQ ID NO: 69 – MyD88 co-stimulatory signaling domain SEQ ID NO: 70 – OX40 co-stimulatory signaling domain SEQ ID NO: 71 – ZAP70 co-stimulatory signaling domain SEQ ID NO: 72 – 2B4 co-stimulatory signaling domain SEQ ID NO: 73 – CD2 co-stimulatory signaling domain SEQ ID NO: 74 – CD28H co-stimulatory signaling domain SEQ ID NO: 75 – CD30 co-stimulatory signaling domain SEQ ID NO: 76 – CD84 co-stimulatory signaling domain SEQ ID NO: 77 – CRTAM co-stimulatory signaling domain SEQ ID NO: 78 – DNAM-1 co-stimulatory signaling domain SEQ ID NO: 79 – DR3 co-stimulatory signaling domain SEQ ID NO: 80 – GITR co-stimulatory signaling domain SEQ ID NO: 81 – HVEM co-stimulatory signaling domain SEQ ID NO: 82 – SLAMF1 co-stimulatory signaling domain SEQ ID NO: 83 – TIM1 co-stimulatory signaling domain SEQ ID NO: 84 – SLAMF3 co-stimulatory signaling domain SEQ ID NO: 85 – NTBA co-stimulatory signaling domain SEQ ID NO: 86 – CRACC co-stimulatory signaling domain SEQ ID NO: 87 – Albumin leader peptide SEQ ID NO: 88 – Synthetic, modified albumin leader peptide SEQ ID NO: 89 – CD8α leader peptide SEQ ID NO: 90 – CD33 leader peptide SEQ ID NO: 91 – EPO leader peptide SEQ ID NO: 92 – IL-2 leader peptide SEQ ID NO: 93 – Mouse IgK V3 leader peptide SEQ ID NO: 94 – Human IgK V3 leader peptide SEQ ID NO: 95 – Synthetic, modified human IgK V3 leader peptide SEQ ID NO: 96 – tPA leader peptide SEQ ID NO: 97 – SEAP leader peptide SEQ ID NO: 98 – Synthetic consensus leader peptide SEQ ID NO: 99 – Synthetic secrecon leader peptide SEQ ID NO: 100 – representative BaEV-gp SEQ ID NO: 101 – G4S-GMRTEDL SEQ ID NO: 102 – G4S- GMRTED SEQ ID NO: 103 - GMRTEDL SEQ ID NO: 104 – TTTPAPRPPTPAPTIASQPLSLRPEAGGGGSGMRTEDL SEQ ID NO: 105 - CD8β hinge (C155S)-G4S TTAQPTKKSTLKKRVSRLPRPETQKGPLSSPGGGGS SEQ ID NO: 106 - Epratuzumab heavy chain SEQ ID NO: 107 - Epratuzumab light chain SEQ ID NO: 108 - Inotuzumab heavy chain SEQ ID NO: 109 - Inotuzumab light chain SEQ ID NO: 110 - Moxetumomab heavy chain SEQ ID NO: 111 - Moxetumomab light chain SEQ ID NO: 112 - Pinatuzumab heavy chain SEQ ID NO: 113 - Pinatuzumab light chain SEQ ID NO: 114 - Belantamab heavy chain SEQ ID NO: 115 - Belantamab light chain SEQ ID NO: 116 - Ispectamab heavy chain SEQ ID NO: 117 - Ispectamab light chain SEQ ID NO: 118 - Elranatamab heavy chain SEQ ID NO: 119 - Elranatamab light chain SEQ ID NO: 120 - Pavurutamab heavy chain SEQ ID NO: 121 - Pavurutamab light chain SEQ ID NO: 122 – Syncytin-1 leader peptide SEQ ID NO: 123 – CD8B leader peptide SEQ ID NO: 124 – CD28 leader peptide SEQ ID NO: 125 – CD3zeta leader peptide SEQ ID NO: 126 – CD16A leader peptide SEQ ID NO: 127 – NKp30 leader peptide SEQ ID NO: 128 – NKp44 leader peptide SEQ ID NO: 129 – NKp46 leader peptide BRIEF DESCRIPTION OF THE DRAWINGS The detailed description of preferred embodiments of the invention provided herein is best comprehended when studied in conjunction with the accompanying drawings. The drawings depict presently preferred embodiments intended to elucidate the features of the invention. However, it is essential to note that the scope of the invention is not confined to the exact configurations and instrumentalities exemplified in the drawings. Figure 1., comprising Figures 1A-B, is a series of images showing schematic representations highlighting the similarities and differences between the endogenous human CD16A protein, the Engineered Valency-Enhanced CD16A (EVE16) receptor, and the standard chimeric antigen receptor (CAR) receptor. Of note, EVE16 receptor is composed of the target-binding domain, the linker domain, the F_C-binding domain, the hinge domain, the transmembrane domain, and the cytoplasmic domain (Figure 1A). In this example, the cytoplasmic domain of EVE16 comprises 4-1BB and DAP10 co- stimulatory sequences, although other co-stimulatory sequences can also be used. Figure 1B exemplifies the open-reading frame (ORF) composition and the primary protein structure of an EVE16 receptor that contains FMC63 scFv target-binding domain (targeting CD19) and 4-1BB/DAP10 co-stimulatory domain. Figure 2., comprising Figures 2A-G, is a series of images showing primary and tertiary structures of proteins important for the assembly of the Engineered Valency-Enhanced CD16A (EVE16) receptor. Figures 2A and 2B depict primary and tertiary structures of human CD3zeta (A) and FCER1G (B) proteins, essential for the EVE16 plasma membrane localization. Figures 2C and 2D depict primary and tertiary structures of human CD16A protein (C) as well as its predicted leader peptide cleavage site (D). Figure 2E depicts primary and tertiary structures of human CD27 protein, with an outlined ectodomain sequence that functions as a CD70 ligand. Figure 2F depicts primary and tertiary structures of human CD8A protein, with outlined leader peptide sequence that can be used for the expression of various plasma membrane proteins, and particularly the EVE16 receptor. Figure 2G depicts primary and tertiary structures of an example EVE16 protein containing CD8A leader peptide and target-binding domain composed of CD27 ectodomain. Figure 3., comprising Figures 3A-B, is a series of images showing that the linker domain of EVE16 is necessary for the surface expression of the full receptor, but its presence alone is not entirely sufficient for proper surface expression. Figure 3A depicts the open-reading frame composition of EVE16 receptors containing various linker domain constructs. Each EVE16 receptor included the CD8α leader peptide and CD27 ectodomain as the target- binding domain, while the cytoplasmic domain consisted of the native CD16A cytoplasmic domain. Different CD27-EVE16 receptors were expressed in the Jurkat cell line, and the stably transduced populations were stained for surface CD27 and CD16A (mean fluorescence intensities represented on the bar graph, Figure 3A). Figure 3B depicts flow cytometry plots of Jurkat cells stably transduced with the indicated EVE16 receptors, stained for surface CD27 and CD16A. Untransduced Jurkat cells were used as a negative control. Figure 4., comprising Figures 4A-B, is a series of images showing that the expression of the CD27-EVE16 receptor containing a flexible linker domain is functional in cytokine- induced memory-like Natural Killer (CIML NK) cells. Figure 4A shows flow cytometry plots of untransduced CIML NK cells, or CIML NK cells transduced with lentiviral particles harboring indicated EVE16 receptors and stained for the surface expression of CD27 and CD16A. Figure 4B shows the result of a 6-hour cytotoxicity assay of the indicated CIML NK cells against OCI-AML3 cell line (CD70-expressing) at the indicated effector-to-target ratios. Figure 5., comprising Figures 5A-B, is a series of images showing a library of linker domains used for the optimization of EVE16 surface expression. Figure 5A depicts open- reading frame composition of each linker domain used for the assembly of CD27-EVE16 receptors. Figure 5B shows amino acid sequence and some of the biochemical characteristics of linker domains used for the optimization of EVE16 surface expression. Figure 6, comprising Figures 6A-C, is a series of images showing the optimization of EVE16 surface using various linker domains. Figure 6A shows flow cytometry plots, and Figure 6B shows mean fluorescence intensities of Jurkat cell lines stably expressing indicated CD27-EVE16 receptors. Cells were stained for surface expression of CD27 and CD16A. Figure 6C shows the binding of recombinant human CD70 to the Jurkat cells stably expressing indicated CD27-EVE16 receptors. Each CD27-EVE16 receptor is bis- cistronic, containing an eGFP marker and utilizing a P2A self-cleavable peptide. Figure 7., is a series of images showing that the CD27-EVE16 receptor containing the optimized linker domain is functional in CIML NK cells. CIML NK cells were transduced with a bis-cistronic expression vector containing the indicated CD27-EVE16 receptor and the eGFP marker. CIML NK cells were stained for surface CD27 and CD16A, and flow cytometry plot was generated from eGFP-positive gated cells. A 6-hour cytotoxicity assay with the indicated CIML NK cells was performed against OCI-AML3 cell line at the indicated effector-to-target ratio. Figure 8., is a series of images showing that the FC-binding domain is necessary for the proper surface expression of the EVE16 receptor. Jurkat cells were stably transduced with indicated FMC63-EVE16 receptor mutants and stained for surface FMC63 scFv and CD16A. Each FMC63-EVE16 receptor is bis-cistronic, containing an eGFP marker, and utilizing a P2A self-cleavable peptide. Flow cytometry plots of stained Jurkat cells were gated on live, eGFP-positive cells. Figure 9., comprising Figures 9A-F, is a series of images showing that certain cytoplasmic domains enhance the signaling capacity of the EVE16 receptor. The signaling capacity of CD27-EVE16 receptors with indicated cytoplasmic domains (C-terminal domain, CTD) was evaluated in a cytotoxicity assay (A and C 6-hour assay, B 16-hour assay) using transduced CIML NK cells against OCI-AML3 cell line at the indicated effector-to-target ratio. Each CD27-EVE16 receptor is bis-cistronic, containing an eGFP marker and utilizing a P2A self-cleavable peptide. Flow cytometry plots depict surface staining against CD27 of the untransduced or CIML NK cells transduced with the indicated CD27-EVE16 receptors. Figure 9D shows flow cytometry data of isolated human CD3⁺ T cells transduced with either an anti-CD19 CAR (scFv derived from FMC63) or EVE16 variants containing the indicated intracellular signaling domains. The same T cell populations were evaluated in an overnight cytotoxicity assay against Raji cells to assess functional activation (bottom panel). Figure 9E displays the in vivo antitumor activity of T cells transduced with FMC63-based EVE16 variants harboring different cytoplasmic domains and the optimized NKp44 long linker domain, as described above. Figure 9F shows the in vivo efficacy of T cells transduced with anti-CD20 EVE16 variants (Rituximab-derived scFv) containing the indicated cytoplasmic signaling domains. In both in vivo studies (Figures 9E and 9F), NSG mice were inoculated intravenously with Raji cells on Day 0 and treated with engineered T cells on Day 5. Tumor progression was monitored by bioluminescence imaging using IVIS, and overall survival was recorded. Figure 10., is a series of images showing that the co-expression of CD3zeta enhances the surface expression of the EVE16 receptor. Jurkat cells were stably transduced with FMC63-EVE16 receptor containing 4-1BB costimulatory domain as a bis-cistronic construct co-expressing either the eGFP marker or the full-length human CD3zeta protein (note the open-reading frame composition for each construct). FMC63-EVE16 surface expression was evaluated using surface CD16A staining and flow cytometry analysis. Figure 11 is an image demonstrating that the optimized EVE16 receptor can be directed against multiple target surface antigens. Human CD3⁺ T cells were isolated and transduced with EVE16 variants incorporating an optimized NKp44 long hinge-derived linker domain, an OX40-derived intracellular signaling domain, and single-chain variable fragments (scFvs) specific for CD19 (FMC63), CD20 (Rituximab), CD70 (Cusatuzumab), or CD22 (Pinatuzumab). The immunoactivation potential of each EVE16 variant was evaluated in an overnight cytotoxicity assay using the Raji cell line, which endogenously expresses CD19, CD20, CD22, and CD70. Figure 12, comprising Figures 12A–12D, represents data demonstrating that both the leader peptide sequence and scFv orientation are critical determinants of EVE16 surface expression. Figure 12A shows the open reading frames (ORFs) of a library of anti-CD20 EVE16 variants generated for the screen, each incorporating one of twelve distinct leader peptides. Single-chain variable fragments (scFvs) were derived from four anti-CD20 monoclonal antibodies: Rituximab, Ofatumumab, Ocrelizumab, and Ublituximab. Figure 12B displays flow cytometry analysis of 293T cells transfected with the indicated EVE16 constructs, assessing surface expression using antibodies specific for CD16 and the G4S linker. Figure 12C presents flow cytometry data from Jurkat cells transduced with the same EVE16 variants, showing surface staining with anti-CD16 and anti-G4S linker antibodies, as well as binding to CD20-GFP fusion virus-like particles. Figure 12D compares the expression and functional activity of a Rituximab-based CAR construct and two Rituximab-derived EVE16 variants in isolated human CD3⁺ T cells. Functional activation was assessed in an overnight cytotoxicity co-culture assay using Raji target cells. DETAILED DESCRIPTION All publications and patent applications herein are incorporated by reference to the same extent as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. Where a definition or use of a term in an incorporated reference is inconsistent or contrary to the definition of that term provided herein, the definition of that term provided herein applies and the definition of that term in the reference does not apply. Definitions Unless defined otherwise, technical and scientific terms used herein have the same meaning as commonly understood by a person skilled in the art to which this invention belongs. It is to be understood that different applications of the disclosed invention may be tailored to the specific needs in the art. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments of the invention only, and is not intended to be limiting. When describing Greek symbols, both the Greek symbol itself and the English translation thereof may be used interchangeably. For example, ζ and zeta may be used interchangeably. The term “about” or “around” when referring to a value refers to that value but within a reasonable degree of scientific error. Optionally, a value is “about x” or “around x” if it is within 10%, within 5%, or within 1% of x. The term “approximately” as used herein refers to a range of values that fall within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less in either direction (greater than or less than) of the stated reference value unless otherwise stated or otherwise evident from the context (except where such number would exceed 100% of a possible value). In addition, as used in this specification and the appended claims, the singular forms “a”, “an”, and “the” include plural references unless the content clearly dictates otherwise. Thus, for example, reference to “a cell” includes “cells”, and the like. In general, the terms “comprising” or “comprises” are intended to mean including but not limited to. For example, the phrase “…a modified immune cell receptor protein comprising a binding domain” should be interpreted to mean that the modified immune cell receptor protein comprises a binding domain, but the modified immune cell receptor protein may also comprise further features, such as the extracellular domain of CD16A and a transmembrane domain. In some embodiments of the invention, the words “comprising” or “comprises” are replaced with the phrases “consisting of” or “consists of”. The phrases “consisting of” or “consists of” are intended to be limiting. For example, the phrase “…a modified immune cell receptor protein consisting of a binding domain” should be interpreted to mean that the modified immune cell receptor protein consists of a binding domain, but no further features. In some embodiments of the invention, the word “comprising” is replaced with the phrase “consisting essentially of”. The term “consisting essentially of” means that specific further features can be present, namely those not materially affecting the essential characteristics of the subject matter. The term “nucleic acid” as used herein refers to a polymer of nucleotides, each of which are organic molecules consisting of a nucleoside (a nucleobase and a five-carbon sugar) and a phosphate. The term nucleotide, unless specifically stated or obvious from context, includes nucleosides that have a ribose sugar (i.e., a ribonucleotide that forms ribonucleic acid, RNA) or a 2’-deoxyribose sugar (i.e., a deoxyribonucleotide that forms deoxyribonucleic acid, DNA). Nucleotides serve as the monomeric units of nucleic acid polymers or polynucleotides. The four nucleobases in DNA are guanine (G), adenine (A), cytosine (C) and thymine (T). The four nucleobases in RNA are guanine (G), adenine (A), cytosine (C) and uracil (U). Nucleic acids are linear chains of nucleotides (e.g., at least 3 nucleotides) chemically bonded by a series of ester linkages between the phosphoryl group of one nucleotide and the hydroxyl group of the sugar (i.e., ribose or 2’-deoxyribose) in the adjacent nucleotide. As provided herein, the sequences for the modified immune cell receptor proteins may be encoded on a single nucleic acid or may be encoded by more than one nucleic acid (a set of nucleic acids). The term “antigen” as used herein refers to an entity at least a portion of which is present on the surface of a cell, such as a cancer or immune cell. Antigens may be proteins, peptides, peptide-protein complexes (e.g., a peptide bound to an MHC molecule), protein- carbohydrate complexes (e.g., a glycoprotein), protein-lipid complexes (e.g., a lipoprotein), protein-nucleic acid complexes (e.g., a nucleoprotein), etc. “Engineered Valency-Enhanced CD16A receptor” (EVE16) according to the present disclosure is a modified immune cell receptor protein comprising an active fragment of an immune cell activating receptor CD16A and a target-binding domain. The latter redirects the specificity of the activating receptor to render it specific for a desired or intended target, for example such that activation and signaling occurs after binding a disease target, such as CD19, CD33, CD7, CD123, CD20, CD22, BCMA, GPRC5D, Mesothelin, claudin18.2, PSMA, B7-H6, CD3, CD4, BAFF-R, EGFR, HER2, gp120, gp41, or CD70. “Activating receptor components” as employed herein refers to elements of the modified immune cell receptor protein that are derived from (such as fragments of) an activating receptor. An “activating receptor” as employed herein refers to a cell surface receptor that sends an activating signal to an immune cell, in particular to generate or enhance cytotoxic activity. Activating receptors as employed herein include Killer Activation Receptors (KARs) are receptors expressed on the plasma membrane of Natural Killer cells (NK cells). KARs work together with inhibitory receptors (abbreviated as KIRs in the text), which inactivate them in order to regulate the NK cell function on host or transformed cells. These two kinds of specific receptors have some morphological features in common, such as being transmembrane proteins. The similarities are specially found in the extracellular domains and, the differences tend to be in the intracellular domains. KARs and KIRs can have tyrosine containing activating or inhibitory motifs in the intracellular part of the receptor molecule (they are called ITAMs and ITIMs, respectively). The activating receptors employed herein may comprise several domains, for example an immunoglobulin (Ig)-like domain, a hinge region, a transmembrane domain and a cytoplasmic domain. It is thought that the hinge, transmembrane, and cytoplasmic domains are important for signaling. An active fragment of an immune cell activating receptor as employed herein refers to a fragment of the receptor that is able to induce signaling after a binding event. Naturally occurring variants of CD16A present in the human population may be independently selected from F176V, and 48-L/R/H, and others. An alternative name used for the F176V mutation, or polymorphism, in scientific literature is F158V. “Adaptor proteins” as employed herein refers to signal transducing adaptor protein (STAPs). These are proteins that are accessory to main proteins in a signal transduction pathway. Adaptor proteins contain a variety of protein-binding modules that link protein-binding partners together and facilitate the creation of larger signaling complexes. These proteins tend to lack any intrinsic enzymatic activity themselves, instead mediating specific protein–protein interactions that drive the formation of protein complexes. Examples of adaptor proteins include MYD88, Grb2, SHC1, DAP10, DAP12, as well as FcεRIγ and CD3ζ. Adaptor signaling proteins usually contain several domains within their structure (e.g., Src homology 2 (SH2) and SH3 domains) that allow specific interactions with several other specific proteins. SH2 domains recognize specific amino acid sequences within proteins containing phosphotyrosine residues and SH3 domains recognize proline-rich sequences within specific peptide sequence contexts of proteins. There are many other types of interaction domains found within adaptor and other signaling proteins that allow a rich diversity of specific and coordinated protein–protein interactions to occur within the cell during signal transduction. Adaptor proteins contribute to the selection, differentiation, and activation of Natural Killer (NK) cells, T cells, Natural Killer T (NKT) cells and monocytes. Adaptor proteins are also expressed in a subset of T cells. DAP10, for example, is expressed in NK cells, a subset of T cells and myeloid cells. DAP12, for example, is expressed in NK cells, in peripheral blood monocytes, macrophages, and dendritic cells. FcεRIγ and CD3_ζ, for example, are expressed on at least NK cells, T cells, and monocytes. Thus, in one embodiment the immune cell employed in the present disclosure is independently selected from one or more of a NK cell, a NKT cell, a T cell, a monocyte, macrophage, and a dendritic cell. “Endogenously present” in the cell as employed herein refers to an entity that is native to the cell, in particular it has NOT been introduced by recombinant techniques and/or artificially introduced. Signal transduction is the process by which a chemical or physical signal is transmitted through a cell as a series of molecular events. Extracellular receptors are integral transmembrane proteins and make up most receptors. They span the plasma membrane of the cell, with one part of the receptor on the outside of the cell and the other on the inside. Signal transduction occurs as a result of a ligand binding to the outside region of the receptor (the ligand does not pass through the membrane). Ligand-receptor binding induces a change in the conformation of the inside part of the receptor, a process sometimes called “receptor activation”. This results in either the activation of an enzyme domain of the receptor or the exposure of a binding site for other intracellular signaling proteins within the cell, eventually propagating the signal through the cytoplasm. Gene activations and metabolism alterations are examples of cellular responses to extracellular stimulation that require signal transduction. Gene activation leads to further cellular effects, since the products of responding genes include instigators of activation; transcription factors produced as a result of a signal transduction cascade can activate even more genes. Hence, an initial stimulus can trigger the expression of a large number of genes, leading to physiological events like the increased uptake of glucose from the blood stream and the migration of immune cells to sites of infection. The set of genes and their activation order to certain stimuli is referred to as a genetic program. Generally, in the context of the present disclosure the signaling from the modified immune cell receptor protein will generate activation of an immune cell, for example to generate cytotoxic activity, inflammatory responses, proliferation, phagocytic responses or similar. The term “cytokine” is widely recognized in the field and encompasses a diverse group of proteins pivotal in cellular signaling. Within the cytokine family, notable members include various interleukins, interferons, chemokines, lymphokines, and tumor necrosis factors. Examples of specific cytokines encompass interleukin-2 (IL-2), interleukin-7 (IL-7), interleukin-12 (IL-12), interleukin-15 (IL-15), interleukin-18 (IL-18), and interleukin-21 (IL-21). Cytokines exert their effects by binding to specific cytokine receptors, which are multi-chain receptors. Upon binding with their respective cytokines, these receptors initiate an intracellular signaling cascade, resulting in a change of the cell’s functional state. Notably, cytokine receptors can also be activated through the use of antibodies and various fusion proteins, thereby facilitating functional binding analogous to that achieved through direct cytokine binding. The term "memory-like” signifies a cellular state, specifically in an immune cell, marked by heightened cytotoxicity, proliferative capacity, and other effector functions, such as cytokine secretion or surface marker expression, in comparison to the non-activated cell state. Furthermore, the term “cytokine-induced memory-like” pertains to a cellular state, particularly within an immune cell, that has undergone cytokine treatment. This state is characterized by increased cytotoxicity, proliferative capacity, and other effector functions, including cytokine secretion or surface marker expression, relative to the non-activated cell state. As an illustrative example, a cytokine-induced memory-like T cell refers to a T cell treated with cytokines, demonstrating heightened effector functions upon activation. The phrase “cytokine-induced memory-like state” or “CIML” is intended to mean a trained immunity, or activated state achieved by immune cells in response to stimulation by cytokines. CIML immune cells have undergone transcriptional, epigenetic and metabolic reprogramming and have enhanced effector functions and increased persistence. Examples of CIML immune cells include T cells, CD4+ T cells, CD8+ T cells, γδ T cells, NK cells, NKT cells, dendritic cells, monocytes and macrophages. The term “cytokine-induced memory-like” or, equivalently, “CIML” in reference to the immune cells described herein, means having a “memory” or “memory-like” phenotype and produced using a priming agent. The phrase “immune cell” or “immune effector cell” refers to a cell that may be part of the innate or adaptive immune system and executes a particular effector function such as T cells, αβT cells, NK cells (including memory-like NKs, ML NKs, and CIML NKs), NKT cells (including iNKT cells), B cells, innate lymphoid cells (ILC), cytokine-induced killer (CIK) cells, lymphokine-activated killer (LAK) cells, γδ T cells, mesenchymal stem cells or mesenchymal stromal cells (MSC), monocytes and macrophages. Preferred immune cells are cells with cytotoxic effector function such as αβ T cells, NK cells (including memory-like NKs, ML NKs, and CIML NKs), NKT cells (including iNKT cells), ILC, CIK cells, LAK cells or γδ T cells. “Effector function” means a specialized function of a cell, e.g., in an NK cell an effector function may be cytolytic activity or helper activity including the secretion of cytokines. Examples of immune cells include T cells, CD4+ T cells, CD8+ T cells, γδ T cells, NK cells, NKT cells, dendritic cells, monocytes and macrophages. Natural killer (NK) cells constitute a group of innate immune cells, which are often characterized as cytotoxic lymphocytes that exhibit antibody-dependent cellular cytotoxicity via target-directed release of granzyme, granulysin and perforin. Most NK cells have a specific cell surface marker profile (e.g., CD3-, CD56+, CD16+) in addition to a collection of various activating and inhibitory receptors. While more recently NK cells have become a significant component of certain cancer treatments, generation of significant quantities of NK cells (and especially autologous NK cells) has been a significant obstacle as the fraction of NK cells in whole blood is relatively low. The phrase “cytokine-induced memory-like NK cell” or “ML NK cell” refers to a NK cell derived from an NK cell which has been activated ex vivo with at least one cytokine and maintains an enhanced memory-like function after challenge in the absence of the same cytokines. As used herein, the term “CIML NK cell” refers to a NK cell derived from an NK cell which has been activated with at least one cytokine and exhibits enhanced activation and interferon-gamma responses. Human cytotoxic and phagocytic lymphocytes constitute vital components of the immune system, equipped with the capacity to eliminate diseased cells within the human body either through the directed delivery of cytotoxic granules or by leveraging phagocytic function. The cytotoxic subset of lymphocytes encompasses various immune cell types, including Natural Killer (NK) cells, Natural Killer T (NKT) cells, and cytotoxic T cells such as CD8+ T cells, and gamma-delta T cells, among others. Monocytes and macrophages exemplify human phagocytic cells, adept at selectively engulfing and degrading other cells. While both cytotoxic and phagocytic immune cell types share the common goal of removing target cells from the body, they exhibit significant differences in their targeting mechanisms and interactions with respective target cells. T cells, distinguished by a unique somatically rearranged T-cell receptor (TCR), selectively recognize foreign antigen peptides within the context of major histocompatibility complex (MHC) proteins. In contrast, NK cells, monocytes, and macrophages utilize a set of germline-encoded receptors to engage ligands on the surface of target cells or to recognize antibody-opsonized targets. Regardless of the specific targeting mechanism employed, the ensuing activation signals during surface interactions lead to the release of cytotoxic granules or activation of phagocytic activity, accompanied by other effector phenotypes such as cell proliferation and cytokine secretion. T cells envisaged to be used in the invention may be any type of T cell. The T-cell may be a CD4+ T cell, or helper T cell (Th cell), such as a Th1, Th2, Th3, Th17, Th9, or Tfh cell. The T cell may be a CD8+ T cell, or cytotoxic T cell. The T cell may be a CD4+ or CD8+ memory T cell, such as a central memory T cell or an effector memory T cell. The T cell may be a regulatory T cell (Treg). The T cell may be, for example, a naïve T cell or a T memory stem cell. Naïve T cells are precursors for effector and memory T cell subsets. T stem cell-like memory (T_SCM) cells are a subset of memory lymphocytes endowed with the stem cell–like ability to self-renew and the multipotent capacity to reconstitute the entire spectrum of memory and effector T cell subsets. The term “monocyte” refers to a type of immune cell that is made in the bone marrow and travels through the blood to tissues in the body where it becomes a macrophage or a dendritic cell. Macrophages surround and kill microorganisms, ingest foreign material, remove dead cells, and boost immune responses. When referring to the numbering of amino acids in CD16A amino acid 1 is considered to be the first Methionine of the leader peptide, i.e. the N-terminal amino acid of the full- length protein, with amino acids being counted from that residue. “Signal peptide” and “leader peptide” may be used interchangeably herein. Construct The modified immune cell receptor protein of the present invention comprises: - a target-binding domain, - the extracellular domain of CD16A, wherein the extracellular domain comprises the F_C-binding domain and the hinge domain of CD16A, and - a transmembrane domain, wherein the modified immune cell receptor protein also comprises a flexible linker positioned between the target-binding domain and the FC-binding domain of the extracellular domain of CD16A, wherein the linker domain is at least 10 amino acids in length. In a further embodiment the modified immune cell receptor protein of the present invention comprises: - a target-binding domain, - the extracellular domain of CD16A, wherein the extracellular domain comprises the FC-binding domain and the hinge domain of CD16A, and - a transmembrane domain, and - a cytoplasmic domain comprising the co-stimulatory domain of CD3ζ, wherein the modified immune cell receptor protein also comprises a flexible linker positioned between the target-binding domain and the FC-binding domain of the extracellular domain of CD16A, wherein the linker domain is at least 10 amino acids in length. In a further embodiment the modified immune cell receptor protein of the present invention comprises: - a target-binding domain, - the extracellular domain of CD16A, wherein the extracellular domain comprises the F_C-binding domain and the hinge domain of CD16A, and - a transmembrane domain, and - a cytoplasmic domain comprising the co-stimulatory domain of FcεRI, wherein the modified immune cell receptor protein also comprises a flexible linker positioned between the target-binding domain and the F_C-binding domain of the extracellular domain of CD16A, wherein the linker domain is at least 10 amino acids in length. In a further embodiment the modified immune cell receptor protein of the present invention comprises: - a target-binding domain, - the extracellular domain of CD16A, wherein the extracellular domain comprises the FC-binding domain and the hinge domain of CD16A, and - a transmembrane domain, and - a cytoplasmic domain comprising at least one of the following co-stimulatory domains: 4-1BB, CD28, OX40 and DAP10; wherein the modified immune cell receptor protein also comprises a flexible linker positioned between the target-binding domain and the F_C-binding domain of the extracellular domain of CD16A, wherein the linker domain is at least 10 amino acids in length. In a further embodiment the modified immune cell receptor protein of the present invention comprises: - a target-binding domain, - the extracellular domain of CD16A, wherein the extracellular domain comprises the FC-binding domain and the hinge domain of CD16A, and - a transmembrane domain, and - a cytoplasmic domain comprising at least one of the following co-stimulatory domain combinations: 4-1BB and CD3ζ, 4-1BB and CD28, OX40 and CD28, 4-1BB and DAP10, or OX40 and DAP10; wherein the modified immune cell receptor protein also comprises a flexible linker positioned between the target-binding domain and the FC-binding domain of the extracellular domain of CD16A, wherein the linker domain is at least 10 amino acids in length. Target-binding domain In one embodiment of the invention, the target-binding domain targets a receptor or ligand on a cell, the killing of which cell is desirable. In one embodiment of the invention, the target-binding domain targets an antigen or other ligand on a cell. In one embodiment of the invention, the target-binding domain targets an antigen or other ligand on a cancer cell. In one embodiment of the invention, the target-binding domain targets a cognate receptor or cognate ligand of a cancer antigen on an immune cell. In one embodiment of the invention, the target-binding domain targets a receptor or other ligand on an immune cell. In one embodiment of the invention, the immune cell is a B cell or T cell. In one embodiment of the invention, the killing of the cell by target-binding domain directed targeting and/or antibody-dependent cellular cytotoxicity (ADCC) is desirable. In this embodiment, ADCC may be mediated by naturally occurring antibodies (including antibodies directed at cancer neoantigens), therapeutic antibodies (including IgG1, IgG3 and IgG4 monoclonal antibodies), and cell engagers that bind to the extracellular domain of CD16A. In one embodiment of the invention, the cancer antigen is any one of the cancer antigens provided herein. In one embodiment of the invention, the target-binding domain binds a receptor or other ligand on a B cell. In one embodiment of the invention, the target-binding domain binds any one of the receptors or other ligands on a B cell provided herein. In one embodiment of the invention, the target-binding domain binds a receptor or other ligand on a T cell. In one embodiment of the invention, the target-binding domain binds any one of the receptors or other ligands on a T cell provided herein. In one embodiment of the invention, the target-binding domain comprises an antibody fragment. In one embodiment of the invention, the target-binding domain comprises a single-chain variable antibody fragment (scFv). The target-binding domain may bind to an antigen. In some embodiments, the target- binding domain is an antibody fragment. In some embodiments, the target-binding domain is a single-chain variable antibody fragment (scFv) that includes a variable light (VL) and a variable heavy (VH) domain that may be derived from an immunoglobulin that binds the antigen. The term “derived from” as used herein when referring to protein or nucleic acid sequences refers to a sequence that originates from another, parent sequence. A sequence derived from a parent sequence may be identical, may be a portion of the parent sequence, or may have at least one variant from the parent sequence. Variants may include substitutions, insertions, or deletions. Thus, for example, an amino acid sequence derived from a parent sequence may be identical for a specific range of amino acids of the parent but does not include amino acids outside that specific region. In some embodiments, the scFv may be in an VH-VL orientation in a N to C terminal direction. In some embodiments, the scFv may be in an VL-VH orientation in a N to C terminal direction. In some embodiments of the invention the antigen is on a cancer (e.g., tumor) cell or a cognate receptor or cognate ligand of the antigen on an immune cell. In some embodiments, the cancer antigen may be “tumor-associated” or “tumor-specific” antigen. “Tumor-associated antigen” (TAA), as used herein, refers to antigens that are expressed at a higher level on a cancer, tumor or neoplastic cell as compared to a normal cell derived from the same tissue or lineage as the cancer, tumor or neoplastic cell, or at a level where, while not exclusive to the cancer, tumor or neoplastic cell, allows for targeting of the cancer, tumor or neoplastic cell at a level to treat the cancer. The term "tumor-specific antigen”, as used herein, refers to antigens that are present on a cancer, tumor or neoplastic cell but is not detectable on a normal cell derived from the same tissue or lineage as the cancer, tumor or neoplastic cell. Cancer and tumor antigens include, without limitation, EGFR, CD19, CD20, CD22, NKG2D ligands, CS1, CD138, EpCAM, EBNA3C, GPA7, CD244, CA-125, MUC-1, ETA, MAGE, CAGE, BAGE, HAGE, LAGE, PAGE, NY-SEO-1, GAGE, CEA, CD52, CD30, MUC5AC, c-Met, FAB, WT-1, PSMA, NY-ESO1, AFP, CSPG-4, IGF1-R, Flt-3, CD276, CD123, CD133, PD-L1, BCMA, GPRC5D, 41BB, CTAG1B, and CD33. Other examples include CD44v7/8, CD138, CD244, CEA, Csl, EBNA3C, EGP-2, EGP-40, E CAM, erb-B2, erb-B 2,3,4, FBP, GD2, GD3, GPA7, Her2, Her2/neu, IL-13R-a2, KDR, k- light chain, LeY, L1 cell adhesion molecule, MAGE-A1, Mesothelin, oncofetal antigen hST4, PSCA, TAG-72, claudin18.2 etc. as well as tumor neoantigens such as EGFRvIII, TA-MUC1, TMPRSS2-ERG, MYB-NFIB, FGFR3-TACC3, EML4-ALK, CCDC6-RET, BCR-ABL, SYT-SSX1/SSX2, PAX3-FOXO1, TPM3/TPM4-ALK, EWS-FLI1, etc. In some embodiments, the antigen on the cancer cell that binds the target-binding domain is the cognate ligand for a receptor naturally present on an immune cell. Therefore, occupying the antigen by the target-binding domain can prevent the antigen’s binding the receptor, keeping the immune cell in an active state. Examples of these “checkpoint” antigens present on cancer cells include PD-L1, epidermal growth factor receptor (EGFR), and HLA-E. In some embodiments, the target-binding domain binds the cognate ligand or cognate receptor naturally present on an immune cell. Therefore, occupying the cognate ligand or cognate receptor by the target binding domain can also prevent the antigen’s binding, keeping the immune cell in an active state. Examples of these “checkpoint” cognate receptors or cognate ligands of antigens present on immune cells include transforming growth factor β (TGFβ), EGF, NKG2A (CD159), and NKG2D. In some embodiments, the target binding domain binds AFP, ALPP, AXL, B7-H3, B-cell maturation antigen (BCMA), GPRC5D, By0H3, CD7, CD19, CD20, CD22, CD33, CD44v6, CD70, CD117, CD147, CD123, CD126, CD171, CAIX, Chlorotoxin, CLDN, CEA, CLDN6, c-Met, c-Met, CPC3, DLL3, EPCAM, EphA2, FAP, FRA, FRα, GD2 ganglioside, GFRα4, GLV, GP100, GPC3, GUCY2C, ERB-B2 receptor tyrosine kinase 2 (HER2), ICAM-1, IL13Rα2, KLK2, KNG2DL, LeY, LMP1, mesothelin, MG7, major histocompatibility complex, class I, E (HLA-E), MHC Class I polypeptide-related sequence A (MICA), MHC Class I polypeptide-related sequence B (MICB), MSLN, MUC16, mucin 1 (MUC1), Nectin4, NY-ESO-1, PSCA, PSMA, ROR2, or VEGFR2. In some embodiments, the target-binding domain binds CD19. CD19 is an attractive target for cancer therapy because it is normally limited to cells of the B-cell lineage. Furthermore, it is expressed on the vast majority of B-cell malignancies, including 80% of acute lymphoblastic leukemias (ALLs), 88% of B-cell lymphomas, and 100% of B-cell leukemias. Therefore, CD19 is a suitable TAA against which to target anti-cancer agents. In contrast to CD20, CD19 is expressed throughout B-cell development, from B-cell precursors through to mature B cells before expression is lost when mature B cells become plasma cells. In some embodiments, the target-binding domain is a scFv that binds CD19. In some embodiments, the target-binding domain is derived from the sequence of a commercially available anti-CD19 antibody, antibody fragment, or derivative thereof. Amino acid sequences of representative anti-CD19 antibody heavy and light chains of which are set forth in Table 1. Any one of the nucleic acids or sets of nucleic acids provided herein may encode any one of the sequences in Table 1. Table 1: Amino acid sequences of representative anti-CD19 antibody fragments Polypeptide Sequence loncastuximab 1 qvqlvqpgae vvkpgasvkl scktsgytft snwmhwvkqa pgqglewige idpsdsytny heavy chain 61 nqnfqgkakl tvdkststay mevsslrsdd tavyycargs npyyyamdyw gqgtsvtvss light chain 181 sstltlskad yekhkvyace vthqglsspv tksfnrgec (SEQ ID NO: 10) target-binding domain is a scFv that binds to CD20. In some embodiments, the target- binding domain is derived from the sequence of a commercially available anti-CD20 antibody, antibody fragment, or derivative thereof. Representative amino acid sequences of heavy and light chains of anti-CD20 antibodies are set forth in Table 2. Any one of the nucleic acids or sets of nucleic acids provided herein may encode any one of the sequences in Table 2. Table 2: Amino acid sequences of representative anti-CD20 antibody fragments Polypeptide Sequence ofatumumab 1 evqlvesggg lvqpgrslrl scaasgftfn dyamhwvrqa pgkglewvst iswnsgsigy v 361 eltknqvslt clvkgfypsd iavewesngq pennykttpp vldsdgsffl yskltvdksr 421 wqqgnvfscs vmhealhnhy tqkslslspg k rituximab 1 qivlsqspai lsaspgekvt mtcrasssvs yihwfqqkpg sspkpwiyat snlasgvpvr embodiments, the target-binding domain is a scFv that binds CD20 such as rituximab. In some embodiments, the target-binding domain is a scFv that binds CD20 which comprises the 3 CDR sequences found within SEQ ID NO: 17 and the 3 CDR sequences found within SEQ ID NO: 18. In some embodiments, the target-binding domain is a scFv that binds CD20 which comprises SEQ ID NO: 17 and SEQ ID NO: 18. In some embodiments, the target-binding domain is rituximab present in a VH to VL orientation, in a N terminal to C terminal direction. In some embodiments, the target- binding domain is rituximab present in a VL to VH orientation, in a N terminal to C terminal direction. In some embodiments, the target-binding domain is rituximab present in a VH to VL orientation, in a N terminal to C terminal direction, in combination with a NKp44 leader peptide as described herein. In some embodiments, the target-binding domain is rituximab present in a VL to VH orientation, in a N terminal to C terminal direction, in combination with a CD8A leader peptide as described herein. In some embodiments, the target-binding domain is ofatumumab present in a VH to VL orientation, in a N terminal to C terminal direction. In some embodiments, the target-binding domain binds CD22 (also known as Siglec-2). In some embodiments, the target-binding domain is a scFv that binds to CD22. In some embodiments, the target-binding domain is derived from the sequence of a commercially available anti-CD22 antibody, antibody fragment, or derivative thereof. Representative amino acid sequences of heavy and light chains of anti-CD22 antibodies are set forth in Table 2a. Any one of the nucleic acids or sets of nucleic acids provided herein may encode any one of the sequences in Table 2a. Table 3a: Amino acid sequences of representative anti-CD22 antibody fragments Polypeptide Sequence Epratuzumab heavy chain QVQLVQSGAEVKKPGSSVKVSCKASGYTFTSYWLHWVRQAPGQGLEWIGYINPRNDYTEYNQNFKDKATI G M S I D I S In some embodiments, the target-binding domain is a scFv that binds CD22. In some embodiments, the target-binding domain is a scFv that binds CD22 such as Pinatuzumab. In some embodiments, the target-binding domain is a scFv that binds CD22 which comprises the 3 CDR sequences found within SEQ ID NO: 112 and the 3 CDR sequences found within SEQ ID NO: 113. In some embodiments, the target-binding domain is a scFv that binds CD22 which comprises SEQ ID NO: 112 and SEQ ID NO: 113. In some embodiments, the target-binding domain binds B-cell maturation antigen (BCMA, also known as CD269 and TNFRSF17). In some embodiments, the target-binding domain is a scFv that binds to BCMA. In some embodiments, the target-binding domain is derived from the sequence of a commercially available anti-BCMA antibody, antibody fragment, or derivative thereof. Representative amino acid sequences of heavy and light chains of anti-BCMA antibodies are set forth in Table 2b. Any one of the nucleic acids or sets of nucleic acids provided herein may encode any one of the sequences in Table 2b. Table 4b: Amino acid sequences of representative anti-BCMA antibody fragments Polypeptide Sequence Belantamab h h i QVQLVQSGAEVKKPGSSVKVSCKASGGTFSNYWMHWVRQAPGQGLEWMGATYRGHSDTYYNQKFKGRVTI D I D I T M D In some embodiments, the target-binding domain binds CD117. In some embodiments, the target-binding domain is a scFv that binds to CD117. Anti-CD117 antibodies and binding domains thereof are known in the art. See, e.g., U.S. Patents 10,111,966, 10,882,915, and 10,899,843, and such sequences are incorporated herein by reference. Any one of the nucleic acids or sets of nucleic acids provided herein may encode any one of such sequences. In some embodiments, the target-binding domain binds mesothelin. In some embodiments, the target-binding domain is a scFv that binds mesothelin. Anti-mesothelin antibodies and binding domains thereof are known in the art. See, e.g., U.S. Patents 8,481,7039,023,3519,416,1909,719,996, and 10,851,175 and U.S. Patent Application Publications 2019/0218294 and 2022/0056147, and such sequences are incorporated herein by reference. Any one of the nucleic acids or sets of nucleic acids provided herein may encode any one of such sequences. In some embodiments, the target-binding domain binds PD-L1. When targeting a checkpoint molecule, the target-binding domain may be but does not need to be derived from an antibody fragment, in some cases the target binding domain can be derived from a cognate ligand of a checkpoint molecule. In some embodiments, the target-binding domain is derived from at least a portion of the PD1 extracellular domain. In some embodiments, the target-binding domain is derived from a commercially available anti-PDL1 antibody, antibody fragment, or derivative thereof, e.g., atezolizumab (Tecentriq®), avelumab (Bavencio®), or durvalumab (Imfinzi®), the amino acid sequences of the heavy and light chains of which are set forth in Table 5. Any one of the nucleic acids or sets of nucleic acids provided herein may encode any one of such sequences. Table 5: Amino acid sequences of representative anti-PD-L1 antibody fragments Polypeptide Sequence atezolizumab 1 evqlvesggg lvqpggslrl scaasgftfs dswihwvrqa pgkglewvaw ispyggstyy avelumab light 1 qsaltqpasv sgspgqsiti sctgtssdvg gynyvswyqq hpgkapklmi ydvsnrpsgv chain (SEQ ID 61 snrfsgsksg ntasltisgl qaedeadyyc ssytssstrv fgtgtkvtvl gqpkanptvt NO: 22) 121 lfppsseelq ankatlvcli sdfypgavtv awkadgspvk agvettkpsk qsnnkyaass , , CD70. In one embodiment of any one of the compositions or methods provided herein, the target-binding domain comprises an anti-CD19 antibody or antibody fragment thereof, PD1 or an anti-PDL1 antibody of antibody fragment thereof, or CD27. In some embodiments, the target is a receptor or other ligand on an immune cell, such as a B cell or T cell. Immune cells expressing the modified immune cell receptor protein of the invention can be used in, for example, B cell or T cell depletion therapy. As an example, the target-binding domain binds a receptor or other ligand on a B cell where the receptor or other ligand is, for example, Siglec-10, LILRB/PIR-B, CD31, FcyRIIIB, CD19, CD20, CD22, CD25, CD32, CD40, CD47, CD52, CD80, CD86, CD267, CD268, CD268, IgM, IgD, IgG, IgA or IgE. As another example, the target-binding domain binds a receptor or other ligand on a T cell where the receptor or other ligand is, for example, CD43, CD44, CD45, LFAI, CD4, CD8, CD3, LAT, CD27, CD96, CD28, TIGIT, ICOS, BTLA, HVEM, 4-1BB, OX40, DR3, GITR, CD30, 10 SLAM, CD2, 2B4, TIM I, TIM2, TIM3, CD226, CD160, LAG3, LAIRI, CD112R, CTLA-4, PD-I, PD-LI or PD-L2. In some embodiments, the target is a B cell maturation antigen, wherein the B cell maturation antigen is, for example, (BCMA), GPRC5D, CD19, CD20, CD27, CD70, or CD117, or mesothelin. In a preferred embodiment of the invention, the target-binding domain binds CD70, CD19, CD33, CLL1, or IL-3 receptor. In a preferred embodiment of the invention, the target- binding domain comprises CD27. In a preferred embodiment of the invention, the target- binding domain comprises the sequence of SEQ ID NO: 25. In a preferred embodiment of the invention, the target-binding domain comprises the sequence of SEQ ID NO: 25, or a variant thereof that retains the functionality of the CD27 ectodomain. In a preferred embodiment of the invention, the target-binding domain comprises the sequence of SEQ ID NO: 25, or a variant thereof that retains the functionality of the CD27 ectodomain that has at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the sequence of SEQ ID NO: 25. Assays to determine whether variant of the CD27 ectodomain are known to the skilled person, such as binding assays to determine whether the variant binds to CD70. SEQ ID NO: 25 -CD27 ectodomain MALPVTALLLPLALLLHAARPKSCPERHYWAQGKLCCQMCEPGTFLVKDCDQHR KAAQCDPCIPGVSFSPDHHTRPHCESCRHCNSGLLVRNCTITANAECACRNGWQC RDKECTECDPLP In some embodiments, the target-binding domain binds CD70. In some embodiments, the target-binding domain is a scFv that binds CD70. In some embodiments, the target- binding domain binds CD19. In some embodiments, the target-binding domain is a scFv that binds CD19. In some embodiments, the target-binding domain is a scFv that binds CD19 such as FMC63. In some embodiments, the target-binding domain is a scFv that binds CD19 which comprises the 3 CDR sequences found within SEQ ID NO: 26 and the 3 CDR sequences found within SEQ ID NO: 27. In some embodiments, the target-binding

SEQ ID NO: 27- FMC63 light chain EIVMTQSPATLSLSPGERATLSCRASQDISKYLNWYQQKPGQAPRLLIYHTSRLHS GIPARFSGSGSGTDYTLTISSLQPEDFAVYFCQQGNTLPYTFGQGTKLEIK In some embodiments, the target-binding domain binds CD33. In some embodiments, the target-binding domain is a scFv that binds CD33. In some embodiments, the target- binding domain is a scFv that binds CD33, such as gemtuzumab. In some embodiments, the target-binding domain is a scFv that binds CD33, which comprises the 3 CDR sequences found within SEQ ID NO: 28 and the 3 CDR sequences found within SEQ ID NO: 29. In some embodiments, the target-binding domain is a scFv that binds CD33, which comprises SEQ ID NO: 28 and SEQ ID NO: 29. SEQ ID NO: 28- Gemtuzumab heavy chain EVQLVQSGAEVKKPGSSVKVSCKASGYTITDSNIHWVRQAPGQSLEWIGYIYPYN GGTDYNQKFKNRATLTVDNPTNTAYMELSSLRSEDTAFYYCVNGNPWLAYWGQ GTLVTVSS SEQ ID NO: 29- Gemtuzumab light chain DIQLTQSPSTLSASVGDRVTITCRASESLDNYGIRFLTWFQQKPGKAPKLLMYAAS NQGSGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQTKEVPWSFGQGTKVEVK In some embodiments, the target-binding domain binds CLL1. In some embodiments, the target-binding domain is a scFv that binds CLL1. In some embodiments, the target- binding domain binds the IL-3 receptor. In some embodiments, the target-binding domain is a scFv that binds the IL-3 receptor. In some embodiments, the target-binding domain is, or comprises, IL-3. In a preferred embodiment of the invention, the target-binding domain binds CD20, CD22 or CD70. In the modified immune cell receptor protein of the invention, a flexible linker is present between the target-binding domain and the extracellular domain of CD16A, wherein the linker is at least 10 amino acids in length. The inventors have found that overcoming steric hindrance and enhancing access to the target antigen on cell surfaces requires careful optimization of the length and flexibility of the linker positioned between the target-binding domain and the extracellular domain of CD16A of the modified immune cell receptor protein of the invention. The use of linkers derived hinge domains from CD28, CD8, or IgG molecules is widespread in the chimeric antigen receptor field. The rigidity of these hinges can vary greatly, from highly rigid (e.g. CD28 stalk) to highly flexible (CH3-CH2 domain from IgG) structures. While the precise mechanism remains unclear, it is postulated that the linker domain folds beneath the inverted V-shaped ectodomain of CD16A, extending into the extracellular space from one of the sides of CD16A (see Figure 2). For optimal target binding, this requires a minimum length linker with sufficient flexibility. Consequently, specific requirements regarding linker domain length and sequence are imperative to ensure proper target engagement and immune effector functions. The linker domain of the modified immune cell receptor of the invention has sufficient flexibility to allow folding beneath the V-shaped ectodomain of CD16A and is at least 10 amino acids in length. Suitable flexibility of the linker can be achieved through the optimal incorporation of certain amino acids including glycine and serine. Suitable peptide linkers for use in connecting, or bridging, or being positioned between, the target binding domain to the extracellular domain of CD16A are amino acid sequences include those that allow the domains to fold independently from one another and providing sufficient flexibility to allow the domains to retain their functionality. In some embodiments the linker may be at least 10 to about 70 amino acids in length, such as from about 10 to about 30 amino acids, e.g. about 20 amino acids in length. In a preferred embodiment the linker is at least 10 to about 70 amino acids in length, at least 20 to about 70 amino acids in length, or at least 30 to about 70 amino acids in length. In preferred embodiment, the linker is 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69 or 70 amino acids in length. Suitable flexible linkers may comprise Serine and/or Glycine residues which may be contiguous or separated by one or more amino acid. Appropriate linking groups may be designed using conventional modelling techniques. Flexible linkers may include a poly- Glycine-Serine sequence such as: GGGGSGGGGS (SEQ ID NO:30), GGGGSGGGGSGGGGS (SEQ ID NO:31), GGGGSGGGGSGGGGSGGGGS (SEQ ID NO:32), GSTSGSGKPGSGEGSTKG (SEQ ID NO:33), KESGSVSSEQLAQFRSLD (SEQ ID NO:34), EGKSSGSGSESKST (SEQ ID NO:35), or GSAGSAAGSGEF (SEQ ID NO:36). In a preferred embodiment of the invention, the linker contains no more than one cysteine residue. Two Cysteine residues may form di-sulphide bridges which may reduce the flexibility of the linker containing said residues. Proline is the most rigid of the 20 naturally occurring amino acids and is frequently introduced to rigidify flexible regions of protein to enhance thermostability. In a preferred embodiment of the invention the linker contains no more than 30% Proline residues. In a preferred embodiment the linker comprises an amino acid sequence derived from the hinge domain of NKp44, NKp46, CD8α, CD8β, KIR2DS1, KIR3DS1 or CD27. Examples of preferred flexible linkers include, but are not limited to, the following: delta CD8α: TTTPAPRPPTPAPTIASQPLSLRPEAGGGGS (SEQ ID NO: 37) NKp44 long: ASASTQTSWTPRDLVSSQTQTQSSVPPTAGARQAPESPSTIPVPSQPQNSTLRPGPA APGGGGS (SEQ ID NO: 38) NKp44 short: ASASTQTSWTPRDLVSSQTQTQSSVPPTAGAGGGGS (SEQ ID NO: NKp46 long: GDIENTSLAPEDPTFPADTWGTYLLTTETGLQGGGGS (SEQ ID NO: 40) KIR2DS1: SNSWPSPTEPSSETGNPRHLHGGGGS (SEQ ID NO: 41) KIR3DS1: SSSWPSPTEPSSKSGNLRHLHGGGGS (SEQ ID NO: 42) CD27 short: NPSLTARSSQALSPHPQPTHLPYVSEMLEARGGGGS (SEQ ID NO: 43) CD27 long: NPSLTARSSQALSPHPQPTHLPYVSEMLEARTAGHMQTLADFRQLPARTLSTHWP PQRSGGGGS (SEQ ID NO: 44) delta CD8α plus G₄SGMRTEDL: TTTPAPRPPTPAPTIASQPLSLRPEAGGGGSGMRTEDL (SEQ ID NO: 104) CD8β hinge (C155S)-G4S: TTAQPTKKSTLKKRVSRLPRPETQKGPLSSPGGGGS (SEQ ID NO: 105) The invention encompasses variants of the above sequences, wherein the variant linker sequences are at least 10 amino acids in length, contain no more than one cysteine residue and no more than 30% proline residues, and wherein the linker retains sufficient flexibility to allow folding beneath the V-shaped extracellular of CD16A of the modified immune cell receptor protein of the invention. The invention encompasses variants of the above sequences, wherein the variant linker sequences are at least 10 amino acids in length, contain no more than one cysteine residue and no more than 30% proline residues and wherein the variant linker sequence has at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% sequence identity to the one of the SEQ ID NOs set out above. Extracellular domain of CD16A The modified immune cell receptor protein of the present invention comprises the extracellular domain of CD16A, or variants thereof that maintain the functionality of the extracellular domain of CD16A. The functionality of the extracellular domain of CD16A can be tested by experiments known to the skilled person, such as binding assays to determine whether antibody Fc domain binding to CD16A is maintained. The extracellular domain of CD16A consists essentially of the FC-binding domain of CD16A and the hinge domain of CD16A. In some embodiments the hinge domain of CD16A contains an ADAM17 cleavage site. In some embodiments the hinge domain of CD16A is a variant that is not cleavable by ADAM17. In some embodiments the hinge domain of CD16A is a variant that is not cleavable. The extracellular domain of CD16A is considered to correspond to amino acids P25 to Y207 of CD16A. ADAM17, originally referred to as tumor necrosis factor (TNF)-α-converting enzyme (TACE), is expressed on NK cells, and to a lesser extent on T cells, and is known to cleave multiple targets, including CD16A, CD62L, TNF-α, TNF receptor I, and TNF receptor II. ADAM17 is expressed on NK cells generally, as well as the CD3-CD56^bright and CD3- CD56^dim NK cell subsets. ADAM17 is also expressed on CD3⁺CD56⁺ NKT cells, but ADAM17 is not highly expressed on CD3⁺CD56- T cells (Romee et al., Blood 121(18):3599- 608 (2013) and Kato et al., Front. Cell. Dev. Biol. 6:153 (2018)). Immune cell activation, for example, via stimulation with phorbol myristate acetate, or IL-12 and IL-18, results in increased ADAM17 activity and therefore target shedding. Activation of immune cells expressing the modified immune cell receptor protein as disclosed herein results in ADAM17-mediated protein cleavage within the hinge domain of the extracellular domain of CD16A, releasing the target-binding domain and the FC-binding domain into the extracellular space as a soluble protein. In some embodiments, the hinge domain contains the amino acid sequence AVSTI (SEQ ID NO: 45), or a variant thereof. As used herein, a “variant” is any molecule with the same desired activity (such as cleavable by ADAM17 wherein the variant is a cleavable variant) but which may be a truncated version or a version with a sequence % identity of at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more. In any one of the compositions or methods provided herein, any one of the domains or other molecules or entities may be a variant of any one of the relevant sequences provided herein. In some embodiments, the variant contains a serine at position 3, when numbered according to SEQ ID NO: 45 and one or more variants of amino acids at positions 1, 2, 4, and/or 5. In some embodiments, the variant contains a proline at position 3, when numbered according to SEQ ID NO: 45 and one or more variants of amino acids at positions 1, 2, 4, and/or 5. In some embodiments, the extracellular domain of CD16A has the amino acid sequence set forth below (SEQ ID NO:46), or a variant thereof. CD16A extracellular domain: SEQ ID NO: 46 PKAVVFLEPQWYRVLEKDSVTLKCQGAYSPEDNSTQWFHNESLISSQASSYFIDAA TVDDSGEYRCQTNLSTLSDPVQLEVHIGWLLLQAPRWVFKEEDPIHLRCHSWKNT ALHKVTYLQNGKGRKYFHHNSDFYIPKATLKDSGSYFCRGLVGSKNVSSETVNITI TQGLAVSTISSFFPPGYQ In some embodiments of any one of the compositions or methods provided herein, the extracellular domain comprises a variant of SEQ ID NO: 46 such that it has a higher affinity for IgG as compared to the wild-type sequence. In some embodiments of this, for example, the extracellular domain has a F176V substitution (i.e., a valine at position 176 in place of the phenylalanine). In some embodiments, the extracellular domain of CD16A comprises the amino acid sequence of SEQ ID NO:46, or a variant thereof that retains the functionality of the CD16A extracellular domain that has at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the sequence of SEQ ID NO: 46. Assays to determine whether variant of the CD16A extracellular domain are known to the skilled person, such as binding assays to determine whether the variant maintains its F_C binding capability. It is intended that the extracellular domain of CD16A protein variants described herein or encoded by any of the nucleic acid or set of nucleic acids provided herein retains all functionality of the extracellular domain of CD16A, including ADCC activity. ADCC activity can be determined by tests known to the skilled person, such as employing cytotoxicity assays with monoclonal antibodies and target cancer cell lines. Transmembrane domain The transmembrane domain can enable retention and controlled release of at least the target- binding domain if not both the target-binding domain and extracellular domain of the modified immune cell receptor protein from the cell surface after ADAM17-mediated cleavage. The transmembrane domain generally localizes the modified immune cell receptor protein to the endoplasmic reticulum during translation and delivery to the cell surface. In one embodiment of the invention the transmembrane domain interacts with signaling adaptor proteins CD3ζ and Fc Fragment of IgE Receptor Ig (FCER1G). In one embodiment of the invention, the transmembrane domain comprises a transmembrane domain of a protein cleavable by ADAM17. In one embodiment of the invention the transmembrane domain is of any one of the relevant proteins provided herein. In one embodiment of the invention, the transmembrane domain comprises any one of the relevant specific sequences provided herein. The transmembrane domain may be derived from CD3α, CD3β, CD3γ, CD3ζ, CD3ε, CD4, CD5, CD8α, CD9, CD16A, CD22, CD28, CD33, CD37, CD45, CD62L, CD64, CD80, CD86, CD134, CD154, 4-1BB (also known CD137 or TNF Receptor Superfamily Member 9 (TNFRSF9)), FcεRIα, FcεRIβ, FcεRIγ, ICOS, KIR2DS2, MHC class I, MHC class II, or NKG2D, which includes variants thereof. In some embodiments, the transmembrane domain is derived from CD16A or CD62L. In some embodiments, the transmembrane domain is derived from CD3ζ, CD4, CD8α, CD28, or CD137 (4-1BB). Amino acid sequences of representative transmembrane domains are listed in Table 4. Any one of the nucleic acids or sets of nucleic acids provided herein may encode any one of such sequences. Table 4: Amino acid sequences of transmembrane domains Transmembrane domain Sequence In a preferred embodiment of the invention, the transmembrane domain is derived from CD16A, or a variant thereof that maintains the activity of the transmembrane domain of CD16A. Assays to determine the functionality of the transmembrane domain of CD16A are known to the skilled person, such as assays to determine whether the variant can interact with CD3ζ and Fc Fragment of IgE Receptor Ig (FCER1G). The CD16A transmembrane domain can be considered to correspond to V209 to V229 of CD16A, i.e. VSFCLVMVLLFAVDTGLYFSV (SEQ ID NO: 52). In a preferred embodiment of the invention, the transmembrane domain comprises SEQ ID NO: 52, or a variant thereof that maintains the activity of the transmembrane domain of CD16A that has at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 52. Cytoplasmic domain In some embodiments of any one of the compositions or methods provided herein, the modified immune cell receptor protein further comprises a cytoplasmic domain (CD) of any one of the proteins cleavable by ADAM17 provided herein, which includes variants thereof, which can be connected to the transmembrane domain. The CD domain can provide signaling capacities to the modified immune cell receptor protein. In preferred embodiments, the CD domain is derived from CD16A, which includes variants thereof. The CD16A CD domain can interact with the adaptor proteins CD3ζ and FCER1G, each which contain ITAMs for downstream signaling pathways that include the kinases Syk and ZAP70. See, Lanier, Curr. Opin. Immunol.15(3):308-14 (2003). In some embodiments, the cytoplasmic domain is derived from CD16A, but lacks the CD16A signal peptide/leader peptide. The CD16A cytoplasmic domain is considered to correspond to K230 to K254 of CD16A, i.e. KTNIRSSTRDWKDHKFKWRKDPQDK (SEQ ID NO: 53). In a preferred embodiment of the invention, the cytoplasmic domain is derived from CD16A, or a variant thereof that maintains the activity of the cytoplasmic domain of CD16A that has at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the sequence of SEQ ID NO: 53. Assays to determine the functionality of the cytoplasmic domain of CD16A are known to the skilled person, such as assays to determine whether the variant can interact with the adaptor proteins CD3ζ and FCER1G. Co-stimulatory domain In some embodiments of any one of the compositions or methods provided herein, the cytoplasmic domain of the modified immune cell receptor protein of the invention may comprise the cytoplasmic domain of CD16A and one or a plurality, e.g., 2 or 3, co- stimulatory signaling domains described herein, e.g., selected from 4-1BB, CD3ζ, FcεRI, CD28, CD27, ICOS, DAP10, and OX40. In some embodiments of any one of the compositions or methods provided herein, the cytoplasmic domain of the modified immune cell receptor protein of the invention comprises one or a plurality, e.g., 2 or 3, co-stimulatory signaling domains described herein, e.g., selected from 4-1BB, CD3ζ, FcεRI, CD28, CD27, ICOS, DAP10, and OX40, but does not comprise the cytoplasmic domain of CD16A. In some embodiments, the cytoplasmic domain may include a CD3ζ co-stimulatory signaling domain as a primary signaling domain. In some embodiments, the cytoplasmic domain may include a CD3ζ co-stimulatory signaling domain as a primary signaling domain, and/or any of the following pairs of co-stimulatory signaling domains from the extracellular to the intracellular direction: 4-1BB-CD27; CD27-4-1BB; 4-1BB-CD28; CD28-4-1BB; OX40-CD28; CD28-OX40; 4-1BB-CD3ζ; CD3ζ-4-1BB; CD28-CD3ζ; CD3ζ-CD28; CD28-4-1BB; 4-1BB-CD28; OX40-DAP10; DAP10-OX40; 4-1BB-DAP10 In a preferred embodiment, the cytoplasmic domain of the modified immune cell receptor protein of the invention comprises the CD3ζ co-stimulatory signaling domain as set out in SEQ ID NO: 54, or variants thereof that retain the functionality of the CD3ζ co-stimulatory signaling domain. In a preferred embodiment, the cytoplasmic domain of the modified immune cell receptor protein of the invention comprises the CD3ζ co-stimulatory signaling domain as set out in SEQ ID NO: 54, or variants thereof the have 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 54 that retain the functionality of the CD3ζ co-stimulatory signaling domain. Assays to determine the functionality of the CD3ζ co-stimulatory signaling domain variants are known to the skilled person, for example, increased cellular effector functionality upon immune cell receptor signaling due to target antigen engagement. Some immune effector functions of relevance to this embodiment include cytotoxicity against target cells, increased immune cell proliferation, and increased cytokine secretion. In a preferred embodiment, the cytoplasmic domain of the modified immune cell receptor protein of the invention comprises one or more of the following co- stimulatory signaling domain combinations: 4-1BB and CD3ζ, 4-1BB and CD28, OX40 and CD28, 4-1BB and DAP10, or OX40 and DAP10. In a preferred embodiment, the cytoplasmic domain of the modified immune cell receptor protein of the invention comprises the following co-stimulatory signaling domains: FcεRI as set out in SEQ ID NO: 66, 4-1BB as set out in SEQ ID NO 63 and CD28 as set out in SEQ ID NO: 59, OX40 as set out in SEQ ID NO: 70 and CD28 as set out in SEQ ID NO: 59, 4-1BB as set out in SEQ ID NO 63 and DAP10 as set out in SEQ ID NO: 64, or OX40 as set out in SEQ ID NO: 70 and DAP10 as set out in SEQ ID NO: 64. In a preferred embodiment, the cytoplasmic domain of the modified immune cell receptor protein of the invention comprises the following co-stimulatory signaling domains: 4-1BB as set out in SEQ ID NO 63 and CD28 as set out in SEQ ID NO: 59, OX40 as set out in SEQ ID NO: 70 and CD28 as set out in SEQ ID NO: 59, 4-1BB as set out in SEQ ID NO 63 and DAP10 as set out in SEQ ID NO: 64, or OX40 as set out in SEQ ID NO: 70 and DAP10 as set out in SEQ ID NO: 64, or variants thereof that have 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% sequence identity to the SEQ ID NOs set out above, that retain the functionality of the co-stimulatory domains set out above. Assays to determine the functionality of the co-stimulatory signaling domain variants set out above are known to the skilled person, for example, increased immune cell proliferation and effector functionality. In some embodiments, the primary signaling domain is derived from CD3ζ, FcεRI, CD27, CD28, CD40, KIR2DS2, MyD88, 2B4, DAP10 or OX40. In some embodiments, the co- stimulatory signaling domain is derived from one or more of CD3γ, CD3δ, CD3ε, CD3ζ, CD4, CD5, CD8α, CD9, CD16, CD22, CD27, CD28, CD33, CD37, CD40, CD45, CD68, CD72, CD80, CD86, CD137 (4-1BB), CD154, CLEC-1, 4-1BB, DAP10 (hematopoietic cell signal transducer ((HCST)), DAP12 (TYROBP), Dectin-1, FcαRI, FcγRI, FcγRII, FcγRIII, IL-2RB, ICOS, KIR2DS2, MyD88, OX40, and ZAP70. Amino acid sequences of representative signaling domains are listed in Table 5. Any one of the nucleic acids or sets of nucleic acids provided herein may encode any one of such sequences. Table 5: Amino acid sequences of representative co-stimulatory signaling domains Signaling domain Sequence CD3ζ (SEQ ID NO:54) RVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGG S G S S S DAP10 (SEQ ID CWLTKKKYSSSVHDPNGEYMFMRAVNTAKKSRLTDVTL NO:64) P T G GI D P S L P G G P C L L D P Q Q P Q Q P CD30 (SEQ ID NO:75) CHRRACRKRIRQKLHLCYPVQTSQPKLELVDSRPRRSSTQLRSGASVTEP VAEERGLMSQPLMETCHSVGAAYLESLPLQDASPAGGPSSPRDLPEPRV D L C N E P V L T V P A I Leader peptide In some embodiments of any one of the compositions or methods provided herein, a leader peptide is included in the modified immune cell receptor protein, such as N-terminal to the target-binding domain. The term “leader peptide” as used herein refers to a short (e.g., 5- 30 or 10-100 amino acids long) stretch of amino acids that directs the transport of the protein. Modified immune cell receptor proteins containing a leader peptide and transmembrane domain can be trafficked to the plasma membrane. In some embodiments, the leader peptide is derived from albumin, CD8α, CD33, erythropoietin (EPO), IL-2, human or mouse Ig-kappa chain V-III (IgK VIII), tissue plasminogen activator (tPA), or secreted alkaline phosphatase (SEAP). Leader peptides may also be synthetic (i.e., non-naturally occurring). Amino acid sequences of representative leader peptides are listed in Error! Reference source not found.. Any one of the nucleic acids or sets of nucleic acids provided herein may encode any one of such sequences. Table 6: Amino acid sequences of leader peptides Leader peptide Sequence Albumin (SEQ ID NO:87) MKWVTFISLLFLFSSAYS Further leader peptides envisaged by the present invention include those derived from Syncytin-1, CD8B, CD28, CD3zeta, CD16A, NKp30, NKp44 and NKp46. Leader peptides may also be synthetic (i.e., non-naturally occurring). Amino acid sequences of representative leader peptides are listed in Error! Reference source not found.a. Any one of the nucleic acids or sets of nucleic acids provided herein may encode any one of such sequences. Table 7a: Further amino acid sequences of leader peptides Leader peptide Sequence Syncytin-1 (SEQ ID NO:122) MALPYHIFLFTVLLPSFTLT ion encompasses α-CD19 scFv (FMC63) fused to CD16A canonical isoform. Thus, in a preferred embodiment the modified immune cell receptor protein of the invention comprises, in a N-terminal to C -terminal direction: the CD8α leader peptide as set out in SEQ ID NO: 89, the FMC63 scFv comprising SEQ ID NOs: 26 and 27, the linker as set out in SEQ ID NO: 38, the extracellular domain of CD16A as set out in SEQ ID NO: 46, the transmembrane domain of CD16A as set out in SEQ ID NO: 52, the co-stimulatory signaling domain of CD137 (4-1BB) as set out in SEQ ID NO: 63, and the co-stimulatory signaling domain of DAP10 set out in SEQ ID NO: 64. Vector The modified immune cell receptor protein-encoding nucleic acid(s) may be introduced to an immune cell by a suitable vector or set of vectors. A vector or set of vectors can be configured to contain the elements necessary to effect transport into the immune cell and effect expression of the nucleic acid(s) after transformation. Such elements include an origin of replication, a poly-A tail sequence, a selectable marker, and one or more suitable sites for the insertion of the nucleic acid sequences, such as a multiple cloning site (MCS), one or more suitable promoters, each promoter operatively linked to the insertion sites of the nucleic acid sequences and the selectable marker, and additional optional regulatory elements. The term "promoter" as used herein refers to a nucleic acid sequence that regulates, directly or indirectly, the transcription of a corresponding nucleic acid coding sequence to which it is operably linked, which in the context of the present disclosure, is a modified immune cell receptor protein-encoding sequence. A promoter may function alone to regulate transcription, or it may act in concert with one or more other regulatory sequences (e.g., enhancers or silencers, or regulatory elements that may be present in the nucleic acid sequences or the vectors). Promoters are located near the transcription start sites of genes, on the same strand and upstream on the DNA (towards the 5' region of the sense strand). Promoters typically range from about 100-1000 base pairs in length. The term "operatively linked" as used herein is to be understood that a nucleic acid sequence is spatially situated or disposed in the vector relative to another nucleic acid sequence, e.g., a promoter is operatively linked to drive the expression of a nucleic acid coding sequence (e.g., the modified immune cell receptor protein-encoding nucleic acid sequence). In some embodiments, a vector contains a single promoter operatively linked to a modified immune cell receptor protein encoding nucleic acid. In some embodiments, the vector has a strong mammalian promoter, for example a cytomegalovirus (CMV) promoter, a simian virus 40 (SV40) early promoter, synthetic promoters (e.g., RPBSA (synthetic, from Sleeping Beauty), or CAG (synthetic, CMV early enhancer element, chicken β-Actin, and splice acceptor of rabbit β -Globin)) or promoters derived from the β-actin, phosphoglycerate kinase (PGK), or factor EF1α genes. In some embodiments, the promoter may have a core region located close to the nucleic acid coding sequence. In some embodiments, the promoter is modified to remove methylation sensitive motifs (e.g., a cytosine nucleotide is followed by a guanine nucleotide, or “CpG”) or by the addition of a regulatory sequence that binds transcriptional factors that repress DNA methylation. In some embodiments, the vector includes A/T-rich, nuclear matrix interacting sequences, known as scaffold matrix attachment regions (S/MAR), which enhance transformation efficiency and improve the stability of transgene expression. In some embodiments, the vector is a viral vector, for example, a retroviral vector, a lentiviral vector, an adenoviral vector, a herpesvirus vector, an adenovirus, or an adeno- associated virus (AAV) vector. As used herein, the term “lentiviral vector” is intended to mean an infectious lentiviral particle. Lentivirinae (lentiviruses) is a subfamily of enveloped retrovirinae (retroviruses), that are distinguishable from other viruses by virion structure, host range, and pathological effects. An infectious lentiviral particle will be capable of invading a target host cell, including infecting, and transducing non-dividing cells and immune cells. In some embodiments, the vector containing RNA is a non-integrative and non-replicative recombinant lentivirus vector. The construction of lentiviral vectors has been described, for example, in U.S. Patents 5,665,577, 5,981,276, 6,013,516, 7,090,837, 8,119,119 and 10,954,530. Lentivirus vectors include a defective lentiviral genome, i.e., in which at least one of the lentivirus genes gag, pol, and env, has been inactivated or deleted. A lentiviral vector can exhibit functions additional to, or different from, a naturally occurring lentivirus. For example, a lentiviral vector can be modified to change or reduce a lentivirus characteristic. A lentiviral vector also can be modified to exhibit characteristics of one or more other retroviruses, retroviral vectors, host cells or heterologous cells. Modifications can include, for example, pseudotyping, modifying binding and/or fusion functions of the envelope polypeptide, incorporating heterologous, chimeric, or multifunctional polypeptides into the vector, incorporating non-lentivirus genomes, or incorporating heterologous genes into the lentiviral vector genome. The terms “pseudotyping”, “pseudotyped”, “pseudotyped vector”, and “pseudotyped vector particle” are used herein to refer to a vector bearing components (e.g., envelop or capsid) from more than one source. The sources may be from a heterologous virus or non-viral proteins. Non-viral proteins may include antibodies and antigen-binding fragments thereof. A representative pseudotyped vector is a vector bearing non-glycoprotein components derived from a first virus and envelope glycoproteins derived from a second virus. The host range of a pseudotyped vector may thus be expanded or altered depending on the type of cell surface receptor bound by the glycoprotein derived from the second virus. In some embodiments, the lentiviral vector is pseudotyped with a baboon endogenous retroviral (BaEV) envelope glycoprotein (BaEV-gp). The nucleic acid sequence of a representative BaEV-gp is set forth below. The nucleic acid sequence of a representative BaEV-gp is set forth below (SEQ ID NO:100). 1 atgggtttca ctacgaaaat tatctttctg tataatctgg tactcgtata tgcgggtttc 61 gacgatccca ggaaagcgat cgaacttgtc cagaagagat acgggaggcc ctgtgactgc 121 agcggagggc aagtatcaga acccccctct gatcgggtca gccaagttac ttgcagcggc 181 aaaacagctt acctgatgcc ggatcagaga tggaaatgca aatccatacc caaggacacc 241 agtccgagtg gaccattgca ggaatgtccg tgtaatagtt accaatcaag cgtccattca 301 agttgctaca cgtcatacca gcaatgtcgc tcaggaaata aaacctatta tacggcgaca 361 ctgcttaaaa cccaaacggg tggcacctct gatgttcagg ttctcggaag tacgaataag 421 ttgattcaga gtccctgcaa cggtatcaaa ggccagtcaa tttgttggtc tacgacagcg 481 cctatccatg tgagtgacgg cggtgggccg ttggatacaa cacgaataaa aagtgtacag 541 cggaaacttg aggagataca caaagccctc taccccgagc ttcagtacca tcccctggcc ^{601 atccctaagg tcagggacaa tctcatggta gacgctcaaa ccctcaacat cctcaatgcc} 661 acctacaatc tcttgttgat gtctaacaca agcttggtag atgactgctg gctctgtctt 721 aaattgggcc ctccgactcc cctcgctata cccaacttcc ttctgtcata cgtaacgcgc 781 agctccgaca acatatcatg tctgataatc ccgccgttgc ttgtgcagcc catgcagttc 841 tctaacagct cctgcttgtt cagtccatct tataattcaa cagaagaaat tgatttgggc 901 catgtagctt tcagtaactg tacatcaata actaacgtca ctggccccat ctgcgccgtg 961 aacggttctg tcttcctctg cggcaacaat atggcttata catacttgcc aactaactgg 1021 accggtctgt gtgtattggc cacgctgttg cctgacatag atataatccc tggcgacgaa 1081 cccgtcccta tcccagccat cgaccatttt atttatcgcc ccaagcgcgc gattcagttt 1141 atccctctgc tcgctgggtt gggcattacg gctgctttta ctacgggggc taccggcctt 1201 ggagtgtccg ttacccaata tacgaaactg tccaatcaat tgatttcaga cgtgcaaatc 1261 ttgagctcta ctatccagga tctgcaggac caggtagact ctctggcgga agtcgtcttg 1321 caaaatcggc gggggttgga tctgctgacc gccgagcagg gcggcatctg tcttgctctt 1381 caagaaaaat gctgttttta cgtgaacaaa tcaggtattg taagagataa aataaaaact 1441 ttgcaagaag agctcgaaag gaggcggaaa gacctggcgt ctaatcctct gtggactggc 1501 ctgcaggggc tcctccccta tttgctgccc tttcttggtc cgctcctgac tttgttgctg 1561 ctcctgacta ttgggccatg catcttcaat cgactcaccg cgttcatcaa tgataaactc 1621 aacataatcc acgctatgtg a BaEV is an endogenous gammaretrovirus that had a recombination event between a Papio cynocephalus endogenous retrovirus and a simian betaretrovirus. BaEV is intimately related with the infectious feline endogenous retrovirus RD114. The env gene from RD114 is thought to be originally derived from the BaEV envelope gp. These two viruses are stable in human and macaque sera, giving them a great potential for in vivo gene therapy. They also recognize the sodium-dependent neutral amino acid transport (ASCT- 2) in human cells, but only BaEV also recognizes ASCT-1, giving BaEV a wider tropism. ASCT-1 and -2 receptors have a 57% identical sequence, and they are expressed in a wide number of cells. In some embodiments, the lentiviral vector is pseudotyped with the feline endogenous retrovirus RD114 glycoprotein. In some embodiments, the vector is a pseudotyped lentiviral vector for the use of transduction in NK cells. Lentivirus pseudotyped with glycoprotein G from vesicular stomatitis virus (VSV-G) binds to low density lipoprotein receptor (LDL-R), which is not normally expressed on NK cells. BaEV-gp pseudotyped lentivirus (BaEV-LV) binds to ASCT2, which is expressed on NK cells, furthermore NK ASCT2 expression is upregulated after IL-12, IL-15, and IL-18 treatment (Dong et al., Proc. Natl. Acad. Sci. U.S.A.119(25):e2122379119 (2022)). NK cells can be transduced with BaEV-LV, and IL-12, IL-15 and IL-18 pretreatment further improves transduction efficiency. CD56 bright (CD56^bright; CD56^br) NK cells express higher levels of ASCT2 compared to CD56 low expressing cells (CD56^dim) with and without IL-12, IL-15, and IL-18 treatment and showed significantly higher BaEV-LV transduction rate. NK cells derived from human PBMCs as well as from mouse spleens express ASCT2 and can be transduced with BaEV-LV. NK cells may be transduced with pseudotyped lentivirus vectors encoding a modified immune cell receipt protein that achieves 40-60% transduction efficiency. The term “bright” as used herein in the context of marker expression (e.g., CD56^bright) refers to a cell having a signal that is higher or more intense than a comparative control cell, wherein a user or computer may differentiate two populations of cells based on the levels or intensity of the signal. In other embodiments, the vector is a non-viral vector, representative examples of which include plasmids, mRNA, circular RNA (circRNA), linear single-stranded DNA (ssDNA) or linear double-stranded DNA (dsDNA), minicircles, and transposon-based vectors, such as Sleeping Beauty (SB)-based vectors and piggyBac(PB)-based vectors. In yet other embodiments, the vector may include both viral and non-viral elements. In some embodiments, the vector is a plasmid. In addition to a promoter operatively linked to the nucleic acids, the plasmid may also contain other elements e.g., that facilitate transport and expression of the nucleic acid in an immune cell. The plasmid may be linearized with restriction enzymes, in vitro transcribed to produce mRNA, and then modified with a 5’ cap and 3’ poly-A tail. In some embodiments, a carrier encapsulates the vector. The carrier may be lipid-based, e.g., lipid nanoparticles (LNPs), liposomes, lipid vesicles, or lipoplexes. In some embodiments, the carrier is an LNP. In certain embodiments, an LNP includes two or more concentric bilayers separated by aqueous compartments. Lipid bilayers may be functionalized and/or crosslinked to one another. Lipid bilayers may include one or more ligands, proteins, or channels. Lipid carriers, e.g., LNPs may include one or more cationic/ionizable lipids, one or more polymer conjugated lipids, one or more structural lipids, and/or one or more phospholipids. A “cationic lipid” refers to positively charged lipid or a lipid capable of holding a positive charge. Cationic lipids include one or more amine group(s) which bear the positive charge, depending on pH. A “polymer conjugated lipid” refers to a lipid with a conjugated polymer portion. Polymer conjugated lipids include PEGylated lipids, which are lipids conjugated to polyethylene glycol (PEG). A “structure lipid” refers to a non-cationic lipid that does not have a net charge at physiological pH. Exemplary structural lipids include cholesterol, fecosterol, sitosterol, ergosterol, campesterol and the like. A “phospholipid” refers to lipids that have a triester of glycerol with two fatty acids and one phosphate ion. Phospholipids in LNPs assemble the lipids into one or more lipid bilayers. LNPs, their method of preparation, formulation, and delivery are disclosed in, e.g., U.S. Patent Application Publication Nos.2004/0142025, 2007/0042031, and 2020/0237679 and U.S. Patents 9,364,435, 9,518,272, 10,022,435, and 11,191,849. Lipoplexes, liposomes, and lipid nanoparticles may include a combination of lipid molecules, e.g., a cationic lipid, a neutral lipid, an anionic lipid, polypeptide-lipid conjugates, and other stabilization components. Representative stabilization components include antioxidants, surfactants, and salts. Compositions and preparation methods of lipoplexes, liposomes, and lipid nanoparticles are known in the art. See, e.g., U.S. Patents 8,058,069, 8,969,353, 9,682,139, 10,238,754, U.S. Patent Application Publications 2005/0064026 and 2018/0291086, and Lasic, Trends Biotechnol.16(7):307-21 (1998), Lasic et al., FEBS Lett.312(2-3):255-8 (1992), and Drummond et al., Pharmacol. Rev. 51(4):691-743 (1999). Host cells In certain embodiments, the nucleic acids and vectors described above can be expressed in a supporter or host cell line. Mammalian cell lines such as Chinese hamster ovary (CHO) cells or 293T cells are particularly suitable for these purposes. In certain embodiments, the nucleic acids and vectors described above can be expressed in an alternative host cell, such as a bacterial cell, for example E. coli. In certain embodiments, the invention encompasses a cell comprising the nucleic acids and vectors described herein. Immune cells One aspect of the present disclosure is a genetically modified (or transformed) immune cell containing any one of the nucleic acids or sets of nucleic acids or any one of the vectors or sets of vectors provided herein. As used herein, "immune cell" refers to a cell of hematopoietic origin functionally involved in the initiation and/or execution of innate and/or adaptative immune response. A combination of different immune cells may be used. In certain embodiments, T cells are used. Representative examples of T cells include cytotoxic lymphocytes, cytotoxic T cells (CD8⁺ T cells), T helper cells (CD4⁺ T cells), αβ T cells and/or γδ T cells, NK T (NKT) cells, and Th17 T cells. In some embodiments, the immune cells are CD8⁺ T cells. In some embodiments, the immune cells are CD4⁺ T cells. In some embodiments, the immune cells are a combination of CD8⁺ T cells and CD4⁺ T cells. T cells may be primary T cells isolated from healthy patients and engineered to express a modified immune cell receptor protein. Certain types of T cells have preferential properties when it comes to in vivo persistence, expansion, and effector function against cancer cells. Naïve (TN) and stem cell-like memory T (TSCM) cells are characterized by surface expression of CD45RA and CD62L. T_N and T_SCM cells have been shown to provide improved anti-cancer effect in clinical trials due to their low exhaustion state and the ability to differentiate into several types of effector T cells. In an embodiment, the invention encompasses an immune cell, such as a naïve (TN) and stem cell-like memory T (TSCM) cell modified to express the modified immune cell receptor protein of the invention. In an embodiment, the invention encompasses an immune cell, such as a naïve (T_N) and stem cell-like memory T (T_SCM) cells comprising a nucleic acid or vector encoding the modified immune cell receptor protein of the invention. In some embodiments, the immune cells are NK cells. In some embodiments, the immune cells are a NK cell line, primary NK cells, memory-like NK cells, or cytokine-induced memory-like (CIML) NK cells. In some embodiments, the immune cells are monocytes or macrophages. In some embodiments, the immune cells are part of a mixed population of immune cells comprising NK cells and T cells. In some embodiments, the NK cells within the mixed immune cell population comprise a NK cell line, primary NK cells, memory-like NK cells, or cytokine-induced memory-like (CIML) NK cells. In some embodiments, the T cells within the mixed immune cell population are naïve (TN) and stem cell-like memory T (TSCM) cells, cytotoxic lymphocytes, cytotoxic T cells (CD8⁺ T cells), T helper cells (CD4⁺ T cells), αβ T cells and/or γδ T cells, NK T (NKT) cells, Th17 T-cells, and CIML T cells. In some embodiments, the T cells comprise CD8⁺ T cells. In some embodiments, the T cells comprise CD4⁺ T cells. In some embodiments, the T cells comprise a combination of CD8⁺ T cells and CD4⁺ T cells. Immune cells include cells derived from stem cells. The stem cells can be adult stem cells (e.g., induced pluripotent stem cells (iPSC)), embryonic stem cells, cord blood stem cells, progenitor cells, bone marrow stem cells, induced pluripotent stem cells, totipotent stem cells or hematopoietic stem cells. In some embodiments, the immune cells are derived from peripheral blood mononuclear cells (PBMC), cell lines, or cell bank cells. The collection, isolation, purification, and differentiation of cells from body fluids and tissues is known in the art. See, for example, Brown et al., PloS One 5:e11373-9 (2010), Rivera et al., Curr. Protoc. Stem Cell Biol.54:e117-21 (2020), Seki et al., Cell Stem Cell 7:11-4 (2010), Takahashi et al., Cell 126:663-76 (2006), Fusaki et al., Proc. Jpn. Acad. Ser. B Phys. Biol. Sci.85:348-62 (2009), Park et al., Nature 451:141-6 (2008), and U.S. Patents 10,214,722, 10,370,452, 10,428,309, 10,844,356, 11,141,471, 11,162,076, and 11,193,108 and U.S. Patent Application Publications 2012/0121544, 2018/0362927, 2019/0112577, and 2021/0015859. In certain embodiments, the immune cells are iPSC derived cells. In certain embodiment, the immune cells are Dendritic cells (DCs). NK cells are produced in the bone marrow and mature in secondary lymphoid tissues through distinct stages from CD56^brightCD16- to CD56^dimCD16⁺ cells that represents the most abundant NK population in peripheral blood. In some embodiments, iPSCs may be induced to differentiate into NK cells as set forth in Ruiz et al., Stem Cell Res.41:101600- 26 (2019), Laskowski et al., Stem Cell Reports 7:139-48 (2016), Ni et al., Methods Mol. Biol.1029:33-41 (2013), and Euchner et al., Front. Immunol.12:640672-11 (2021). In some embodiments, the cells are NK cells derived from cord blood as set forth in Mehta et al., Front. Med. (Lausanne) 2:93-10 (2016)), Chabannon et al., Front. Immunol.7:504-9 (2016), Shah et al., PLoS One 8:e76781-9 (2013); Zhao et al., Front Immunol 11:584099-8 (2020)). In some embodiments, the cells are NK cells obtained from PBMCs as set forth in Koehl et al., Front. Oncol.3:118-12 (2013)) and Becker et al., Cancer Immunol. Immunother.65:477-84 (2016)). In some embodiments, the cells are primary NK cells, also known as “conventional NK cells” (cNK). Typically, cNK cells are CD56⁺ NK cells that may be isolated from human blood. cNK cells may be isolated from a normal, healthy donor, with a known HLA type, and preferably with an HLA match (autologous) or partial HLA match (allogeneic or syngenic) to the subject in need thereof. cNK cells are purified by depleting non-NK cells in the donor sample, e.g., PBMCs. Purification may be performed by any means known in the art, e.g., by using a Miltenyi NK cell isolation kit. In some embodiments, the cells are memory-like NK cells. Memory-like NK cells are produced, typically in vitro, from cNK cells, isolated from a subject, in some cases, from the same subject in need of ACT. In some embodiments, the cells are cytokine-induced memory-like (CIML) NK cells. CIML NK cells are produced by stimulating NK cells with one or, more typically a combination, of IL-12, IL-15, and IL-18. CIML NK cells produce IFN-γ, a prototype NK cell functional readout, in response to leukemia target cells or after stimulation with IL-12, IL-15, and IL-18. Upon restimulation with cytokines or target tumor cells, a larger fraction of CIML NK cells produce higher levels of IFN-γ as compared with cNK cells. CIML NK cells adoptively transferred into leukemia-bearing mice inhibit tumor growth to a greater degree as compared to conventional NK cells. See, e.g., Cooper et al., Proc. Natl. Acad. Sci. USA 106:1915-9 (2009); Ni et al., J. Exp. Med.209:2351-65 (2012); Keppel et al., J. Immunol.190:4754-62 (2013); Romee et al., Sci. Transl. Med.8(357):357ra123-26 (2016). In some embodiments, the cells are allogeneic to the subject receiving the cells, that is, the cells have a complete or at least a partial HLA-match with the subject. In some embodiments, the cells are autologous. The term “autologous” as used herein refers to any material (e.g., NK cells or T cells) derived from the same subject to whom it is later re- introduced. The term “allogeneic” as used herein refers to any material derived from a different subject of the same species as the subject to whom the material is later introduced. Two or more individual subjects are allogeneic when the genes at one or more loci are not identical (typically the HLA loci). In some embodiments, the cells are engineered to down-regulate HLA-A/B/C molecules. Various methods for down-regulation are recognized by skilled practitioners and encompass genetic manipulation of genes encoding HLA-A/B/C or Beta-2 microglobulin (B2M). These genes can be manipulated through direct engineering of genomic DNA loci using CRISPR/Cas9 or related systems, TALEN enzymes or similar systems, Zinc-finger nucleases or related systems, or by gene insertion into loci using engineered transposons or similar systems. Additionally, HLA-A/B/C or B2M protein expression can be down- regulated through the use of short-interfering RNA (siRNA) or similar systems (shRNAs, microRNAs, etc.) that target mRNA encoding HLA-A/B/C or B2M proteins. Assessment of Major Histocompatibility Complex-I (MHC-I) down-regulation can be performed by staining cells for HLA-A/B/C proteins or the B2M protein on the cell surface using appropriate antibodies and flow cytometry analysis. In some embodiments, the cells are from NK cell lines. Suitable NK cell lines are known in the art and include NK-92, NKG, NKL, KHYG-1, YT, NK-YS, SNK-6, IMC-1, YTS, NKL cells, and high affinity NK (haNK, an NK/T cell lymphoma cell line). NK cell lines enable cell-based immunotherapies within the context of allogeneic adoptive transfer and without or lessened risk of graph versus host disease (GvHD). Furthermore, the use of NK cells lines avoids the need for leukapheresis, facilitating cell procurement, and avoiding undesirable side-effects. See, e.g., Leung et al., Clin. Cancer Res.20:3390-400 (2014); Tonn et al., Cytotherapy 15:1563-70 (2013). In certain embodiments the immune cells express endogenous CD3ζ. In certain embodiments, the immune cells are modified to comprise an exogenous nucleic acid encoding CD3ζ, as well as comprising a nucleic acid encoding the modified immune cell receptor of the invention. Thus, in this embodiment, there is co-expression of CD3ζ and the modified immune cell receptor of the invention, with CD3ζ being overexpressed when compared with the expression level of CD3ζ in an immune cell where the exogenous nucleic acid encoding CD3ζ is not present. In some embodiments the immune cells are transduced with a bis-cistronic nucleic acid construct comprising a nucleic acid encoding CD3ζ and a nucleic acid encoding the modified immune cell receptor protein of the invention. In certain embodiments the immune cells express endogenous FcεRIγ. In certain embodiments, the immune cells are modified to comprise an exogenous nucleic acid encoding FcεRIγ, as well as comprising a nucleic acid encoding the modified immune cell receptor of the invention. Thus, in this embodiment, there is co-expression of FcεRIγ and the modified immune cell receptor of the invention, with FcεRIγ being overexpressed when compared with the expression level of FcεRIγ in an immune cell where the exogenous nucleic acid encoding FcεRIγ is not present. In some embodiments the immune cells are transduced with a bis-cistronic nucleic acid construct comprising a nucleic acid encoding FcεRIγ and a nucleic acid encoding the modified immune cell receptor protein of the invention. Methods of introducing the vectors containing the modified immune cell receptor protein- encoding nucleic acids into immune cells are known in the art. See, e.g., U.S. Patents 7,399,633, 7,575,925, 10,072,062, 10,370,452, and 10,829,735 and U.S. Patent Publications 2019/0000880 and 2021/0407639. In some embodiments, a lentiviral vector is transduced into immune cells. In other embodiments, the method entails the use of gamma-retroviral vectors. See, e.g., U.S. Patents 9,669,049, 11,065,311, and 11,230,719. In some embodiments, the method entails the use of Adenovirus, Adeno-associated virus (AAV), dsRNA, ssDNA, or dsRNA to deliver the first, the second, and the third nucleic acids. See, e.g., U.S. Patent 10,563,226, and U.S. Patent Application Publications 2019/0225991, 2020/0080108, and 2022/0186263. In some embodiments, the method entails ex vivo or in vivo delivery of linear, circular, or self-amplifying mRNAs. See, e.g., U.S. Patents 7,442,381, 7,332,322, 9,822,378, 9,254,265, 10,532,067, and 11,291,682. In some embodiments, the method entails the use of a transposase to integrate the vector-delivered nucleic acids into the immune cell’s genome. See, e.g., U.S. Patents 7,985,739, 10,174,309, 11,186,847, and 11,351,272. In some embodiments, the method entails the use of self-replicating episomal nano-vectors. See, e.g., U.S. Patents 5,624,820, 5,674,703, and 9,340,775. In some embodiments, a plasmid containing a modified immune cell receptor protein- encoding nucleic acid is transfected into immune cells. In some embodiments, the vector(s) containing the nucleic acid sequence(s) is delivered to an immune cell by lipofection. Lipofection is described, for example, in U.S. Patent Nos.5,049,386, 4,946,787; and 4,897,355. Pharmaceutical compositions Pharmaceutical compositions of the disclosure include compositions comprising therapeutically effective numbers of genetically modified immune cells expressing the modified immune cell receptor protein of the invention and a pharmaceutically acceptable carrier. The term “therapeutically effective number of immune cells” (which indirectly includes a corresponding amount of the modified immune cell receptor protein) as used herein refers to a sufficient number of the immune cells that contain the modified immune cell receptor protein-encoding nucleic acid(s) to provide a desired effect. The number of immune cells administered to a subject will vary between wide limits, depending upon the location, type, and severity of the disease or disorder, the age, body weight, and condition of the individual to be treated, etc. A physician will ultimately determine appropriate number of cells and doses to be used. Typically, the immune cells will be given in a single dose. In some embodiments, the effective number of the genetically modified immune cells is between approximately 1×10⁵ to approximately 1×10¹⁰ cells per subject. In some embodiments, the effective number of genetically modified immune cells is between approximately 1×10⁵ to approximately 6×10⁸ cells per kilogram of subject body weight. Compositions may be provided as sterile liquid preparations, e.g., isotonic aqueous solutions, suspensions, emulsions, dispersions, or viscous compositions, which may be buffered to a selected pH. Liquid carriers include aqueous or non-aqueous carriers alike. Representative examples of liquid carriers include saline, phosphate buffered saline, a soluble protein, dimethyl sulfoxide (DMSO), polyol (e.g., glycerol, propylene glycol, liquid polyethylene glycol, and the like) and suitable mixtures thereof. In some embodiments, the liquid carrier includes a protein dissolved or dispersed therein, representative examples include serum albumin (e.g., human serum albumin, recombinant human albumin), gelatin, and casein. The compositions are typically isotonic, i.e., they have the same osmotic pressure as blood. Sodium chloride and isotonic electrolyte solutions (e.g., Plasma-Lyte®) may be used to achieve the desired isotonicity. Depending on the carrier and the immune cells, other excipients may be added, e.g., wetting, dispersing or emulsifying agents, gelling and viscosity enhancing agents, preservatives and the like as known in the art. Also disclosed is a pharmaceutical composition comprising a CIML immune cell expressing the modified immune cell receptor protein of the invention, or the population of CIML immune cells expressing the modified immune cell receptor protein of the invention, and a pharmaceutically acceptable carrier. Pharmaceutical carriers are known to those skilled in the art. These most typically would be standard carriers for administration of drugs to humans, including solutions such as sterile water, saline, and buffered solutions at physiological pH. Typically, an appropriate amount of a pharmaceutically-acceptable salt is used in the formulation to render the formulation isotonic. Examples of the pharmaceutically-acceptable carrier include, but are not limited to, saline, Ringer's solution and dextrose solution. The pH of the solution is preferably from about 5 to about 8, and more preferably from about 7 to about 7.5. The solution should be RNAse free. Further carriers include sustained release preparations such as semipermeable matrices of solid hydrophobic polymers, which matrices are in the form of shaped articles, e.g., films, liposomes or microparticles. It will be apparent to those persons skilled in the art that certain carriers may be more preferable depending upon, for instance, the route of administration and concentration of composition being administered. Pharmaceutical compositions may include carriers, thickeners, diluents, buffers, preservatives, surface active agents and the like. Pharmaceutical compositions may also include one or more active ingredients such as antimicrobial agents, anti-inflammatory agents, anesthetics, and the like. Preparations for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Aqueous carriers include water, alcoholic/aqueous solutions, emulsions or suspensions, including saline and buffered media. Parenteral vehicles include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's, or fixed oils. Intravenous vehicles include fluid and nutrient replenishers, electrolyte replenishers (such as those based on Ringer's dextrose), and the like. Preservatives and other additives may also be present such as, for example, antimicrobials, anti-oxidants, chelating agents, and inert gases and the like. Treatment applications The compositions and methods provided herein may be used for cell killing and, thus, can be useful for the treatment of any disease or disorder in which cell killing may confer a benefit. Such diseases or disorders include cancer as well as diseases and disorders where B cell depletion, plasma cell depletion or T cell depletion may be beneficial. In some aspects, the present disclosure is directed to treating a cancer in a subject. The method entails administering to a subject in need thereof a therapeutically effective number of the immune cells containing nucleic acid(s) encoding a modified immune cell receptor protein as described herein. The term “cancer” as used herein refers to a disease or disorder characterized by excess proliferation or reduced apoptosis in a subject. Cancers that may be treated with the genetically modified immune cells disclosed herein include both hematopoietic cancers and cancers characterized by the presence of a solid tumor. In some embodiments, the cancer is a myelodysplastic syndrome (MDS). MDS are a group of cancers in which immature blood cells in the bone marrow do not mature into healthy blood cells (e.g., red blood cells, white blood cells, or platelets). Acute myeloid leukemia (AML) is an MDS and a cancer of the blood and bone marrow. AML (also known as myelogenous leukemia and acute nonlymphocytic leukemia) is the most common type of acute leukemia in adults that usually progress quickly if left untreated. In some embodiments, a subject may be suffering from relapse after haploidentical hematopoietic cell transplantation (haplo-HCT) (Shapiro et al., J. Clin. Invest. 132(11):e154334-17 (2022)). In some embodiments, the cancer is a hematopoietic cancer. The hematopoietic cancer may be leukemia, lymphoma, or multiple myeloma. The hematopoietic cancer may also be acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, Hodgkin lymphoma, Non-Hodgkin lymphoma or blastic plasmacytoid dendritic cell neoplasm. In some embodiments, the cancer is characterized by the presence of a solid tumor. In some embodiments, the cancer is a breast cancer, cervical carcinoma, kidney cancer (e.g., renal cell carcinoma (RCC), transitional cell cancer, or Wilms tumor), glioma, glioblastoma, neuroblastoma, skin cancer (e.g., melanoma, basal cell carcinoma, and squamous cell carcinoma of the skin), bladder cancer (e.g., transitional cell carcinoma, also called urothelial carcinoma), lung cancer (e.g., small cell lung cancer, non-small cell lung cancer, including adenocarcinoma and squamous cell carcinoma of the lung), prostate cancer, colorectal cancer, colon cancer, head and neck cancer (e.g., squamous cell carcinoma of the head and neck, laryngeal and hypopharyngeal cancer, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, oral and oropharyngeal cancer, and salivary gland cancer), ovarian cancer (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma, epithelial carcinomas, fallopian tube cancer, and primary peritoneal cancer), pancreatic cancer, gastrointestinal cancer (e.g., adenocarcinoma, primary gastric lymphoma, gastrointestinal cancers (e.g., gastrointestinal stromal tumor (GIST)), and neuroendocrine (carcinoid) cancers), or blastic plasmacytoid DC neoplasm. In some aspects, the present disclosure is directed to treating an autoimmune disease in a subject. “Autoimmune disease” is a disease in which the immune system fails to recognize a subject’s own organs, tissues or cells as self, and produces an immune response to attack those organs, tissues or cells as if they were foreign antigens. Autoimmune diseases are well known in the art; for example, as disclosed in The Encyclopedia of Autoimmune Diseases, Dana K. Cassell, Noel R. Rose, Infobase Publishing, 14 May 2014, the diseases of which are herein incorporated by reference. Examples of autoimmune diseases for which the compositions and methods provided herein may be useful include, without limitation, Achalasia, Addison’s disease, Adult Still's disease, Agammaglobulinemia, Alopecia areata, Amyloidosis, Ankylosing spondylitis, Anti-GBM/Anti-TBM nephritis, Antiphospholipid syndrome, Autoimmune angioedema, Autoimmune dysautonomia, Autoimmune encephalomyelitis, Autoimmune hepatitis, Autoimmune inner ear disease (AIED), Autoimmune myocarditis, Autoimmune oophoritis, Autoimmune orchitis, Autoimmune pancreatitis, Autoimmune retinopathy, Autoimmune urticaria, Axonal & neuronal neuropathy (AMAN), Baló disease, Behcet’s disease, Benign mucosal pemphigoid, Bullous pemphigoid, Castleman disease (CD), Celiac disease, Chagas disease, Chronic inflammatory demyelinating polyneuropathy (CIDP), Chronic recurrent multifocal osteomyelitis (CRMO), Churg-Strauss Syndrome (CSS) or Eosinophilic Granulomatosis (EGPA), Cicatricial pemphigoid, Cogan’s syndrome, Cold agglutinin disease, Congenital heart block, Coxsackie myocarditis, CREST syndrome, Crohn’s disease, Dermatitis herpetiformis, Dermatomyositis, Devic’s disease (neuromyelitis optica), Discoid lupus, Dressler’s syndrome, Endometriosis, Eosinophilic esophagitis (EoE), Eosinophilic fasciitis, Erythema nodosum, Essential mixed cryoglobulinemia, Evans syndrome, Fibromyalgia, Fibrosing alveolitis, Giant cell arteritis (temporal arteritis), Giant cell myocarditis, Glomerulonephritis, Goodpasture’s syndrome, Granulomatosis with Polyangiitis, Graves’ disease, Guillain-Barre syndrome, Hashimoto’s thyroiditis, Hemolytic anemia, Henoch-Schonlein purpura (HSP), Herpes gestationis or pemphigoid gestationis (PG), Hidradenitis Suppurativa (HS) (Acne Inversa), Hypogammalglobulinemia, IgA Nephropathy, IgG4-related sclerosing disease, Immune thrombocytopenic purpura (ITP), Inclusion body myositis (IBM), Interstitial cystitis (IC), Juvenile arthritis, Juvenile diabetes (Type 1 diabetes), Juvenile myositis (JM), Kawasaki disease, Lambert-Eaton syndrome, Leukocytoclastic vasculitis, Lichen planus, Lichen sclerosus, Ligneous conjunctivitis, Linear IgA disease (LAD), Lupus, Lyme disease chronic, Meniere’s disease, Microscopic polyangiitis (MPA), Mixed connective tissue disease (MCTD), Mooren’s ulcer, Mucha- Habermann disease, Multifocal Motor Neuropathy (MMN) or MMNCB, Multiple sclerosis, Myasthenia gravis, Myositis, Narcolepsy, Neonatal Lupus, Neuromyelitis optica, Neutropenia, Ocular cicatricial pemphigoid, Optic neuritis, Palindromic rheumatism (PR), PANDAS, Paraneoplastic cerebellar degeneration (PCD), Paroxysmal nocturnal hemoglobinuria (PNH), Parry Romberg syndrome, Pars planitis (peripheral uveitis), Parsonage-Turner syndrome, Pemphigus, Peripheral neuropathy, Perivenous encephalomyelitis, Pernicious anemia (PA), POEMS syndrome, Polyarteritis nodosa, Polyglandular syndromes type I, II, III, Polymyalgia rheumatica, Polymyositis, Postmyocardial infarction syndrome, Postpericardiotomy syndrome, Primary biliary cirrhosis, Primary sclerosing cholangitis, Progesterone dermatitis, Psoriasis, Psoriatic arthritis, Pure red cell aplasia (PRCA), Pyoderma gangrenosum, Raynaud’s phenomenon, Reactive Arthritis, Reflex sympathetic dystrophy, Relapsing polychondritis, Restless legs syndrome (RLS), Retroperitoneal fibrosis, Rheumatic fever, Rheumatoid arthritis, Sarcoidosis, Schmidt syndrome, Scleritis, Scleroderma, Sjögren’s syndrome, Sperm & testicular autoimmunity, Stiff person syndrome (SPS), Subacute bacterial endocarditis (SBE), Susac’s syndrome, Sympathetic ophthalmia (SO), Takayasu’s arteritis, Temporal arteritis/Giant cell arteritis, Thrombocytopenic purpura (TTP), Thyroid eye disease (TED), Tolosa-Hunt syndrome (THS), Transverse myelitis, Type 1 diabetes, Ulcerative colitis (UC), Undifferentiated connective tissue disease (UCTD), Uveitis, Vasculitis, Vitiligo, and Vogt- Koyanagi-Harada Disease. In some aspects, the compositions or methods provided herein may be used for a subject that has received a transplant. As used herein, “transplant” refers to an organ or tissue moved from a donor to a recipient for the purpose of replacing the recipient’s damaged or absent organ or tissue. Any one of the methods or compositions provided herein may be used for a subject that has undergone a transplant of an organ or tissue. In some embodiments, the subject may be one suspected of having or a likelihood of having transplant rejection. In some aspects, the compositions or methods provided herein may be used for a subject that has graft versus host disease (GVHD). “GVHD” is a complication that can occur after a pluripotent cell (e.g., stem cell) or bone marrow transplant in which the newly transplanted material results in an attack on the transplant recipient's body. In some instances, GVHD takes place after a blood transfusion. Graft-versus-host-disease can be divided into acute and chronic forms. The acute or fulminant form of the disease (aGVHD) is normally observed within the first 100 days post-transplant and is a major challenge to transplants owing to associated morbidity and mortality. The chronic form of graft-versus-host-disease (cGVHD) normally occurs after 100 days. The appearance of moderate to severe cases of cGVHD adversely influences long-term survival. The term “subject” (or “patient”) as used herein includes all members of the animal kingdom prone (or disposed) to or suffering from the indicated disease or disorder. In some embodiments, the subject is a human. Therefore, a subject “having a” disease or disorder or “in need of” treatment according to the present disclosure broadly embraces subjects who have been positively diagnosed, including subjects having active disease who may have been previously treated with one or more rounds of therapy, and subjects who are not currently being treated (e.g., in remission) but who might still be at risk of relapse, and subjects who have not been positively diagnosed but who are predisposed to the disease or disorder (e.g., on account of the basis of prior medical history and/or family medical history, or who otherwise present with a one or more risk factors such that a medical professional might reasonably suspect that the subject was predisposed to the disease or disorder). The terms “treat”, “treating”, and “treatment” as used herein refer to any type of intervention, process performed on, or the administration of an active agent to the subject in need thereof with the therapeutic objective (“therapeutic effect”) of reversing, alleviating, ameliorating, inhibiting, diminishing, slowing down, arresting, stabilizing, or preventing the onset, progression, development, severity or recurrence of a symptom, complication or condition, or biochemical indicia associated with a disease or disorder. In some embodiments, the genetically modified immune cells are T cells, naïve T(T_N) cells or stem cell-like memory T (TSCM) cells, NK cells, NKT cells, Dendritic cells (DC)s, or monocytes or macrophages. In some embodiments, the genetically modified immune cells are a combination of T cells and other types of genetically modified immune cells such as NK cells. In some embodiments, the genetically modified immune cells are a combination of different types of T cells, e.g., CD8⁺ T cells and CD4⁺ T cells. In some embodiments, the genetically modified immune cells are autologous with respect to the subject receiving the cells. In some embodiments, the genetically modified immune cells are allogeneic to the subject receiving the cells. Methods described herein are generally performed on a subject in need thereof. A subject in need of the therapeutic methods described herein can be a subject having, diagnosed with, suspected of having, or at risk for developing, or at risk of progressing to a later stage of, cancer. A determination of the need for treatment will typically be assessed by a history, physical exam, or diagnostic tests consistent with the disease or condition at issue. Diagnosis of the various conditions treatable by the methods described herein is within the skill of the art. The subject can be an animal subject, including a mammal, such as horses, cows, dogs, cats, sheep, pigs, mice, rats, monkeys, hamsters, guinea pigs, and humans, or other animals such as chickens. For example, the subject can be a human subject. Generally, a safe and effective amount of a therapy is, for example, an amount that would cause the desired therapeutic effect in a subject while minimizing undesired side effects. According to the methods described herein, administration can be parenteral, pulmonary, oral, topical, intradermal, intramuscular, intraperitoneal, intravenous, intratumoral, intrathecal, intracranial, intracerebroventricular, subcutaneous, intranasal, epidural, ophthalmic, buccal, or rectal administration. Where the product is a cell therapy, the mode of administration will likely be via injection or infusion. Compositions containing a therapeutically effective number of the genetically modified immune cells may be administered to a subject for the treatment of a disease or disorder by any medically acceptable route. The genetically modified immune cells are typically delivered intravenously, although they may also be introduced into other convenient sites (e.g., to an affected organ or tissue) or modes, as determined by an attending physician. Expansion and differentiation agents can be provided prior to, during or after administration of the cells to increase differentiation, expansion, or persistence of the genetically modified immune cells (e.g., T cells and NK cells). Administration can be autologous or allogeneic. For example, immune cells or progenitors thereof can be isolated from a tissue of body fluid from one subject prior to administration to the same subject (autologous) or a different, compatible subject (allogeneic). The present invention encompasses the modified immune cell receptor proteins of the invention for use in therapy. The present invention encompasses immune cells expressing the modified immune cell receptor proteins of the invention for use in therapy. The present invention modified immune cell receptor proteins of the invention for use in the manufacture of a medicament for the treatment of disease. The present invention encompasses immune cells expressing the modified immune cell receptor proteins of the invention for use in the manufacture of a medicament for the treatment of disease. The therapeutic use or disease to be treated is envisage to be any of the diseases or conditions described herein. Combination Therapy In some embodiments, the present methods may include co-administration of another agent, such as an anti-cancer agent, antibody therapy, cell engager, immunotherapy, etc. The term “co-administered” includes substantially contemporaneous administration, by the same or separate dosage forms, or sequentially, e.g., as part of the same treatment regimen or by way of successive treatment regimens. Thus, if given sequentially, at the onset of administration of the second therapy, the first of the two therapies is, in some cases, still detectable at effective concentrations at the site of treatment. The sequence and time interval may be determined such that they can act together (e.g., synergistically to provide an increased benefit than if they were administered otherwise). For example, the therapeutics may be administered at the same time or sequentially in any order at different points in time; however, if not administered at the same time, they may be administered sufficiently close in time so as to provide the desired therapeutic effect, which may be in a synergistic fashion. Thus, the terms are not limited to the administration of the active agents at exactly the same time. Anti-cancer agents that may be used in combination with the inventive cells are known in the art. See, e.g., U.S. Patent No.9,101,622 (Section 5.2 thereof). An "anti-cancer" agent is capable of negatively affecting cancer in a subject, for example, by killing cancer cells, inducing apoptosis in cancer cells, reducing the growth rate of cancer cells, reducing the incidence or number of metastases, reducing tumor size, inhibiting tumor growth, reducing the blood supply to a tumor or cancer cells, promoting an immune response against cancer cells or a tumor, preventing or inhibiting the progression of cancer, or increasing the lifespan of a subject with cancer. More generally, these other compositions would be provided in a combined amount effective to kill or inhibit proliferation of cancerous cells. This process may involve contacting the cancer cells with recipient cells and the agent(s) or multiple factor(s) at the same time. This may be achieved by contacting the cancer cells with a single composition or pharmacological formulation that includes both agents, or by contacting the cancer cells with two distinct compositions or formulations, at the same time, wherein one composition includes recipient cells and the other includes the second agent(s). In some embodiments, the immune cells of the present disclosure are used in conjunction with chemotherapeutic, radiotherapeutic, immunotherapeutic intervention, targeted therapy, pro-apoptotic therapy, or cell cycle regulation therapy. In some embodiments, the immune cells of the present disclosure are administered after the subject receives lymphodepletion chemotherapy. In some embodiments, the lymphodepletion chemotherapy includes melphalan. In some embodiments, the subject receives a stem cell transplant after the lymphodepletion chemotherapy. Additional ACT potentiating treatments that may be used with the aspects of the present disclosure include melphalan. Melphalan (Alkeran®, Evomela®) attaches alkyl groups to the N-7 position of guanine and N-3 position of adenine of DNA that leads to the formation of monoadducts, and DNA fragmenting when repair enzymes attempt to correct the apparent replication error. Melphalan can also cause DNA cross-linking from the N-7 position of one guanine to the N-7 position of another, preventing DNA strands from separating for synthesis or transcription. Melphalan, an alkylating antineoplastic agent, is used for high- dose conditioning prior to hematopoietic stem cell transplant in patients with multiple myeloma, as well as for palliative treatment of multiple myeloma and for the palliation of non-resectable epithelial carcinoma of the ovary. Melphalan is also used to treat AL amyloidosis, neuroblastoma, rhabdomyosarcoma, breast cancer, ocular retinoblastoma, some conditioning regiments before bone marrow transplant, and in some cases, malignant melanoma. Melphalan may be administered in pill form by mouth. Typically, in 2 mg doses taken on an empty stomach. In some cases, Melphalan may be administered as an injection or intravenous infusion. Dosing depends on weight, height, disease and disease state, and the subject’s general health. Anti-cancer therapies also include a variety of combination therapies with both chemical and radiation-based treatments. Combination chemotherapies include, for example, Abraxane®, altretamine, docetaxel, Herceptin®, methotrexate, Novantrone®, Zoladex®, cisplatin (CDDP), carboplatin, procarbazine, mechlorethamine, cyclophosphamide, camptothecin, ifosfamide, melphalan, chlorambucil, busulfan, nitrosurea, dactinomycin, daunorubicin, doxorubicin, bleomycin, plicomycin, mitomycin, etoposide (VP16), tamoxifen, raloxifene, estrogen receptor binding agents, Taxol®, gemcitabien, Navelbine®, farnesyl-protein tansferase inhibitors, transplatinum, 5-fluorouracil, vincristine, vinblastine and methotrexate, or any analog or derivative variant of the foregoing and also combinations thereof. Anti-cancer therapies also include radiation-based, DNA-damaging treatments. Combination radiotherapies include what are commonly known as gamma-rays, X-rays, and/or the directed delivery of radioisotopes to tumor cells which cause a broad range of damage on DNA, on the replication and repair of DNA, and on the assembly and maintenance of chromosomes. Dosage ranges for radioisotopes vary widely, and depend on the half-life of the isotope, the strength and type of radiation emitted, and the uptake by the neoplastic cells and will be determined by the attending physician. Radiotherapy may include external or internal radiation therapy. External radiation therapy involves a radiation source outside the subject’s body and sending the radiation toward the area of the cancer within the body. Internal radiation therapy uses a radioactive substance sealed in needles, seeds, wires, or catheters that are placed directly into or near the cancer. Immunotherapy, including immune checkpoint inhibitors may also be employed as another therapeutic in the methods provided herein. Immune checkpoint molecules include, for example, PD1, PDL1, CTLA4, KIR, TIGIT, TIM-3, LAG-3, BTLA, VISTA, CD47, and NKG2A. Clinically available examples of immune checkpoint inhibitors include durvalumab (Imfinzi®), atezolizumab (Tecentriq®), and avelumab (Bavencio®). Clinically available examples of PD1 inhibitors include nivolumab (Opdivo®), pembrolizumab (Keytruda®), and cemiplimab (Libtayo®). Additional inhibitors that may be useful in the practice of the present disclosure are known in the art. See, e.g., U.S. Patent Application Publications 2012/0321637, 2014/0194442, and 2020/0155520. Antibody therapy, such as treatment with monoclonal antibodies may also be used in the methods provided herein. Examples of monoclonal antibodies for treatment include, but are not limited to, Abagovomab, Abciximab, Adalimumab, Adecatumumab, Afelimomab, Afutuzumab, Alacizumab pegol, ALD, Alemtuzumab, Altumomab pentetate, Anatumomab mafenatox, Anrukinzumab, Anti-thymocyte globin, Apolizumab, Arcitumomab, Aselizumab, Atlizumab (tocilizumab), Atorolimumab, Bapineuzumab, Basiliximab, Bavituximab, Bectumomab, Belimumab, Benralizumab, Bertilimumab, Besilesomab, Bevacizumab, Biciromab, Bivatuzumab mertansine, Blinatumomab, Brentuximab vedotin, Briakinumab, Canakinumab, Cantuzumab mertansine, Capromab pendetide, Catumaxomab, Cedelizumab, Certolizumab pegol, Cetuximab, Citatuzumab bogatox, Cixutumumab, Clenoliximab, Clivatuzumab tetraxetan, Conatumumab, Dacetuzumab, Daclizumab, Daratumumab, Denosumab, Detumomab, Dorlimomab aritox, Dorlixizumab, Ecromeximab, Eculizumab, Edobacomab, Edrecolomab, Efalizumab, Efungumab, Elotuzumab, Elsilimomab, Enlimomab pegol, Epitumomab cituxetan, Epratuzumab, Erlizumab, Ertumaxomab, Etaracizumab, Exbivirumab, Fanolesomab, Faralimomab, Farletuzumab, Felvizumab, Fezakinumab, Figitumumab, Fontolizumab , Foravirumab, Fresolimumab, Galiximab, Gantenerumab, Gavilimomab, Gemtuzumab ozogamicin, GC1008, Girentuximab, Glembatumumab vedotin, Golimumab, Gomiliximab, Ibalizumab, Ibritumomab tiuxetan, Igovomab, Imciromab, Infliximab, Intetumumab, Inolimomab, Inotuzumab ozogamicin, Ipilimumab, Iratumumab, Keliximab, Labetuzumab, Lebrikizumab, Lemalesomab, Lerdelimumab, Lexatumumab, Libivirumab, Lintuzumab, Lorvotuzumab mertansine, Lucatumumab, Lumiliximab, Mapatumumab, Maslimomab, Matuzumab, Mepolizumab, Metelimumab, Milatuzumab, Minretumomab, Mitumomab, Morolimumab, Motavizumab, Muromonab-CD3, Nacolomab tafenatox, Naptumomab estafenatox, Natalizumab, Nebacumab, Necitumumab, Nerelimomab, Nimotuzumab, Nofetumomab merpentan, Ocrelizumab, Odulimomab, Ofatumumab, Olaratumab, Omalizumab, Oportuzumab monatox, Oregovomab, Otelixizumab, Pagibaximab, Palivizumab, Panitumumab, Panobacumab, Pascolizumab, Pemtumomab, Pertuzumab, Pexelizumab, Pintumomab, Priliximab, Pritumumab, Rafivirumab, Ramucirumab, Ranibizumab, Raxibacumab, Regavirumab Reslizumab, Rilotumumab, Rituximab, Robatumumab, Rontalizumab, Rovelizumab, Ruplizumab, Satumomab pendetide, Sevirumab, Sibrotuzumab, Sifalimumab, Siltuximab, Siplizumab, Solanezumab, Sonepcizumab, Sontuzumab, Stamulumab, Sulesomab, Tacatuzumab tetraxetan, Tadocizumab, Talizumab, Tanezumab, Taplitumomab paptox, Tefibazumab, Telimomab aritox, Tenatumomab, Teneliximab, Teplizumab, Ticilimumab (tremelimumab), Tigatuzumab, Tocilizumab (atlizumab), Toralizumab, Tositumomab, Trastuzumab, Tremelimumab, Tucotuzumab celmoleukin, Tuvirumab, Urtoxazumab, Ustekinumab, Vapaliximab, Vedolizumab, Veltuzumab, Vepalimomab, Visilizumab, Volociximab, Votumumab, Zalutumumab, Zanolimumab, Ziralimumab, and Zolimomab aritox. Antibodies optimized for enhanced ADCC activity may have a particularly synergistic activity when combined with EVE16 expressing cells. NK cell engagers (NKCEs), such as BiKE (bispecific killer cell engager) or TriKE (trispecific killer cell engager), are a novel class of antibody-based therapeutics that exhibit several advantages over other cancer immunotherapies harnessing NK cells. By bridging NK and tumor cells, NKCEs activate NK cells and lead to tumor cell lysis. A growing number of NKCEs are currently undergoing development, with some already in clinical trials³⁷. NKCEs may have a particularly synergistic activity when combined with EVE16 expressing cells since many NKCEs will bind specifically to the extracellular domain of CD16A. In an embodiment of the invention, the immune cells are contemporaneously or sequentially administered in combination with an antibody preparation or a cell engager preparation that binds to the extracellular domain of CD16A, in order to induce a beneficial ADCC effect. In a further embodiment, the separation between dosing of the immune cells and the antibody preparation or the cell engager preparation is at least 1 hour, 6 hours, 24 hours, 48 hours, 1 week or two weeks. EXAMPLES EXAMPLE 1. Materials and methods. Structural predictions of the EVE16 receptor. Protein fold prediction of various EVE16 variants was performed using ESMFold (MetaAI) and AlphaFold (Alphabet). Images were generated and labeled using PyMOL (Schrodinger). Primary protein structures were generated using Protter (Wollscheid Lab). Plasmid cloning. The psPAX2 plasmid, encoding HIV-1 Gag, Pol, Rev, and Tat, was obtained from NovoPro (catalog number V010353), and the pMD2.G plasmid, encoding the VSV-G envelope, was also sourced from NovoPro (catalog number V010404). Gene encoding BaEV-Rless envelope glycoprotein was designed in-house, codon-optimized for expression in human cell lines, and synthesized as a gene block by Integrated DNA Technologies. The BaEV-Rless gene block was cloned in-house via Gibson assembly (NEBuilder HiFi DNA Assembly, New England Biolabs, catalog number E2621S), replacing the VSV-G open-reading frame in the pMD2.G plasmid. The self-inactivating (SIN) lentiviral transfer plasmid was generated in-house. In this plasmid, lentiviral HIV-1 RNA expression is driven by the CMV enhancer and promoter, while transgene expression is controlled by the EF1α core promoter. The transfer plasmid additionally contains the woodchuck hepatitis virus post-transcriptional regulatory element (WPRE), the bovine growth hormone polyadenylation signal (bGH polyA), and the SV40 origin of replication for proper vector function. All plasmids were transformed and propagated using NEB Stable competent E. coli (New England Biolabs, catalog number C3040H), followed by purification with the PureLink HiPure Plasmid Maxiprep Kit (Thermo Fisher, catalog number K210007). All geneblocks encoding EVE16 variants were codon-optimized, synthesized as gene blocks by IDT and subcloned into 3^rd generation lentiviral transfer plasmid described above. All plasmids underwent analysis by gel electrophoresis to confirm purity and size, followed by sequencing with Oxford Nanopore for whole-plasmid validation. Plasmid concentrations were determined via spectrophotometry by measuring absorbance at 230 nm, 260 nm and 280 nm. Manufacturing and Purification of Lentiviral Particles Using Adherent 293T Cell Line. The 293T human embryonic kidney cell line (ATCC, catalog number CRL-3216) was expanded in high-glucose Dulbecco's Modified Eagle's Medium (DMEM, Gibco, catalog number 11-995-065), supplemented with 1 mM sodium pyruvate, 5 mM l- Glutamine, 10 mM HEPES pH 7.0, 100 U/mL penicillin, 100 µg /mL streptomycin, and 10% (v/v) heat-inactivated fetal bovine serum (complete DMEM). During the expansion phase, cells were grown at 37°C CO2 tissue-culture incubator, and split every 2-3 days, maintaining the maximum confluency of approximately 80%. Cells were not used beyond 30 passages. One day prior to transfection, 10 million 293T cells were seeded per 10 cm tissue-culture plate in 10 mL of complete DMEM. The following morning, cells were transfected using polyethyleneimine (PEI) as a transfection reagent. For each 10 cm plate, the lentiviral transfer plasmid (10 µg), packaging plasmid psPAX2 (8.6 µg), and VSV-G envelope expression pMD2.G plasmid (2.6 µg, depending on the variant) were combined in a 1.5 mL Eppendorf tube, and Opti-MEM (Gibco, catalog number 31985062) was added to a final volume of 0.5 mL. The mixture was thoroughly mixed by pipetting at room temperature. In a separate tube, PEI (at a ratio of 1:1 w/w relative to the total plasmid DNA) was resuspended in 0.5 mL Opti-MEM and incubated at room temperature for 5 minutes. The PEI solution was then added to the DNA mixture, mixed gently, and incubated at room temperature for 15 minutes to allow complex formation. The 1 mL PEI/DNA complex was added dropwise to the cells in the 10 cm plate. After 6 hours, the medium was replaced with 10 mL of fresh, pre-warmed complete DMEM.48 hours post- transfection, the supernatant containing lentiviral particles was harvested and centrifuged at 600xg for 5 minutes to remove cellular debris. The supernatant was then filtered through a 0.45 μm PVDF filter unit (Corning, catalog number 431220). The filtered supernatant containing lentiviral particles was either used immediately for cell transduction or stored at 4°C for up to 24 hours before use. For T cell transduction the supernatant was centrifuged at 4°C for 16 hours at 10,000xg to concentrate the lentiviral particles. After centrifugation, the supernatant was discarded, and the pellet containing lentiviral particles was resuspended in 1 mL of lentiviral vector resuspension buffer (100 mM NaCl, 1% w/v sucrose, 1% w/v mannitol, 20 mM Tris-HCl pH 7.3). The resuspended lentiviral particles were aliquoted, flash-frozen in liquid nitrogen, and stored at -80°C until use. Manufacturing and Purification of Lentiviral Particles Using Suspension 293T Cell Line. The adherent 293T human embryonic kidney cell line (ATCC, catalog number CRL- 3216) was trypsinized, washed once with phosphate-buffered saline (PBS) to remove trypsin, and transferred to FreeStyle 293 Expression Medium (Gibco, catalog number 12- 338-018) supplemented with 100 U/mL penicillin, 100 µg/mL streptomycin, 2% (v/v) heat-inactivated fetal bovine serum, and 33 µM phenol red (complete FreeStyle medium). The cells were adjusted to a density of 0.5×10⁶ cells/mL and expanded in the presence of anti-clumping agent (ACA, used at a 2,000x dilution, Gibco, catalog number 0010057AE) at 37°C in a tissue-culture shaker with 8% CO2 (shaking at 120 revolutions per minute). Cell cultures were expanded until they reached a maximum density of 3×10⁶ cells/mL, at which point they were split into fresh complete FreeStyle medium at 0.5×10⁶ cells/mL and continued to expand with ACA. Viability and media color were monitored every 2-3 days, with media exchanges performed as necessary. Cells were expanded using this protocol for at least one week prior to transfection with PEI. On the day of transfection, cells were counted, centrifuged at 600xg for 5 minutes, washed twice with DPBS to remove residual ACA, resuspended in fresh pre-warmed complete FreeStyle medium without ACA at a density of 1.5×10⁶ cells/mL, and returned to the 37°C shaker. DNA plasmids were mixed at the following molar ratios: 1 mol of psPAX2, 1.2 mol of the transfer plasmid, and 0.5 mol of the BaEV-Rless envelope plasmid, using 1.5 µg of total plasmid DNA per million cells. Opti-MEM was added to the plasmid mixture up to 5% of the total cell suspension volume, and the DNA mixture was resuspended thoroughly. In a separate tube, PEI (at a 1:1 w/w ratio relative to total plasmid DNA) was resuspended in Opti-MEM, also at 5% of the total cell suspension volume, and incubated for 5 minutes at room temperature. The PEI solution was then combined with the DNA mixture, gently mixed, and incubated at room temperature for 10 minutes to allow for complex formation. The cell suspension was removed from the 37°C shaker, and the PEI/DNA complex mixture was added dropwise to the cells. After 16 hours, the cells were centrifuged, and the medium was replaced with an equal volume of fresh, pre-warmed complete FreeStyle medium supplemented with ACA. Forty-eight hours post-transfection, cells were centrifuged, and the supernatant containing lentiviral particles was harvested and stored at 4°C. The cells were resuspended in an equal volume of fresh, pre-warmed complete FreeStyle medium supplemented with ACA. Seventy-two hours post-transfection, the cells were again centrifuged, and the supernatant was collected. Both supernatants were pooled and filtered through a Sartolab 0.45 µm PES filtration unit with diatomaceous earth as a filtration aid (Sartorius). Lentiviral particles were concentrated by centrifugation at 10,000xg for 16 hours at 4°C. After centrifugation, the supernatant was discarded, and the pellet containing lentiviral particles was resuspended in 1 mL of lentiviral vector resuspension buffer (100 mM NaCl, 1% w/v sucrose, 1% w/v mannitol, 20 mM Tris-HCl pH 7.3). The resuspended lentiviral particles were aliquoted, flash-frozen in liquid nitrogen, and stored at -80°C until use. Determination of Lentiviral Particle Infectious Titer using Jurkat Cell Line. The Jurkat cell line (Clone E6-1, ATCC catalog number TIB-152) was cultured in RPMI 1640 Medium (ATCC modification, Gibco catalog number A1049101) supplemented with 100 U/mL penicillin, 100 µg/mL streptomycin, and 10% (v/v) heat-inactivated fetal bovine serum (complete RPMI). During the expansion phase, cells were maintained in a 37°C CO₂ tissue-culture incubator and split every 2-3 days, ensuring a maximum density of approximately 3×10⁶ cells/mL. Cells were not used beyond 30 passages. To determine the infectious titer of lentiviral particles, Jurkat cells were centrifuged at 600xg for 5 minutes and resuspended in fresh, pre-warmed complete RPMI at a density of 1×10⁶ cells/mL. A 2 mL aliquot of the cell suspension (2x10⁶ cells) was transferred to each well of a 6-well tissue-culture plate (Corning catalog number 3516). Various volumes of the lentiviral vector (LVV) particle suspension were added to the wells in a dilution series, typically 5 µL, 1 µL, 0.1 µL, 0.05 µL, and 0.025 µL, with one well left untreated to serve as a negative control. Cells were transduced using spinoculation at 1,000xg for 1 hour at 37°C, after which the plate was returned to the 37°C CO₂ incubator. The following day, 1.5 mL of medium was aspirated from each well and replaced with 1.5 mL of fresh, pre- warmed complete RPMI. Forty-eight hours post-transduction, cells from each well were transferred to a 96-well round-bottom plate, washed once with FACS buffer (Dullbeco’s phosphate-buffered saline supplemented with 5% v/v heat-inactivated fetal bovine serum), and resuspended in 200 µL of FACS buffer containing DAPI. Flow cytometry was used to determine the percentage of transduced Jurkat cells by gating on live singlets and comparing fluorescent cell populations to the negative control. The infectious titer was calculated only for groups where 5-20% of cells were fluorescently positive. The titer was determined by multiplying the percentage of transduced cells by the total starting number of cells (2x10⁶) and dividing by the volume of lentivirus used. Generation and analysis of stably transduced Jurkat cell lines. Jurkat cells (clone E6- 1) were obtained from the American Type Culture Collection (ATCC) and transduced with lentiviral particles harboring various indicated EVE16 variants followed by P2A-eGFP transgene. In the case of EVE16 and CD3zeta co-expression constructs, eGFP was replaced with codon-optimized full-length human CD3zeta cDNA. Seven days after transduction, Jurkat cells were stained with PE anti-human CD16 (clone 3G8, Cell Signaling Technology), APC anti-human CD27 (BD Biosciences) or APC anti-FMC63 (Miltenyi) antibodies. Cells were gated on live, eGFP-expressing singlets, and flow plots were generated using FlowJo analysis software. Binding of CD70 to EVE16-expressing Jurkat cell lines was performed using 1 ug biotin-labeled recombinant CD70 (BPS Bioscience). Cells were incubated with recombinant CD70 for 15 minutes on ice, washed and then stained with APC Streptavidin (BioLegend) and analyzed using flow cytometry. Isolation of NK cells. Fresh whole blood sample (150 mL total volume) was divided into 50 mL tubes and diluted 1:1 (v/v) with Buffer A (Phosphate-Buffered Saline (PBS) supplemented with 2% (v/v) Fetal Bovine Serum (FBS) and 1 unit/mL Heparin, pH 7.4). Peripheral Blood Mononuclear Cells (PBMCs) were separated by centrifugation using a density gradient medium, Lymphoprep (STEMCELL Technologies). Following Lymphoprep separation, PBMCs were resuspended at a density 5x10^7 cells/mL in Buffer B (PBS, 2% FBS, and 1 mM EDTA, pH 7.4). Subsequently, human NK and NKT cells were isolated from PBMCs utilizing the EasySep Human NK Cell Isolation Kit (STEMCELL) and the Easy 50 EasySep Magnet (STEMCELL) according to manufacturer instructions. The isolated cells were then resuspended at a density of 2-3x10^6 cells/mL in complete NK MACS media. The complete NK MACS media composition included NK MACS basal medium (Miltenyi Biotec), 10% Human AB serum (Sigma-Aldrich), 1% NK MACS supplement (part of the NK MACS basal medium kit), 100 μM nicotinamide (Sigma-Aldrich), and 1% Penicillin/Streptomycin (ThermoFisher Scientific). The following antibodies were used to determine the purity of NK cells: Brilliant Violet 605 anti-human CD45 (clone 2D1, BioLegend), FITC anti-human CD3 (clone OKT3, BioLegend), APC anti-human CD19 (clone HIB19, BioLegend) and PE anti-human CD56 (clone QA17A16, BioLegend). Live NK cells were defined as DAPI-, CD45+, CD56+, CD19-, CD3-. Freshly isolated population of human NK cells was resuspended at 2x10⁶ cells/mL in complete NK MACS media and placed in a sterile, tissue culture-treated 6-well polystyrene plate at 2 mL total volume per well. The media was then supplemented with 20 ng/mL IL-12 and 25 ng/mL IL-18 and the plate was placed in a 37°C tissue culture incubator for 6 hours. After 6 hours, the cells were washed three times with PBS to remove the cytokines and then resuspended at 2x10⁶ cells/mL in complete NK MACS media and placed in a fresh, sterile, tissue culture-treated 6-well polystyrene plate at 2 mL total volume per well. The media was then supplemented with 10 ng/mL IL-15 and 50 ng/mL IL-18 and the plate was placed in a 37°C tissue culture incubator for 36 hours. NK cells were transduced with lentiviral particles pseudotyped with BaEV-Rless glycoprotein 48 hours after isolation. NK cell cytotoxicity assay using suspension cell lines. NK cells were purified and stimulated with cytokines, and transduced as described above. OCI-AML3 (acute myeloid leukemia) cell line was obtained from the AcceGen (ABC-TC179D) and transduced with lentiviral particles harboring Luciferase-P2A-mScarlet transgene. Transduced cancer cells were purified using flow cytometry-assisted sorting of mScarlet^hi cells and used in subsequent experiments. For cytotoxicity experiments using OCI-AML3 cell line, 100,000 cancer cells per well were seeded in a 96-well round-bottom plate in complete NK MACS media supplemented with 2 ng/mL IL-15 in 100 μL volume. CIML NK cells were added to each well at indicated effector: target ratio (for 1:1100,000 NK cells, etc.) in a 100 uL volume in complete NK MACS media supplemented with 2 ng/mL IL-15. The plate was centrifuged at 300xg for 1 minute to allow cells to settle to the bottom of the well, and the plate was then placed in a 37°C tissue culture incubator for 16 hours. After 16 hours, the cells were washed twice using Annexin V Buffer (140 mM NaCl, 2.5 mM CaCl2, 10 mM HEPES pH 7.4) and resuspended in 200 μL of Annexin V Buffer supplemented with APC- Annexin V (BioLegend), DAPI, and Precision Count Beads (5,000 beads per well, BioLegend). The percentage of live cancer cells was determined using flow cytometry, live cells defined as DAPI-AnnexinV-mScarlet⁺ single cells, normalized to the number of counting beads per well, and divided by the number of cancer cells incubated without NK cells. Isolation of Human Peripheral Blood Mononuclear Cells (PBMCs) from Whole Blood of Healthy Donors. Fresh whole blood samples from healthy donors were obtained from Research Blood Components (Watertown, MA). The whole blood was diluted 1:1 with Dulbecco's Phosphate-Buffered Saline (DPBS) supplemented with 2% (v/v) heat- inactivated fetal bovine serum (FBS, Gibco). The diluted blood was gently layered over a Lymphoprep medium in SepMate-50 tubes (STEMCELL Technologies) and centrifuged at 1,200xg for 20 minutes at room temperature to isolate peripheral blood mononuclear cells (PBMCs). Following centrifugation, the plasma and PBMC layers were carefully transferred to a fresh 50 mL tube. The cells were pelleted by centrifugation at 600xg for 5 minutes, the supernatant was discarded, and the cell pellet was washed once with DPBS/2% FBS buffer. The cells were centrifuged again and resuspended in 10 mL of pre- warmed complete RPMI medium. The total number of PBMCs was counted using Tuerk’s solution (Sigma-Aldrich, catalog number 1092770100), and a small volume of the PBMC suspension was used for flow cytometry to determine the percentage and viability of T cells, B cells, NK cells, and monocytes. After counting, the cells were pelleted by centrifugation at 600xg for 5 minutes, and the supernatant was discarded. The cell pellet was then resuspended in CryoStor CS10 solution (BioLife Solutions, catalog number 210502) at a concentration of 50 million PBMCs per mL. The cell suspension was aliquoted into cryovials, frozen in a controlled-rate freezer, and stored in a liquid nitrogen container until further use. For flow cytometry, the following antibodies were used: Brilliant Violet 605 anti-human CD45 (clone 2D1, BioLegend), FITC anti-human CD3 (clone OKT3, BioLegend), APC anti-human CD19 (clone HIB19, BioLegend), PE/Cyanine7 anti-human CD14 (clone S18004B, BioLegend), APC anti-human CD45RA (clone HI100, BioLegend) and PE anti-human CD56 (clone QA17A16, BioLegend). DAPI stain (4′,6-diamidino-2-phenylindole, Thermo Fisher, catalog number D1306) was used to evaluate cell viability. Prior to antibody staining, Fc receptors were blocked using Human TruStain FcX (BioLegend, catalog number 422301). Isolation, Activation and Transduction of T cells from healthy donors Frozen peripheral blood mononuclear cells (PBMCs) stored in cryovials were thawed by placing the cryovial in a 37°C water bath for 2 minutes. The cell suspension was then transferred to a clean centrifuge tube, diluted 1:10 with pre-warmed complete RPMI, and centrifuged at 600xg for 5 minutes at room temperature. After centrifugation, the supernatant was completely aspirated, and the cell pellet was resuspended in 5 mL of complete RPMI. Viable cells were counted at this stage. To isolate T cells, CD3 MicroBeads and the MultiMACS Cell24 Separator (Miltenyi Biotec) were used. The PBMCs were centrifuged again at 600xg for 5 minutes and resuspended at a concentration of 100×10⁶ cells/mL in cold Wash Buffer (Dulbecco’s phosphate-buffered saline without calcium and magnesium, pH 7.2, supplemented with 2 mM EDTA and 2% (v/v) heat- inactivated fetal bovine serum). CD3 MicroBeads (200 µL per 100×10⁶ cells) were added to the suspension, mixed thoroughly, and incubated in the cold room for 15 minutes. After incubation, the cells were washed twice with cold Wash Buffer and resuspended at 100×10⁶ cells/mL. The suspension was applied to a pre-equilibrated LS column (Miltenyi Biotec) using 1 LS column per 100×10⁶ cells. The column was washed with 15 mL of cold Wash Buffer, and the CD3+ T cells were eluted and washed off the column with additional Wash Buffer. The eluted cells were centrifuged at 600xg for 5 minutes and resuspended in complete TexMACS medium (Miltenyi Biotec, catalog number 130-097-196) supplemented with 100 U/mL penicillin, 100 µg/mL streptomycin, 10% (v/v) heat- inactivated human male AB serum, 5 mM l-Arginine, 10 ng/mL IL-7, and 10 ng/mL IL-15 at a concentration of 1×10⁶ cells/mL. The purity and viability of the isolated T cells were assessed using flow cytometry. Isolated T cells were resuspended at a density of 1 × 10⁶ cells/mL in complete TexMACS medium and seeded into sterile 6-well plates at 2 mL per well. Cells were stimulated with CD3/CD28 agonist polymer (TransAct, Miltenyi Biotec, catalog #130-128-758) at a final concentration of 10 µL/mL and incubated at 37°C for 48 hours. Following activation, T cells were harvested by centrifugation, washed once with DPBS, and resuspended in fresh TexMACS medium at 1 × 10⁶ cells/mL. For transduction, purified VSV-G pseudotyped lentiviral vector was added to each well at a multiplicity of infection (MOI) of 10, together with Vectofusin. The cells were then spinoculated by centrifugation at 1,000×g for 1 hour at 37°C. After spinfection, cells were returned to a tissue culture incubator, and the culture medium was replaced with fresh TexMACS every 24 hours. At 72 hours post-transduction, transduction efficiency was assessed by flow cytometry. Transduced T cells were collected by centrifugation, resuspended in CryoStor10, and cryopreserved until further use. T Cell Cytotoxicity Using Raji Cell Line. T cells were purified, activated, and transduced as described above. Raji (Burkitt’s lymphoma) cell line was obtained from the American Tissue Culture Collection (CCL-86) and maintained in complete RPMI. Raji cells were transduced with lentiviral particles harboring Luciferase-P2A-mScarlet transgene. Transduced cancer cells were purified using flow cytometry-assisted sorting of mScarlet^hi cells and used in subsequent experiments. For cytotoxicity experiments using Raji cell line, 100,000 cancer cells per well were seeded in a 96-well round-bottom plate in complete RPMI media in 100 μL volume. T cells were added to each well at indicated effector-to- target ratio (for 1:1100,000 T cells, etc.) in a 100 uL volume in complete RPMI media. The plate was centrifuged at 300xg for 1 minute to allow cells to settle to the bottom of the well, and the plate was then placed in a 37°C tissue culture incubator for 16 hours. After 16 hours, the cells were washed twice using Annexin V Buffer (140 mM NaCl, 2.5 mM CaCl2, 10 mM HEPES pH 7.4) and resuspended in 200 μL of Annexin V Buffer supplemented with APC-AnnexinV (BioLegend), FITC-anti-human CD19 (HIB19, BioLegend), DAPI, and Precision Count Beads (5,000 beads per well, BioLegend). The percentage of live cancer cells was determined using flow cytometry, live cells defined as DAPI-AnnexinV-mScarlet⁺ single cells, normalized to the number of counting beads per well, and divided by the number of cancer cells incubated without T cells. T Cell In Vivo Activity. All mouse experiments were conducted in compliance with institutional guidelines and approved IACUC protocols. Human T cells used in these studies were prepared as described above. Male NOD.Cg-Prkdc^scidIl2rg^tm1Wjl/SzJ (NSG) mice, aged 6–12 weeks, were obtained from The Jackson Laboratory and used in all experiments. On Day 0, mice were intravenously (i.v.) injected with 1 × 10⁶ Raji cells expressing a Luciferase-P2A-mScarlet transgene, suspended in USP-grade PBS. Where indicated, mice received intraperitoneal (i.p.) injections of human recombinant IL-2 (50,000 IU/injection) every 3 days. On Day 5, mice were administered 3 × 10⁶ T cells via i.v. injection. Mice were monitored every 3 days for body weight and body condition (BC) scores. Where indicated, peripheral blood was collected via submandibular vein puncture for analysis of T cell persistence. A volume of 100 μL blood was collected, red blood cells were lysed, and the remaining leukocytes were stained for surface antigen expression. Bioluminescent imaging was performed weekly using the IVIS system following intraperitoneal injection of luciferin. At experimental endpoint, mice were euthanized, and cardiac blood, spleen, and bone marrow were harvested and processed. Samples were stained with the following antibodies: Brilliant Violet 605 anti-human CD45 (BioLegend), APC anti-human CD3 (BioLegend), and PE anti-human CD56 (BioLegend), and analyzed on an Attune NxT Flow Cytometer (Thermo Fisher Scientific). Flow cytometry data were processed using FlowJo Software (BD Biosciences). Immunophenotyping. For cell surface antibody staining of NK and T cells, 50,000- 100,000 cells were washed and resuspended in 200 μL of FACS buffer (PBS supplemented with 2% FBS).5 μL of Human TruStain (BioLegend) was added to the sample and incubated for 5 min at room temperature to block non-specific binding of IgG antibodies. Cells were incubated with antibodies (2 μL each) on ice for 15-20 minutes, washed twice with 1 mL of FACS buffer, and after the final wash resuspended with 200 μL of FACS buffer supplemented with DAPI (1 µg/mL) and placed on ice before flow cytometry analysis. The Flow Cytometry data was analyzed using Flow-Jo software (BD Biosciences). The following antibodies were used to determine the purity of NK and T cells: Brilliant Violet 605 anti-human CD45 (clone 2D1, BioLegend), FITC anti-human CD3 (clone OKT3, BioLegend), APC anti-human CD19 (clone HIB19, BioLegend), PE anti-human CD56 (clone QA17A16, BioLegend), Brilliant Violet 605 anti-human CD4 (clone SK3, BioLegend), and APC anti-human CD8 (clone SK1, BioLegend). Live NK cells were defined as DAPI-, CD45⁺, CD56⁺, CD19-, CD3- and live T cells were defined as DAPI-, CD45⁺, CD56-, CD19-, CD3⁺. The following antibodies were used for the analysis of NK and T cell phenotype: FITC anti-human CD25 (clone BC96, Biolegend), PE anti-human CD71 (clone CY1G4, Biolegend), FITC anti-human NKp46 (clone 9E2, Biolegend), PE anti-human CD16 (clone 3G8, Cell Signaling Technology), FITC anti-human CD70 (clone 113-16, Biolegend), PE anti-human NKG2D (clone 1D11, Biolegend), APC anti-human CD94 (clone DX22, Biolegend), Brilliant Violet 605 anti-human 4-1BB (clone 4B4-1, Biolegend), APC anti- human CD69 (clone FN50, Biolegend), PE anti-human NKG2C (clone S19005E, Biolegend), APC anti-human NKp44 (clone P44-8, Biolegend), APC anti-human TRAIL (clone RIK-2, Biolegend). For the analysis NK and T cell viability, cells were washed twice with Annexin V Buffer (10 mM HEPES-NaOH pH 7.4, 140 mM NaCl, 2.5 mM CaCl₂), and resuspended with 200 μL Annexin V Buffer supplemented with APC Annexin V (2 μL, BioLegend) and DAPI. Live cells were defined as Annexin V-, DAPI-. EXAMPLE 2. Schematic of CD16A, CAR and EVE16 receptors. CD16A (also known as CD16-II, low affinity immunoglobulin gamma Fc region receptor III-A, IgG Fc receptor III-A, FcγRIIIa, and FcR-10) is an activating receptor expressed on the surface of NK cells, NKT cells, monocytes, macrophages, neutrophils, and certain T cell subsets. The extracellular domain consists of a membrane proximal hinge domain and membrane distal FC-binding domain, the latter composed of two Ig-like domains (Figure 1B and Figure 2C). The FC-binding domain is responsible for binding to the Fc chain of IgG1, IgG3 and IgG4 antibodies. CD16A interacts with disulfide-linked homodimers or heterodimers of CD3zeta and/or the gamma subunit of the high-affinity IgE receptor (FCER1G), via specific transmembrane interactions. The activation of the receptor (via IgG1, IgG3 and IgG4-mediated crosslinking) follows the classical ITAM-signaling cascade. The antibody binding affinity of CD16A determines the strength of the cellular response. Human population possesses two major CD16A polymorphisms, with the V176 allotype exhibiting a higher affinity for antibodies compared to the F176 allotype. Like chimeric antigen receptors (CARs), Engineered Valency-Enhanced CD16A (EVE16) receptors are artificial receptors that can be used to redirect and stimulate immune cells in an antigen-specific manner. EVE16 receptors are designed by modifying the CD16A (F176V) molecule and provide several benefits over traditional CAR designs (Figure 1A- B and Figure 2G). Notably, the receptor consists of an extracellular target-binding domain (e.g. single-chain fragment variable, peptide ligand or other alternative moieties) fused to the CD16A molecule via a flexible linker domain. This composition allows for the simultaneous recognition of two antigens via the fused single-chain fragment variable as well as the FC-binding domain. Unlike CAR, EVE16 receptors do not need to include the intracellular activation domain, as the recognition of target antigen results in signal transduction via the CD16A transmembrane region associated with CD3zeta or FCER1G chains (Figure 1A). EXAMPLE 3. Optimizing the extracellular domain of EVE16 receptor improves its surface expression and signaling capacity. To dissect the role of the linker domain on EVE16 surface expression and function, we generated a series of EVE16 receptors with various linker domains (Figure 3A). The effect of modifications was systematically analyzed by measuring EVE16 receptor expression on the surface of Jurkat cells as well as in cytokine-induced memory-like Natural Killer (CIML NK) cells. To target CD70, a series of EVE16 constructs was designed by fusing the CD16A ectodomain with the CD70-binding ectodomain domain of the CD27 molecule (Figure 2E). This was achieved either by direct fusion or via the incorporation of a CD8A hinge and/or GGGS linker (Fig 3A). Although CD16A expression was detectable, fusing CD27 to the CD16A molecule without the linker domain rendered CD27 expression to be undetectable. (Figure 3A-B, linkerless construct). This result prompted us to investigate the structural characteristics of this EVE16 variant. One defining structural trait of the Fc receptors is their unusually sharp angle between the Ig-like domains (Figure 2C). Consequently, this leads to a highly inflexible, inverted V-shaped arrangement that could hinder the ideal folding of the CD27 fused structure (Figure 2G). To improve flexibility and aid protein folding we next introduced a G4S linker between the CD27 and CD16A ectodomains. The inclusion of G4S linker marginally improved the surface expression of the EVE16 receptor (Figure 3A-B, construct G4S-GMRTEDL). To further stabilize the linker domain, a CD8A stalk domain was introduced between the G4S linker and CD27 ectodomain. Surprisingly, the introduction of the CD8A linker domain into the construct led to a reduction in surface expression of EVE16, as seen by the very dim expression of both CD16A and CD27 (Figure 3A-B, construct CD8A-G4SGMRTED). The CD8A stalk domain contains two cysteine residues that are prone to intermolecular disulfide bond formation (Figure 2F). Modelling the structure of the CD8A-G4S linker containing EVE16 receptor demonstrated an unfavorable steric configuration of the CD8A molecule in the vicinity of CD16A extracellular stalk, resulting in steric hindrance and epitope masking of recognition domains. In an effort to rescue the surface expression of correctly folded EVE16, the cysteine containing hinge region was removed from the EVE16 molecule. Figure 3A and B show that the removal of cysteine containing region from the construct rescued and significantly improved the surface expression of properly folded EVE16 (ΔCD8α hinge- G4S-GMRTEDL linker domain). To further optimize the surface expression of the EVE16 receptor, we sought to remove any possible proteolytic cleavage site from the CD16A molecule. The CD16A preprotein contains a 16-amino acid long signal peptide/leader peptide at its N-terminus (Figure 2C- D). To map out the exact position of the signal peptidase cleavage site SignalP prediction methodology was used (Figure 2D). The analysis revealed that the signal peptidase recognition site overlapped with the GMRTEDL sequence, which was situated just after the 16 amino acid long leader sequence. To eliminate the residual cleavage motif from the mature protein, we removed the GMRTEDL cleavage site from the deltaCD8-G4S variant. Eliminating the signal peptidase recognition site from the constructs did not result in any additional improvement or reduction of the receptor surface expression, hence we designed a new library of linker domains that lacks the GMRTEDL peptidase cleavage site (Figures 5 and 6). In order to determine if the increase in receptor surface expression seen in Jurkat cells can be reproduced in cytokine-induced memory-like NK cells (CIML NK), we compared the levels of expression for G4S and the deltaCD8-G4S EVE16 constructs. FACS analysis confirmed that the surface expression of the EVE16 receptor was greatly improved when the G4S flexible linker and deltaCD8A hinge were both present, similar to the results observed in Jurkat cells (Figure 4A). To test if the improved surface expression enhances effector functions, in vitro cytotoxicity assays were performed. CD70-targeting EVE16 receptors were transduced into CIML NK cells, and co-cultured with CD70-expressing OCI-AML3 acute myeloid leukaemia cells and the percentage of tumor cell lysis was determined using flow cytometry. CIML NK cells transduced with the deltaCD8-G4S EVE16 construct demonstrated marginally improved cellular cytotoxicity compared to cells transduced with G4S EVE16 (Figure 4B). EXAMPLE 4. The Fc-binding domain is necessary for the surface expression of EVE16. To test whether the intact extracellular domain of CD16A is necessary for optimal surface expression of the retargeting construct, a series of molecules were generated (Figure 8). First, a prototypic Engineered Valency-Enhanced CD16A receptor (EVE16) was designed by N-terminally fusing the anti-CD19 (FMC63) single-chain variable fragment (scFv) with the enhanced binding affinity (F176V) variant CD16A molecule via an NKp44-derived linker. Next, using the prototype construct a series of deletion mutants were generated, in which either one or both Ig-like domains were removed from the EVE16 molecule. To assess the impact of extracellular domains on the surface expression of EVE16 variants, Jurkat cells were transduced with the relevant constructs. The surface expression was then measured using flow cytometry 7-days post-transfection. FACS analysis revealed that the presence of both Ig-like domains was necessary for the surface expression of EVE16 receptors. This finding contradicts prevailing assumptions in the field, which suggest that, in the presence of CD3zeta, the transmembrane domain alone of EVE16 should be necessary and sufficient for its surface expression. Our investigation reveals that both the transmembrane and F_C-binding domains are essential for the EVE16 surface expression. EXAMPLE 5. EVE16 receptor can be redirected to an antigen of choice and can be utilized as a payload delivery molecule. To confirm the capability of the EVE16 receptor to support the expression of diverse payloads, the CD27 ectodomain was interchanged with various single-chain variable fragments (e.g. anti-CD19 (FMC63), anti-CD20 (derived from Rituximab), anti-CD22 scFv (derived from Pinatuzumab) or anti-CD70 (derived from Cusatuzumab). We demonstrate that constructs bearing different scFv’s can be expressed in EVE16 receptor format on the surface of primary human T cells, and can activate T cells robustly when co- cultured with CD19, CD20, CD22 and CD70-expressing Raji cells (Figure 11) EXAMPLE 6. Linker domain length and presence of G4S sequence determine the surface expression of EVE16 receptor. With the understanding that both a flexible G4S linker and a longer stalk domain play an essential role in the surface expression of the EVE16 receptor, we aimed to determine if alternative, more flexible stalk domains could be utilized to further improve EVE16 expression levels. Overcoming steric hindrance and enhancing access to the target antigen on cell surfaces requires careful optimization of hinge length and flexibility. The use of hinge domains derived from CD28, CD8, or IgG molecules is widespread in the chimeric antigen receptor field. The rigidity of these hinges can vary greatly, from highly rigid (e.g. CD28 stalk) to highly flexible (CH3-CH2 domain from IgG) structures. Proline is the most rigid of the 20 naturally occurring amino acids and is frequently introduced to rigidify flexible regions of protein to enhance thermostability. Analysis of the CD8A hinge revealed a relatively high (~ 16%) proline content, hence we sought to screen for linkers with low proline content that were similar to or longer than the truncated CD8A stem utilized in the previous experiments (Figure 5A-B). The stalk domain of both natural killer receptors (NKR) and killer immunoglobulin (KIR) receptors is characterized by its flexibility and lack of defined secondary structure. To test the effect of hinge domain on the surface expression of EVE16, eight novel constructs were generated utilizing the stalk domain of CD8B, CD27, NKp44, NKp46, KIR2DS1, KIR3DS1 receptors (Figure 5A). Jurkat cells were transduced with the newly designed constructs and surface expression was compared to the stalkless (G4S linker containing only) and truncated CD8A containing EVE16 receptor variants. All EVE16 receptors with flexible, long linkers demonstrated a significantly higher level of surface expression, according to FACS analysis (Figure 6A). In terms of CD27 and CD16A mean fluorescence, the NKp44 receptor variant with a longer stalk outperformed all the other evaluated constructs (Figure 6A-B). The effect of the elevated surface expression of the EVE16 receptor on target antigen binding was examined by staining Jurkat cells with biotin-labeled recombinant human CD70 protein. The data presented in Figure 6C indicate a clear link between the expression levels of the EVE16 receptor and the binding of the target antigen, as determined by FACS analysis. In order to determine the impact of EVE16 linker variants on the cytotoxic activity, CIML NK cells were transduced with deltaCD8A and NKp44 (long) stalk containing EVE16 receptors. FACS analysis of transduced cells revealed comparable transduction efficiencies (Figure 7). Following transduction, effector cells were co-incubated with OCI-AML3 target cells and cytotoxicity was evaluated using flow cytometry. In general, the functional activity was in line with the linker length, as NKp44 stalk-containing EVE16 receptor variant modified CIML NK cells demonstrated higher levels of cytotoxicity at various effector to target ratios, (Figure 7). EXAMPLE 7. The incorporation of co-stimulatory domains can further improve EVE16 receptor-mediated effector activation and cytotoxicity in vitro. Restricted expansion and survival of T cells are key factors behind the limited efficacy of CAR-modified T cells. The inclusion of co-stimulatory molecules in the CAR designs has resulted in improved efficiency, proliferation, and durability of the cells, as exemplified by the presence of CD28 and 4-1BB costimulatory domain in second-generation CARs. Historically, co-stimulatory molecules have been included in the receptor design, typically positioned between the transmembrane and CD3zeta activation domains, as illustrated in Figure 1. Novel, alternative designs segregate the target recognition and intracellular signaling domains (such as those in split CAR designs) or include additional co- stimulatory domains in the form of chimeric co-stimulatory receptors (CCR). The EVE16 receptor design enables the easy, plug and play integration of single or tandem co-stimulatory molecules, which are fused directly to the N-terminal cytoplasmic tail of the CD16A receptor. In order to enhance the cytotoxicity, proliferation, and survival of modified immune cells, a set of EVE16 receptors with co-stimulatory domains were developed. Additionally, the impact of combining CD3zeta fusion in tandem was examined. To this end, CIML NK cells were transduced with the respective co-stimulatory domain containing CD70-targeting EVE16 receptor. Receptor surface expression, short term (6 h) and overnight cytotoxicity were evaluated using OCI-AML3 target cells. Figure 9A-C shows that the incorporation of co-stimulatory molecules does not have a detrimental effect on EVE16 surface expression in CIML NK cells. In the majority of the tested molecules, in vitro cytotoxicity evaluation revealed marginally increased cytolytic function of co-stimulatory receptor containing EVE16 modified CIML NK cells, however the incorporation of 2B4 and 4-1BB co-stimulatory domains revealed significant enhancement of CD27-EVE16 mediated cytotoxicity. To further assess the influence of various co-stimulatory cytoplasmic domains on EVE16- mediated T cell activation, primary human CD3⁺ T cells were transduced with FMC63- based EVE16 constructs incorporating one of the following intracellular signaling domains: OX40, 4-1BB, 4-1BB-CD3ζ, or 4-1BB-DAP10. Surface expression of all EVE16 variants was confirmed by flow cytometry (Figure 9D). Functional activity was evaluated using an overnight cytotoxicity assay against Raji cells. While all EVE16 variants induced greater T cell activation compared to the untransduced control, only the OX40-containing variant achieved activation levels comparable to the conventional FMC63-CAR (Figure 9D). To determine the in vivo efficacy of EVE16 constructs, NSG mice were inoculated with Raji cells and treated five days later with T cells transduced with either FMC63-CAR or EVE16 variants containing OX40 or 4-1BB-DAP10 cytoplasmic domains. All groups receiving engineered T cells demonstrated tumor control; however, the FMC63-EVE16- OX40 variant exhibited the most potent antitumor activity among EVE16-transduced groups (Figure 9E). Subsequently, anti-CD20 EVE16 variants were tested in a similar in vivo model. T cells expressing EVE16 constructs with cytoplasmic domains derived from OX40, CD28, or a CD28-OX40 tandem configuration were administered to NSG mice previously inoculated with Raji cells (Figure 9F). All constructs conferred measurable antitumor activity, with the strongest effects observed in T cells expressing either the OX40 or CD28-OX40 signaling domains. EXAMPLE 8. Co-expression of CD3zeta enhances the surface expression of the EVE16 receptor. CD16A surface expression is contingent upon its interaction with signaling adaptor molecules including CD3zeta and/or FCER1G. The incorporation of the homo or heterodimeric signaling adaptors is a rate limiting step for the assembly and surface expression of functional CD16A receptor. Given that CD3zeta expression is stable within the cell, and it competes with multiple other receptor complexes such as TCR, NKp30, and NKp46, we hypothesized that the presence of EVE16 on the cell surface may rely on the availability of CD3zeta. By employing a bis-cistronic construct, EVE16 was co-expressed with or without CD3zeta in Jurkat cells (Figure 10). Analysis of the surface expression was performed by staining the cells with fluorochrome-conjugated anti-CD16 antibody and using flow cytometry. Consistent with our hypothesis that CD3zeta is rate-limiting for the surface expression of EVE16 receptors, Figure 10 shows that the over-expression of CD3zeta led to a significant increase in EVE16 surface expression, as indicated by higher mean fluorescent intensity of CD16A. EXAMPLE 9. Optimization of Leader Peptide and scFv Orientation Enhances Surface Expression of EVE16 Previous results demonstrated that the linker and cytoplasmic domains of EVE16 critically influence its surface expression and functional activity in human T and NK cells. To further enhance the surface expression of EVE16, we next focused on optimizing the leader peptide and scFv orientation using an anti-CD20-EVE16 model system (Figure 12A). A library of twelve leader peptides was constructed, each derived from human Type I transmembrane or secreted proteins highly expressed in immune or other relevant cell types. These leader peptides were paired with four anti-CD20 scFvs derived from Rituximab, Ofatumumab, Ocrelizumab, and Ublituximab. Each scFv was expressed in both VL–VH and VH–VL orientations, resulting in a total of 96 unique EVE16 constructs. The EVE16 variants were cloned into a lentiviral expression vector co-expressing full- length human CD3ζ under a bicistronic system using P2A self-cleaving peptide. The EVE16 library was first evaluated in HEK 293T cells following transient transfection (Figure 12B). Surface expression was assessed by flow cytometry using antibodies specific for CD16 and the G4S linker (for scFv detection). The analysis showed that both leader peptide identity and scFv orientation significantly influenced surface expression levels. To validate these findings in a more physiologically relevant context, the same EVE16 library was transduced into Jurkat T cells and analyzed by flow cytometry (Figure 12C). Surface expression was assessed using anti-CD16, anti-G4S linker antibodies, and a virus- like particle displaying a CD20-GFP fusion protein. Consistent with the results in 293T cells, both leader peptide and scFv orientation had a significant impact on EVE16 expression and CD20 binding. To determine whether these findings translated to primary human T cells, we selected two anti-CD20 EVE16 variants—both derived from Rituximab scFv—with either the CD8A or NKp44 leader peptide, and with distinct VL–VH or VH–VL orientations, as indicated in Figure 12D. These were compared to a conventional anti-CD20 CAR. Transduced CD3⁺ T cells were evaluated for surface expression by flow cytometry and tested for cytotoxic activity in an overnight killing assay against Raji target cells. 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Claims

CLAIMS 1. A modified immune cell receptor protein comprising: - a target-binding domain, - the extracellular domain of CD16A, wherein the extracellular domain comprises the F_C-binding domain and the hinge domain of CD16A, and - a transmembrane domain, wherein the modified immune cell receptor protein also comprises a flexible linker positioned between the target-binding domain and the extracellular domain of CD16A, wherein the linker is at least 10 amino acids in length.

2. The protein of claim 1, wherein the linker comprises no more than 1 Cysteine residue.

3. The protein of claim 1 or claim 2, wherein the linker comprises no more than 30% Proline residues.

4. The protein of any one of the preceding claims wherein the linker comprises at least 5% Serine and/or Glycine residues.

5. The protein of any one of the preceding claims, wherein the linker is at least 11, 12, 13, 14, 15, 16, 17, 19 or 20 amino acids in length.

6 The protein of any one of the preceding claims, wherein the linker is no more than 70 amino acids in length.

7. The protein of any one of the preceding claims, wherein the linker comprises an amino acid sequence derived from the hinge domain of NKp44, NKp46, CD8α, CD8β, KIR2DS1, KIR3DS1 or CD27.

8. The protein of any one of the preceding claims, wherein the linker comprises the amino acid sequence of any one of SEQ ID NOs: 30 to 44, 104 and 105, or sequence variants thereof wherein the linker sequence variant: (a) is at least 10 amino acids in length, comprises no more than 1 Cysteine residue, no more than 30% Proline residues and at least 5% Serine and/or Glycine residues; and (b) has at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% sequence identity to any one of SEQ ID NOs: 30 to 44, 104 and 105.

9. The protein of claim 8, wherein the linker comprises the amino acid sequence of any one of SEQ ID NOs: 37 to 44 and 105, or sequence variants thereof wherein the linker sequence variant: (a) is at least 10 amino acids in length, comprises no more than 1 Cysteine residue, no more than 30% Proline residues and at least 5% Serine and/or Glycine residues; and (b) has at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% sequence identity to any one of SEQ ID NOs: 37 to 44, 104 and 105.

10. The protein of any one of the preceding claims, further comprising a cytoplasmic domain.

11. The protein of claim 10, wherein the cytoplasmic domain is derived from CD16A.

12. The protein of claim 10 or claim 11, wherein the cytoplasmic domain comprises the cytoplasmic domain of CD16A as set out in SEQ ID NO: 53, or a variant thereof that has least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 53 and retains the functionality of the cytoplasmic domain of CD16A.

13. The protein of any one of claims 10 to 12, wherein the cytoplasmic domain comprises a cytoplasmic domain from a protein other than CD16A in a position C-terminal to the transmembrane domain.

14. The protein of any one of claims 10 to 13, wherein the cytoplasmic domain comprises a co-stimulatory signaling domain derived from CD3ζ.

15. The protein of claim 14, wherein the cytoplasmic domain comprises the amino acid sequence of SEQ ID NO: 54, or variants thereof that have at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 54 and retain the functionality of the CD3ζ co-stimulatory signaling domain.

16. The protein of any one of claims 10 to 15, wherein the cytoplasmic domain comprises a co-stimulatory signaling domain derived from the cytoplasmic domain of one or more of CD3ζ, FcεRI, CD28, 4-1BB, DAP10, OX40 and 2B4.

17. The protein of claim 16, wherein the cytoplasmic domain comprises the amino acid sequence of any one of SEQ ID NOs: 54, 66, 59, 63, 64, 70 and 72, or variants thereof that have at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% sequence identity to any one of SEQ ID NOs: 54, 66, 59, 63, 64, 70 and 72 and retain the functionality of the corresponding co-stimulatory signaling domain as set out in any one of SEQ ID NOs: 54, 66, 59, 63, 64, 70 and 72.

18. The protein of claim 16, wherein the cytoplasmic domain comprises one or more of the following co-stimulatory signaling domain combinations: 4-1BB and CD3ζ, 4-1BB and CD28, OX40 and CD28, 4-1BB and DAP10, or OX40 and DAP10.

19. The protein of any one of the preceding claims, wherein the extracellular domain comprises the amino acid sequence of SEQ ID NO:46, or a variant thereof that retains the functionality of the CD16A extracellular domain that has at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% sequence identity to the sequence of SEQ ID NO: 46.

20. The protein of claim 19, wherein the extracellular domain comprises an extracellular domain of CD16A containing the F176V mutation.

21. The protein of any one of the preceding claims, wherein the transmembrane domain is derived from CD16A, CD8A or CD28.

22. The protein of any one of the preceding claims, wherein the transmembrane domain comprises SEQ ID NO: 52, or a variant thereof that maintains the activity of the transmembrane domain of CD16A that has at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 52.

23. The protein of any one of the preceding claims, wherein the target-binding domain is a single-chain fragment variable (scFv).

24. The protein of claim 23, wherein the scFv comprises the 3 CDR sequences found within SEQ ID NO: 26 and the 3 CDR sequences found within SEQ ID NO: 27.

25. The protein of claim 23, wherein the scFv comprises the 3 CDR sequences found within SEQ ID NO: 28 and the 3 CDR sequences found within SEQ ID NO: 29. 26. The protein of claim 23, wherein the scFv comprises any one of SEQ ID NOs: 1 to 24,

26 to 29, and 106 to 121.

27. The protein of any one of claim 1 to 22, wherein the target-binding domain is a naturally occurring ligand.

28. The protein of claim 27, wherein the target-binding domain comprises CD27.

29. The protein of claim 28, wherein the target-binding domain comprises the sequence of SEQ ID NO: 25, or a variant thereof that retains the functionality of the CD27 ectodomain that has at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the sequence of SEQ ID NO: 25.

30. The protein of any one of any one of the preceding claims, wherein the target- binding domain binds to a cancer antigen, B-cell antigen, T-cell antigen or a ligand or receptor on a T cell.

31. The protein of claim 30, wherein the target-binding domain binds to a cancer antigen selected from EGFR, CD19, CD20, CD22, NKG2D ligands, CS1, CD138, EpCAM, EBNA3C, GPA7, CD244, CA-125, MUC-1, ETA, MAGE, CAGE, BAGE, HAGE, LAGE, PAGE, NY-SEO-1, GAGE, CEA, CD52, CD30, MUC5AC, c-Met, FAB, WT-1, PSMA, NY-ESO1, AFP, CSPG-4, IGF1-R, Flt-3, CD276, CD123, CD133, PD-L1, BCMA, GPRC5D, 41BB, CTAG1B, CD33, CD44v7/8, CD138, CD244, CEA, Csl, EBNA3C, EGP-2, EGP-40, E CAM, erb-B2, erb-B 2,3,4, FBP, GD2, GD3, GPA7, Her2, Her2/neu, IL-13R-a2, KDR, k-light chain, LeY, L1 cell adhesion molecule, MAGE-A1, Mesothelin, oncofetal antigen hST4, PSCA, TAG-72, claudin18.2, as well as tumor neoantigens such as EGFRvIII, TA-MUC1, TMPRSS2-ERG, MYB-NFIB, FGFR3- TACC3, EML4-ALK, CCDC6-RET, BCR-ABL, SYT-SSX1/SSX2, PAX3-FOXO1, TPM3/TPM4-ALK and EWS-FLI1.

32. The protein of claim 30, wherein the target-binding domain binds to a B-cell antigen selected from Siglec-10, LILRB/PIR-B, CD31, FcyRIIIB, CD19, CD20, CD22, CD25, CD32, CD40, CD47, CD52, CD80, CD86, CD267, CD268, CD268, IgM, IgD, IgG, IgA and IgE.

33. The protein of claim 30, wherein the target-binding domain binds to a T-cell antigen selected from CD43, CD44, CD45, LFAI, CD4, CD8, CD3, LAT, CD27, CD96, CD28, TIGIT, ICOS, BTLA, HVEM, 4-1BB, OX40, DR3, GITR, CD30, SLAM, CD2, 2B4, TIM I, TIM2, TIM3, CD226, CD160, LAG3, LAIRI, CD112R, CTLA-4, PD-I, PD- LI or PD-L2.

34. The protein of claim 30, wherein the target-binding domain binds to a receptor on a T cell, such as a the αβ T-cell receptor or γδ T-cell receptor.

35. The protein of any one of the preceding claims, also comprising a leader peptide.

36. The protein of claim 35, wherein the leader peptide comprises any one of SEQ ID NOs: 87 to 99 and 122 to 129.

37. A nucleic acid encoding the protein of any one of claims 1 to 36.

38. The nucleic acid of claim 37, which is a bi-cistronic construct further comprising a nucleic acid protein encoding CD3ζ.

39. A vector comprising the nucleic acid of claim 37 or claim 38.

40. The vector of claim 39, which is a viral vector.

41. An isolated host cell comprising the protein of any one of claims 1 to 36, the nucleic acid of claim 37 or claim 38, or the vector of claim 39 or claim 40.

42. An immune cell or population of immune cells comprising the protein of any one of claims 1 to 36, the nucleic acid of claim 37 or claim 38, or the vector of claim 39 or claim 40.

43. The immune cell or population of immune cells of claim 42, wherein the cell or cells also comprise an exogenous nucleic acid encoding CD3ζ.

44. The immune cell or population of immune cells of claim 43, wherein the exogenous nucleic acid encoding CD3ζ is part of a bi-cistronic nucleic acid construct comprising the nucleic acid of claim 37.

45. The immune cell or population of immune cells of any one of claims 42 to 44, wherein the immune cell(s) express signaling adaptor proteins CD3ζ and/or Fc Fragment of IgE Receptor Ig (FCER1G).

46. The immune cell or population of immune cells of any one of claims 41 to 45, wherein the cell(s) is/are NK cell(s), NKT, T cells, naïve T (TN) cells, stem cell-like memory T (T_SCM) cells, monocytes, macrophages, DC(s) or iPSC-derived cell(s).

47. The immune cell or population of immune cells of claim 46, wherein the cell(s) is/are cytokine-induced memory-mike (CIML) NK cell(s).

48. The immune cell or population of immune cells of claim 46, wherein the cell(s) is/are T cell(s).

49. The immune cell or population of immune cells of claim 48, wherein the T cell(s) is/are naïve T(TN) cells or stem cell-like memory T (TSCM) cells.

50. The immune cell or population of immune cells of claim 46, wherein the cell(s) is a/are monocyte(s).

51. The immune cell or population of immune cells of claim 46, wherein the cell(s) is a/are macrophage(s).

52. The immune cell or population of immune cells of claim 46, wherein the cell(s) is a/are NKT cell(s).

53. The immune cell or population of immune cells of claim 46, wherein the cell(s) is a/are Dendritic cells (DCs).

54. The immune cell or population of immune cells of any one of claims 42 to 49, wherein the population of immune cells comprises both NK cells and T cells.

55. A pharmaceutical composition comprising a therapeutically effective amount of the nucleic acid of claim 37 or claim 38, the vector of claim 39 or claim 40, or the immune cell(s) of any one of claims 42 to 54.

56. The immune cell of any one of claims 42 to 54, or the pharmaceutical composition of claim 55, for use in therapy.

57. The immune cell of any one of claims 42 to 54, or the pharmaceutical composition of claim 55, for use in a method of treating or preventing cancer.

58. A method of treating a subject with autoimmune disease, comprising: administering to the subject the immune cell of any one of claims 42 to 54 or the pharmaceutical composition of claim 55.

59. A method of treating a subject with a transplant, comprising: administering to the subject the immune cell of any one of claims 42 to 54 or the pharmaceutical composition of claim 55.

60. A method of treating a subject with graft versus host disease (GVHD), comprising: administering to the subject the immune cell of any one of claims 42 to 54 or the pharmaceutical composition of claim 55.

61. The method of any one of claims 58 to 60, wherein the immune cells are allogeneic but have a complete or partial HLA-match with the subject.

62. The method of claim 61, wherein the immune cells are engineered to downregulate HLA-A/B/C molecules.

63. The method of any one of claims 58 to 62, wherein the immune cells are autologous.

64. The method of any one of claims 58 to 63, further comprising isolating immune cells from a tissue or body fluid sample of the subject prior to the administering of the immune cell.

65. The method of claim 64, wherein the immune cells are isolated based on CD56 expression.

66. The method of claim 64, wherein the immune cells are isolated based on CD45RA expression.

67. The method of claim 64, wherein the immune cells are isolated based on CD3 expression.

68. The method of claim 64, wherein the immune cells are isolated based on CD8 expression.

69. The method of claim 64, wherein the immune cells are isolated based on CD4 expression.

70. The method of any one of claims 58 to 69, wherein the immune cells are contemporaneously or sequentially administered in combination with an antibody preparation or a cell engager preparation that binds to the extracellular domain of CD16A, in order to induce a beneficial ADCC effect.

71. The method of claim 70, where the separation between dosing of the immune cells and the antibody preparation or the cell engager preparation is at least 1 hour, 6 hours, 24 hours, 48 hours, 1 week or two weeks.