WO2024148212A2 - T cell receptors directed to sox2 protein - Google Patents

Abstract

The present invention relates to compositions and methods for generating modified T cells comprising nucleic acids encoding a T cell receptor (TCR) specific for Sox2 protein. Also included are methods and pharmaceutical compositions comprising said modified T cells for adoptive therapy for use in treating cancer..

Description

Attorney Docket No.046483-7413WO1(03398) T CELL RECEPTORS DIRECTED TO SOX2 PROTEIN CROSS-REFERENCE TO RELATED APPLICATION The present application is entitled to priority under 35 U.S.C. § 119(e) to U.S. Provisional Patent Application No.63/478,856, filed January 6, 2023, which is hereby incorporated by reference in its entirety herein. STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT This invention was made with government support under grants CA238108 and CA204261 awarded by the National Institute of Health. The government has certain rights in the invention. BACKGROUND OF THE INVENTION Multiple myeloma (MM), a cancer of bone marrow plasma cells, is the second most common hematological malignancy, with >34000 new cases and >12000 myeloma- related deaths expected in the US in 2022. Initial response rates and survival in MM have improved with the development of new therapies. Though nearly all patients with newly diagnosed myeloma respond to first-line therapy, most patients, even those who achieve complete responses, eventually relapse and die of drug-resistant disease. These results demonstrate that potent cytoreduction is not consistently curative in MM and that the most critical unmet need for MM patients is new treatment approaches to prevent relapse. Therefore, a need in the art exists for improved therapies for MM, especially immunotherapy-based treatment strategies that target cancer cell populations otherwise resistant to existing treatment strategies. The invention of the current disclosure addresses this need. SUMMARY OF THE INVENTION As described herein, the present disclosure relates to compositions and methods useful for generating modified T cells comprising nucleic acids encoding a T cell receptor (TCR) specific for Sox2 protein. Also provided are methods and pharmaceutical compositions comprising said modified T cell for use in adoptive therapy for the treatment of cancer. -1- 51532213.1 Attorney Docket No.046483-7413WO1(03398) In one aspect, the disclosure provides an isolated nucleic acid encoding a first polypeptide, a linker polypeptide, and a second polypeptide, wherein the first polypeptide is a T cell receptor (TCR) alpha chain comprising a third complementarity determining region (CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 11 or SEQ ID NO: 13; the second polypeptide is a TCR beta chain comprising a third complementarity determining region (CDR3) comprising an amino acid set forth in SE ID NO: 12 or SEQ ID NO: 14; and the linker polypeptide is a self-cleaving polypeptide; wherein the TCR has antigenic specificity for an epitope of Sox2 protein. In certain embodiments, the TCR comprises a TCR alpha chain comprising the amino acid sequence set forth in SEQ ID NO: 7 or SEQ ID NO: 9 and a TCR beta chain comprising the amino acid sequence set forth in SEQ ID NO: 8 or SEQ ID NO: 10. In certain embodiments, the epitope of Sox2 comprises the amino acid sequence set forth in SEQ ID NO: 1 or SEQ ID NO: 2. In certain embodiments, the epitope of Sox2 is presented by HLA-B*07:02. In certain embodiments, the nucleic acid comprises a nucleic acid sequence set forth in SEQ ID NO: 3 or SEQ ID NO: 5. In certain embodiments, the nucleic acid encodes a polypeptide comprising the amino acid sequence set forth in SEQ ID NO: 4 or SEQ ID NO: 6. In another aspect, the current disclosure provides a recombinant expression vector comprising the isolated nucleic acid of any one of the above aspects or embodiments or any aspect or embodiment disclosed herein. In another aspect, the current disclosure provides a modified T cell comprising the nucleic acid of any one of the above aspects or embodiments or any aspect or embodiment disclosed herein. In another aspect, the current disclosure provides a modified T cell comprising an exogenous nucleic acid encoding a T cell receptor (TCR) specific for Sox2 protein, wherein the TCR comprises an alpha chain comprising a third complementarity determining region (CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 11 or SEQ ID NO: 13; and a beta chain comprising a CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 12 or SEQ ID NO: 14. In certain embodiments, the T cell further comprises a modified endogenous genetic locus. -2- 51532213.1 Attorney Docket No.046483-7413WO1(03398) In certain embodiments, the endogenous genetic locus encodes the TCR alpha chain, beta chain, or both alpha and beta chains. In certain embodiments, the modification reduces or eliminates expression of the genes encoded by the locus. In certain embodiments, the modification is accomplished by use of a CRISPR system. In certain embodiments, the current disclosure provides the modified T cell of any of the above aspects or embodiments or any aspect or embodiment disclosed herein, wherein the TCR alpha chain comprises an amino acid sequence set forth in SEQ ID NO: 7 or SEQ ID NO: 9; and the TCR beta chain comprises an amino acid sequence set forth in SEQ ID NO: 8 or SEQ ID NO: 10. In certain embodiments, the TCR has antigenic specificity for an epitope of Sox2 comprising the amino acid sequence set forth in SEQ ID NO: 1 or SEQ ID NO: 2. In certain embodiments, the epitope of Sox2 is presented by HLA-B*07:02. In certain embodiments, the nucleic acid comprises the nucleic acid sequence set forth in SEQ ID NO: 3 or SEQ ID NO: 5. In certain embodiments, the nucleic acid encodes a polypeptide comprising the amino acid sequence set forth in SEQ ID NO: 4 or SEQ ID NO: 6. In certain embodiments, the T cell is a CD4+ T cell. In certain embodiments, the T cell is a CD8+ T cell. In another aspect, the current disclosure provides a method for generating a modified T cell comprising modifying expression of an endogenous genetic locus encoding TCR alpha and/or beta chains; and introducing into the T cell an exogenous nucleic acid encoding a T cell receptor (TCR) specific for an epitope of Sox2 protein, wherein the TCR comprises an alpha chain comprising a third complementarity determining region (CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 11 or SEQ ID NO: 13; and a beta chain comprising a CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 12 or SEQ ID NO: 14; wherein the T cell is capable of expressing the TCR. In certain embodiments, the modification of the endogenous locus reduces or eliminates expression of endogenous TCR alpha or beta chains. In certain embodiments, the modification is accomplished by a CRISPR system. -3- 51532213.1 Attorney Docket No.046483-7413WO1(03398) In certain embodiments, the epitope of Sox2 protein comprises the amino acid sequence set forth in SEQ ID NO: 1 or SEQ ID NO: 2. In certain embodiments, the epitope of Sox2 protein is presented by HLA- B*07:02. In certain embodiments, the T cell is obtained from the group consisting of peripheral blood mononuclear cells, cord blood cells, a purified population of T cells, and a T cell line. In another aspect, the current disclosure provides a method for stimulating a T cell-mediated immune response to a target cell or tissue in a subject that expresses Sox2 protein, comprising administering to the subject an effective amount of a modified T cell comprising a nucleic acid encoding a T cell receptor (TCR) specific for an epitope of Sox2 protein, wherein the TCR comprises an alpha chain comprising a third complementarity determining region (CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 11 or SEQ ID NO: 13; and a beta chain comprising a CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 12 or SEQ ID NO: 14. In certain embodiments, the modified T cell further comprises a modified endogenous genetic locus. In certain embodiments, the endogenous genetic locus encodes a TCR alpha chain and/or beta chain. In certain embodiments, the modification reduces or eliminates expression of the endogenous TCR alpha and/or beta chain. In certain embodiments, the modification is accomplished by a CRISPR system. In certain embodiments, the Sox 2 antigen comprises the amino acid sequence set forth in SEQ ID NO: 1 or SEQ ID NO: 2. In certain embodiments, the epitope of Sox2 is presented by HLA-B*07:02. In certain embodiments, the target cell or tissue is a cancer cell or tissue. In certain embodiments, the cancer is selected from the group consisting of glioblastoma, non-small cell lung cancer, breast cancer, prostate cancer, and multiple myeloma (MM). In another aspect, the current disclosure provides a method of treating a condition in a subject related to Sox2 expression, comprising administering to the subject a -4- 51532213.1 Attorney Docket No.046483-7413WO1(03398) therapeutically effective amount of a pharmaceutical composition comprising the modified T cell of any one of claims 8 – 20 and a pharmaceutically acceptable carrier or excipient. In certain embodiments, the method of the above aspects or embodiments or any aspect or embodiment disclosed herein comprises administering to the subject one or more additional therapeutic agents. In certain embodiments, the additional therapeutic agent is selected from the group consisting of chemotherapy, chimeric-antigen receptor (CAR)-T cell therapy, monoclonal antibody therapy, biologic therapy, allogeneic stem cell transplant, radiologic therapy, and any combination thereof. In certain embodiments, the condition is cancer. In certain embodiments, the cancer is selected from the group consisting of glioblastoma, non-small cell lung cancer, breast cancer, prostate cancer, and multiple myeloma (MM). In another aspect, the current disclosure provides a pharmaceutical composition comprising the modified T cell of any of the above aspects or embodiments or any aspect or embodiment disclosed herein and a pharmaceutically acceptable carrier. BRIEF DESCRIPTION OF THE DRAWINGS The following detailed description of preferred embodiments of the invention will be better understood when read in conjunction with the appended drawings. For the purpose of illustrating the invention, there are shown in the drawings embodiments which are presently preferred. It should be understood, however, that the invention is not limited to the precise arrangements and instrumentalities of the embodiments shown in the drawings. FIGs.1A-1B illustrate the identification of Sox2 peptides presented by HLA- B*07:02. (FIG.1A) Sox2 peptides computationally predicted to be presented by HLA- B*07:02. Grey shading denotes peptides detected by mass spectrometry to be presented on HLA-B*07:02 in K-562 cells co-transduced with HLA-B*07:02 and Sox2. (FIG.1B) IFNγ ELISPOT assays from PBMCs of an HLA-B*07:02 + MGUS patient after stimulation with specific Sox2 peptides, pooled Sox2 peptides (PepMix) or influenza -5- 51532213.1 Attorney Docket No.046483-7413WO1(03398) peptides (INFA) as a positive control; specific reactivity to Sox2 peptide B7-4 was identified. FIGs.2A-2B illustrate the stimulation of peptide-specific T cells from patient specimens. (FIG.2A) PBMC derived from MUGS or long-term responders to anti- BCMA or CD19 CAR therapy was used as a source of dendritic cells (DC) and purified CD8+ T cells. DC / T cells cultures were established in the presence of peptide and cultured for 10-14 days. T cells from primary cultures were restimulated with HLA- B*07:02 expressing K562 cells pulsed with peptide and expansion of SOX2-specific T cells monitored using p/HLA custom multimers. (FIG.2B) Representative dot plots of CD8/p-HLA multimer staining as determined by flow cytometry. Results demonstrated detection of CD8+ T cells specific for peptide B7-4 (upper panel) and B7-9 (lower panel). FIGs.3A-3B illustrate the expression and function of isolated TCRs. (FIG.3A) TCR952 and (FIG.3B) TCR954 were expressed in Jurkat cells harboring NFAT dependent eGFP reporter system. Expression of TCRs (transduced, blue) was confirmed upon staining with p-HLA multimers and CD8. Culture of these TCR expressing Jurkat cells with cognate peptide and matched HLA-B*07:02 expressing APCs lead to the activation of NFAT and expression of eGFP. These results demonstrate that these TCRs can recognize peptides B7-4 and B7-9 encoded by SOX2. FIGs.4A-4B illustrate the cytotoxic function of transduced T cells. (FIG.4A) TCR952 and TCR954 were expressed in CD8+ T cells and expression confirmed upon staining with p-HLA multimers and CD8. (FIG.4B) Avidity of TCRs was determined using titrated concentrations of cognate peptide in a 4h ⁵¹Cr-release assays using HLA- B*07:02-expressing cells as APCs. Both TCRs display avidities of approximately 1nM (ng/mL). FIGs.5A-5B illustrate the recognition of endogenously processed and presented SOX2 antigens. Studies were conducted using 4h ⁵¹Cr-release assays using TCR954- engineered CD8+ T cells as effectors and K562 / HLA-B*07:02 cells expressing full length SOX2 as targets. (FIG.5A) TCR954-expressing T cells can recognize and kill cells expressing full length SOX2 (K562/B7/Sox2). (FIG.5B). To evaluate recognition of myeloma cells by TCR954, CD8+ T cells engineered to expressed TCR954 were co- culture at various E:T ratios with L363 (left) or L363-SOX2 expressing myeloma cells (right) for 16 h. The resulting T cell cultures were plated on methylcellulose to evaluate -6- 51532213.1 Attorney Docket No.046483-7413WO1(03398) inhibition of colony formation by myeloma cells. In a dose dependent manner, a reduction in number of colony forming cells in L363-SOX2 cultures is observed upon co- culture with TCR954-expressing T cells. FIG.6 illustrates TCR954-engineered T cells used as effectors in xCELLigence live cell cytotoxicity assays for their ability to recognize as targets various tumor cell lines of multiple histologies (Ewing sarcoma – SK-N-MC and A673; Cervical Adenocarcinoma, C33). All 3 cell lines have documented expression of SOX2 and, by proteomics, processing and presentation of YPQHPGLNA (SEQ ID NO: 2) has been validated in SK-N-MC cells. These results strongly suggest that SOX2-derived peptides may be valid immunological targets beyond multiple myeloma and TCRs, such a TCR952 and TCR954, may have a therapeutic potential in malignant diseases of various histologies. FIG.7 is a diagram illustrating an experimental scheme for identification and validation of Sox2 epitopes. Computational neoantigen prediction was used to identify HLA class I-restricted 9- and 10-mer candidate Sox2 peptides. Processing and presentation of Sox2 peptides were validated biochemically by HLA class I immunoprecipitation, peptide elution and tandem mass spectrometry using monoallelic cell lines co-transduced with HLA-B7:02 and full length ubiquinated Sox2 protein. Immunogenicity was evaluated using PBMCs from patients with MGUS and SMM which were pulsed with peptides followed by assessment of antigen specificity by IFN- γ Elispot assay. Sox2 epitopes were validated by the isolation of Sox2-specific TCRs which were used as probes to detect tumor cell antigen processing and presentation. This figure was created with BioRender.com. FIGs.8A-8C illustrate the validation of HLA*B7:02-restricted Sox2 peptide processing and presentation. (FIG.8A) FACS plot demonstrating co-expression of HLA- B*07:02 (as detected by pan-HLA class I W6/32 and HLA-B*07 Abs) and ubiquinated full-length Sox2 (as detected by mCherry expression) in K562 cells following lentiviral transduction and flow cytometric cell sorting. (FIG.8B) RT-PCR demonstrating the expression of full length Sox2 transcript in K562 transduced cells. (FIG.8C) MS/MS fragmentation pattern of Sox2 ions eluted from HLA- B*07:02 with the corresponding peptide B7-4 and peptide B7-9. FIGs.9A-9C illustrate the assessment of Sox2 antigen immunogenicity and -7- 51532213.1 Attorney Docket No.046483-7413WO1(03398) identification of Sox2-specific TCR sequences. (FIG.9A) Representative T-cell responses detected by IFN-γ ELISpot assay of peptide-pulsed PBMC. After 12 days of culture, specificity against peptide 1 was detected in a patient with SMM (FIG.9B) FACS histogram plots demonstrating p-HLA multimer analysis demonstrating positive Sox2- specific HLA-B*07:02-restricted CD8+ T cell responses against peptide B7-4 and B7-9. (FIG.9C) IFN-γ ELISPOT assays of Sox2 specific CD8+ T cells showed responses to HLA-B*07:02 transfected 721.221 target cells pulsed with synthetic peptides. FIGs.10A-10C illustrate the validation and functional characterization of Sox- specific TCRs. (FIG.10A) FACS histogram plots showing TCR α/β expression and p- HLA multimer staining following lentiviral engineering of JASP90 reporter cells with Sox2-specific TCR952 (peptide B7-4) and TCR954 (peptide B7-9) constructs. (FIG.10B) FACS plots demonstrating appropriate antigen recognition. TCR signaling is indicated by eGFP expression upon NFAT activation following an 18h co-culture of JASP90 reporter cells expressing TCR952 or TCR954 with HLA class I matched cognate peptide- pulsed (Blue) or non-peptide pulsed (control) (Red) K562 cells. (FIG.10C) TCR avidity was determined as the mean effective peptide concentration (EC50) required to achieve 50% NFAT activation of TCR-engineered JASP90 reporter cells. Specific Activity (%) = (%GFPTest – %GFPMin) / (%GFPMax - %GFPMin) x 100. J-TCR952 and J-TCR954 cells were co-cultured with monoallelic 721.221 cell lines pulsed with titrated concentrations of cognate Sox2 peptides. A representative experiment of three independent evaluations is shown. FIGs.11A-11H illustrate that Sox2 TCRα/β gene transfer to gene-edited TCRnull primary CD8+Tcells confers cytotoxic activity against human tumor cells. (FIG.11A) Schematic diagram showing experimental scheme for Sox2-specific TCR transfer to primary CD8+ T cells. (FIG.11B) 4h ⁵¹Cr-release cytotoxicity assay demonstrating TCR954 tumoricidal activity against K562 engineered to express Sox2 and HLA- B*07:02. (FIG.11C) Colony formation assays demonstrating TCR954 tumor lysis activity against L-363 engineered to express Sox2 (FIG.11D) Colony formation assay showing decrease clonogenic activity of residual L-363 after 24h co-culture with TCR954 CD8+ T cells (FIG.11E)4h ⁵¹Cr-release cytotoxicity assay demonstrating TCR954 tumoricidal activity against endogenous Sox2 sarcoma cell line SK-NM-C engineered to express HLA-B*07:02 (FIG.11F) Cellular impedance analysis showed TCR 954 -8- 51532213.1 Attorney Docket No.046483-7413WO1(03398) recognition and lysis of SK-NM-C is HLA-B*07:02 -restricted at an E:T ratio of 2.5: 1. Data are presented as mean values ± SD (n = 2 biologically independent samples). (FIG. 11G) Live cell imaging demonstrating recognition and tumor lysis of TCR954 against HLA calls I matched SK-NM-C sarcoma cell line at an E:T ratio of 5:1. In contrast, no cytolysis was observed by TCR952. Representative green (eGFP expressed by tumor) and Red (Annexin V-CF954) overlay images are shown. (FIG.11H) MS/MS fragmentation pattern of Sox2 ions eluted from HLA-B*07:02 with the corresponding peptide B7-9. FIG.12 is a UMAP plot from single-cell RNAseq of multiple myeloma cells from bone marrow of a relapsed/refractory MM patient. MM cells were identified based on expression of PC transcription factors (e.g., CD138, BLIMP1, XBP1) and monoclonal Ig heavy/light chain genes from paired single-cell Ig transcript sequencing. Five transcriptional subsets of MM cells were identified (clusters 0-4). Cluster 3 (blue) clearly separated from other clusters in UMAP analysis and distinctly exhibited enhanced expression of embryonic stem cell transcriptional networks; Sox2 target genes VIM, SULF2, and CST3 were among the most differentially expressed genes in cluster 3 vs others. FIGs.13A-13D illustrate correlation of Sox2 expression to MM and that endogenous immune responses to Sox2 often accompany anti-tumor immune responses. (FIG.13A) Overall survival in MM patients by Sox2 expression based on analysis of the publicly available MMRF COMMPASS dataset. (FIG.13B) Anti-Sox2 Ab responses after ASCT + CART19 as assessed by ELISA. (FIG.13C) Anti-Sox2 T cell responses against a subset of Sox2 peptides (“mixes 3-4”) after ASCT + CART19; graph represents % reactive (after background subtraction) to Sox2 peptides by CFSE dilution after incubation with autologous PBMCs. Arrows highlight subjects #1 and #5. (FIG.13D) Reactivity against overlapping regions of Sox2 among T cells from subject #1, identifying peak reactivity in region of aa 161-219. FIGs.14A-14F illustrate the identification of 2 Sox2-specific HLA-B*07:02- restricted TCRs from a single patient with stable MGUS. (FIG.14A) peptide/HLA multimer staining showing expansion of T cells recognizing either B7-4 or B7-9 peptide following stimulation of PBMCs with these peptides from a MGUS patient. (FIG.14B) IFNγ ELISPOTs of PBMCs pre-stimulated with by APCs + B7-4 peptide in response to -9- 51532213.1 Attorney Docket No.046483-7413WO1(03398) 721.221 cells expressing HLA-B*07:02 +/- Sox2. (FIG.14C) Further enrichment of CD8+ T cells recognizing B7-4 and B7-9 following flow cell sorting and expansion of HLA/p multimer+ cells. (FIG.14D). Distribution of TCR clonotypes from targeted sequencing of TCR b chain variable region DNA (top) or a and b variable region transcripts from the enriched cultures presented in panel C; results are only shown for the B7-4- specific cultures. (FIG.14E) HLA/p multimer staining of TCR-null SUPT1 cells following lentiviral transduction of TCRs deduced from sequencing studies depicted in panel E, confirming that transduced TCRs recognize the B7-4 and B7-9 peptides bound to HLA-B*07:02. FIG.15 is a diagram of the nucleic acid sequence of the GLE952 B7-4 TCR ORF (SEQ ID NO: 3), top, with its complementary sequence below, illustrating various features. FIG.16 is a diagram of the nucleic acid sequence of the GLE954 B7-9 TCR ORF (SEQ ID NO: 5), top, with its complementary sequence below, illustrating various features. FIG.17 is a diagram of the amino acid sequence of the GLE952 B7-4 TCR ORF (SEQ ID NO: 4). TRA CDR3 (SEQ ID NO: 11) and TRB CDR3 (SEQ ID NO: 12) sequences are indicated within the boxes. FIG.18 is a diagram of the amino acid sequence of the GLE954 B7-9 TCR ORF (SEQ ID NO: 6). TRA CDR3 (SEQ ID NO: 13) and TRB CDR3 (SEQ ID NO: 14) sequences are indicated within the boxes. FIG.19 illustrates that Sox2-specific TCRαβ gene transfer in JASP90 reporter cells enables proper antigen recognition and TCR signaling. FIG.20 illustrates the generation of Sox2-TCR redirected CRISPR-edited TCR αβnull CD8+ T cells. FIG.21 illustrates that TCR954 CD8+ T cells recognize endogenous over- expressed Sox2 in K562/HLA-B*07:02 cells. FIG.22 illustrates TCR954 CD8+ cells recognize endogenous over-expressed Sox2 in L-363 cells. FIG.23 illustrates Sox2 protein expression in indicated cell lines as detected by Western blot. -10- 51532213.1 Attorney Docket No.046483-7413WO1(03398) DETAILED DESCRIPTION Definitions Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention pertains. Although any methods and materials similar or equivalent to those described herein can be used in the practice for testing of the present invention, the preferred materials and methods are described herein. In describing and claiming the present invention, the following terminology will be used. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting. The articles “a” and “an” are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element. “About” as used herein when referring to a measurable value such as an amount, a temporal duration, and the like, is meant to encompass variations of ±20% or ±10%, more preferably ±5%, even more preferably ±1%, and still more preferably ±0.1% from the specified value, as such variations are appropriate to perform the disclosed methods. “Activation,” as used herein, refers to the state of a T cell that has been sufficiently stimulated to induce detectable cellular proliferation. Activation can also be associated with induced cytokine production, and detectable effector functions. The term “activated T cells” refers to, among other things, T cells that are undergoing cell division. The term “antibody,” as used herein, refers to an immunoglobulin molecule which specifically binds with an antigen. Antibodies can be intact immunoglobulins obtained from natural sources or from recombinant sources and can be immunoreactive portions of intact immunoglobulins. Antibodies are typically tetramers of immunoglobulin molecules. Tetramers may be naturally occurring or reconstructed from single chain antibodies or antibody fragments. Antibodies also include dimers that may be naturally occurring or constructed from single chain antibodies or antibody fragments. The antibodies in the present invention may exist in a variety of forms including, for example, polyclonal antibodies, monoclonal antibodies, Fv, Fab and F(ab')2, as well as single chain antibodies (scFv), humanized antibodies, and human antibodies (Harlow et al., 1999, In: Using Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory Press, NY; -11- 51532213.1 Attorney Docket No.046483-7413WO1(03398) Harlow et al., 1989, In: Antibodies: A Laboratory Manual, Cold Spring Harbor, New York; Houston et al., 1988, Proc. Natl. Acad. Sci. USA 85:5879-5883; Bird et al., 1988, Science 242:423-426). The term “antibody fragment” refers to a region of an intact antibody and refers to the antigenic determining variable regions of an intact antibody. Examples of antibody fragments include, but are not limited to, Fab, Fab', F(ab')₂, and Fv fragments, linear antibodies, scFv antibodies, single-domain antibodies, such as camelid antibodies (Riechmann, 1999, Journal of Immunological Methods 231:25-38), composed of either a VL or a VH domain which exhibit sufficient affinity for the target, and multispecific antibodies formed from antibody fragments. The antibody fragment also includes a human antibody or a humanized antibody or a fragment of a human antibody or a humanized antibody thereof. The term “antigen” or “Ag” as used herein is defined as a molecule that provokes an immune response. This immune response may involve either antibody production, or the activation of specific immunologically competent cells (e.g., T cells), or both. The skilled artisan will understand that any macromolecule, including virtually all proteins or peptides, can serve as an antigen. Furthermore, antigens can be generated from recombinant or genomic DNA. A skilled artisan will understand that any DNA, which comprises a nucleotide sequence or a partial nucleotide sequence encoding a protein that elicits an immune response therefore encodes an “antigen” as that term is used herein. Furthermore, one skilled in the art will understand that an antigen need not be encoded solely by a full-length nucleotide sequence of a gene. It is readily apparent that the present invention includes, but is not limited to, the use of partial nucleotide sequences of more than one gene and that these nucleotide sequences are arranged in various combinations to elicit the desired immune response. Moreover, a skilled artisan will understand that an antigen need not be encoded by a “gene” at all. It is readily apparent that an antigen can be generated, synthesized or originate from a biological sample. Such a biological sample can include, but is not limited to a tissue sample, a tumor sample, a cell or a biological fluid. The term “anti-tumor effect” as used herein, refers to a biological effect which can be manifested by a decrease in tumor volume, a decrease in the number of tumor cells, a decrease in the number of metastases, an increase in life expectancy, or amelioration of -12- 51532213.1 Attorney Docket No.046483-7413WO1(03398) various physiological symptoms associated with the cancerous condition. An “anti-tumor effect” can also be manifested by the ability of the peptides, polynucleotides, cells and antibodies of the invention in prevention of the occurrence of tumor in the first place. As used herein, the term “autologous” is meant to refer to any material originating from the same individual to which it is later to be re-introduced into the individual. “Allogeneic” refers to a graft derived from a different animal of the same species. “Xenogeneic” refers to a graft derived from an animal of a different species. The term “cancer” as used herein is defined as disease characterized by the rapid and uncontrolled growth of aberrant cells. Cancer cells can spread locally or through the bloodstream and lymphatic system to other parts of the body. Examples of various cancers include but are not limited to, breast cancer, prostate cancer, ovarian cancer, cervical cancer, skin cancer, pancreatic cancer, colorectal cancer, renal cancer, liver cancer, brain cancer, lymphoma, leukemia, lung cancer, multiple myeloma, thyroid cancer, and the like. The term “chimeric antigen receptor” or “CAR,” as used herein, refers to an artificial T cell receptor that is engineered to be expressed on an immune effector cell and specifically bind an antigen. CARs may be used as a therapy with adoptive cell transfer. T cells are removed from a patient and modified so that they express the receptors specific to a particular form of antigen. In some embodiments, the CARs have been expressed with specificity to a tumor associated antigen, for example. CARs may also comprise an intracellular activation domain, a transmembrane domain and an extracellular domain comprising a tumor associated antigen binding region. In some aspects, CARs comprise fusions of single-chain variable fragments (scFv) derived monoclonal antibodies, fused to CD3-zeta transmembrane and intracellular domain. The specificity of CAR designs may be derived from ligands of receptors (e.g., peptides). In some embodiments, a CAR can target cancers by redirecting the specificity of a T cell expressing the CAR specific for tumor associated antigens. The term “chimeric membrane protein” refers to an engineered membrane protein having an extracellular domain and intracellular domain derived from or capable of activating one or more signaling and/or receptor molecules. For example, the chimeric membrane protein described herein comprises a single chain variable fragment (scFv) -13- 51532213.1 Attorney Docket No.046483-7413WO1(03398) directed against CD3 and an intracellular domain comprising a fragment of an intracellular domain of CD28 and 4-1BB. As used herein, the term “conservative sequence modifications” is intended to refer to amino acid modifications that do not significantly affect or alter the binding characteristics of the antibody containing the amino acid sequence. Such conservative modifications include amino acid substitutions, additions and deletions. Modifications can be introduced into an antibody of the invention by standard techniques known in the art, such as site-directed mutagenesis and PCR-mediated mutagenesis. Conservative amino acid substitutions are ones in which the amino acid residue is replaced with an amino acid residue having a similar side chain. Families of amino acid residues having similar side chains have been defined in the art. These families include amino acids with basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine, tryptophan), nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine), beta-branched side chains (e.g., threonine, valine, isoleucine) and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine). Thus, one or more amino acid residues within the CDR regions of an antibody can be replaced with other amino acid residues from the same side chain family and the altered antibody can be tested for the ability to bind antigens using the functional assays described herein. “Co-stimulatory ligand,” as the term is used herein, includes a molecule on an antigen presenting cell (e.g., an aAPC, dendritic cell, B cell, and the like) that specifically binds a cognate co-stimulatory molecule on a T cell, thereby providing a signal which, in addition to the primary signal provided by, for instance, binding of a TCR/CD3 complex with an MHC molecule loaded with peptide, mediates a T cell response, including, but not limited to, proliferation, activation, differentiation, and the like. A co-stimulatory ligand can include, but is not limited to, CD7, B7-1 (CD80), B7-2 (CD86), PD-L1, PD- L2, 4-1BBL, OX40L, inducible costimulatory ligand (ICOS-L), intercellular adhesion molecule (ICAM), CD30L, CD40, CD70, CD83, HLA-G, MICA, MICB, HVEM, lymphotoxin beta receptor, 3/TR6, ILT3, ILT4, HVEM, an agonist or antibody that binds Toll ligand receptor and a ligand that specifically binds with B7-H3. A co-stimulatory ligand also encompasses, inter alia, an antibody that specifically binds with a co- -14- 51532213.1 Attorney Docket No.046483-7413WO1(03398) stimulatory molecule present on a T cell, such as, but not limited to, CD27, CD28, 4- 1BB, OX40, CD30, CD40, PD-1, ICOS, lymphocyte function-associated antigen-1 (LFA- 1), CD2, CD7, LIGHT, NKG2C, B7-H3, and a ligand that specifically binds with CD83. A “co-stimulatory molecule” refers to the cognate binding partner on a T cell that specifically binds with a co-stimulatory ligand, thereby mediating a co-stimulatory response by the T cell, such as, but not limited to, proliferation. Co-stimulatory molecules include but are not limited to an MHC class I molecule, BTLA and a Toll ligand receptor. A “co-stimulatory signal”, as used herein, refers to a signal, which in combination with a primary signal, such as TCR/CD3 ligation, leads to T cell proliferation and/or upregulation or downregulation of key molecules. The term “derived from” refers to being generated, synthesized, or originating from a particular source, such that the derived matter is related to the source. The derived matter does not need to be identical to the particular source. In one embodiment, an antigen is derived from a protein. In another embodiment, a single-chain variable fragment is derived from a monoclonal antibody. A “disease” is a state of health of an animal wherein the animal cannot maintain homeostasis, and wherein if the disease is not ameliorated then the animal’s health continues to deteriorate. In contrast, a “disorder” in an animal is a state of health in which the animal is able to maintain homeostasis, but in which the animal’s state of health is less favorable than it would be in the absence of the disorder. Left untreated, a disorder does not necessarily cause a further decrease in the animal’s state of health. “Effective amount” or “therapeutically effective amount” are used interchangeably herein, and refer to an amount of a compound, formulation, material, or composition, as described herein effective to achieve a particular biological result or provides a therapeutic or prophylactic benefit. Such results may include, but are not limited to, anti-tumor activity as determined by any means suitable in the art. “Encoding” refers to the inherent property of specific sequences of nucleotides in a polynucleotide, such as a gene, a cDNA, or an mRNA, to serve as templates for synthesis of other polymers and macromolecules in biological processes having either a defined sequence of nucleotides (i.e., rRNA, tRNA and mRNA) or a defined sequence of amino acids and the biological properties resulting therefrom. Thus, a gene encodes a protein if transcription and translation of mRNA corresponding to that gene produces the -15- 51532213.1 Attorney Docket No.046483-7413WO1(03398) protein in a cell or other biological system. Both the coding strand, the nucleotide sequence of which is identical to the mRNA sequence and is usually provided in sequence listings, and the non-coding strand, used as the template for transcription of a gene or cDNA, can be referred to as encoding the protein or other product of that gene or cDNA. As used herein “endogenous” refers to any material from or produced inside an organism, cell, tissue or system. As used herein, the term “exogenous” refers to any material introduced from or produced outside an organism, cell, tissue or system. The term “expand” as used herein refers to increasing in number, as in an increase in the number of T cells. In one embodiment, the T cells that are expanded ex vivo increase in number relative to the number originally present in the culture. In another embodiment, the T cells that are expanded ex vivo increase in number relative to other cell types in the culture. The term "ex vivo," as used herein, refers to cells that have been removed from a living organism, (e.g., a human) and propagated outside the organism (e.g., in a culture dish, test tube, or bioreactor). The term “expression” as used herein is defined as the transcription and/or translation of a particular nucleotide sequence driven by its promoter. “Expression vector” refers to a vector comprising a recombinant polynucleotide comprising expression control sequences operatively linked to a nucleotide sequence to be expressed. An expression vector comprises sufficient cis-acting elements for expression; other elements for expression can be supplied by the host cell or in an in vitro expression system. Expression vectors include all those known in the art, such as cosmids, plasmids (e.g., naked or contained in liposomes) and viruses (e.g., lentiviruses, retroviruses, adenoviruses, and adeno-associated viruses) that incorporate the recombinant polynucleotide. The term “human leukocyte antigen” or “HLA” as used herein refers to the cell surface protein complexes responsible for the presentation of antigenic epitopes, typically peptide epitopes, to CD4+ and CD8+ T cells. HLA complexes comprise two main classes: class I, which are expressed by most cells and present mostly intracellular antigens to CD8+ T cells and consist of a monomeric polypeptide alpha chain complexed with a non-epitope-binding protein called β₂ microglobulin (B2M); and class II, which presents mostly extracellular antigens to CD4+ T cells and consists of a hetero dimer of -16- 51532213.1 Attorney Docket No.046483-7413WO1(03398) an alpha and beta chains. The genes encoding HLA proteins are highly polymorphic which allow them to present a wide variety of antigens. “Identity” as used herein refers to the subunit sequence identity between two polymeric molecules particularly between two amino acid molecules, such as, between two polypeptide molecules. When two amino acid sequences have the same residues at the same positions, e.g., if a position in each of two polypeptide molecules is occupied by an Arginine, then they are identical at that position. The identity or extent to which two amino acid sequences have the same residues at the same positions in an alignment is often expressed as a percentage. The identity between two amino acid sequences is a direct function of the number of matching or identical positions; e.g., if half (e.g., five positions in a polymer ten amino acids in length) of the positions in two sequences are identical, the two sequences are 50% identical; if 90% of the positions (e.g., 9 of 10), are matched or identical, the two amino acids sequences are 90% identical. The term “immunoglobulin” or “Ig,” as used herein is defined as a class of proteins, which function as antibodies. Antibodies expressed by B cells are sometimes referred to as the BCR (B cell receptor) or antigen receptor. The five members included in this class of proteins are IgA, IgG, IgM, IgD, and IgE. IgA is the primary antibody that is present in body secretions, such as saliva, tears, breast milk, gastrointestinal secretions and mucus secretions of the respiratory and genitourinary tracts. IgG is the most common circulating antibody. IgM is the main immunoglobulin produced in the primary immune response in most subjects. It is the most efficient immunoglobulin in agglutination, complement fixation, and other antibody responses, and is important in defense against bacteria and viruses. IgD is the immunoglobulin that has no known antibody function but may serve as an antigen receptor. IgE is the immunoglobulin that mediates immediate hypersensitivity by causing release of mediators from mast cells and basophils upon exposure to allergen. The term “immune response” as used herein is defined as a cellular response to an antigen that occurs when lymphocytes identify antigenic molecules as foreign and induce the formation of antibodies and/or activate lymphocytes to remove the antigen. The phrases “an immunologically effective amount”, “an anti-immune response effective amount”, “an immune response-inhibiting effective amount”, or “therapeutic amount” refer to the amount of the composition of the present invention to be -17- 51532213.1 Attorney Docket No.046483-7413WO1(03398) administered to a subject which amount is determined by a physician, optionally in consultation with a scientist, in consideration of individual differences in age, weight, immune response, type of disease/condition, and the health of the subject (patient) so that the desired result is obtained in the subject. “Isolated” means altered or removed from the natural state. For example, a nucleic acid or a peptide naturally present in a living animal is not “isolated,” but the same nucleic acid or peptide partially or completely separated from the coexisting materials of its natural state is “isolated.” An isolated nucleic acid or protein can exist in substantially purified form, or can exist in a non-native environment such as, for example, a host cell. A “lentivirus” as used herein refers to a genus of the Retroviridae family. Lentiviruses are unique among the retroviruses in being able to infect non-dividing cells; they can deliver a significant amount of genetic information into the DNA of the host cell, so they are one of the most efficient methods of a gene delivery vector. HIV, SIV, and FIV are all examples of lentiviruses. Vectors derived from lentiviruses offer the means to achieve significant levels of gene transfer in vivo. By the term “modified” as used herein, is meant a changed state or structure of a molecule or cell of the invention. Molecules may be modified in many ways, including chemically, structurally, and functionally. Cells may be modified through the introduction of nucleic acids. By the term “modulating,” as used herein, is meant mediating a detectable increase or decrease in the level of a response in a subject compared with the level of a response in the subject in the absence of a treatment or compound, and/or compared with the level of a response in an otherwise identical but untreated subject. The term encompasses perturbing and/or affecting a native signal or response thereby mediating a beneficial therapeutic response in a subject, preferably, a human. In the context of the present invention, the following abbreviations for the commonly occurring nucleic acid bases are used. “A” refers to adenosine, “C” refers to cytosine, “G” refers to guanosine, “T” refers to thymidine, and “U” refers to uridine. Unless otherwise specified, a “nucleotide sequence encoding an amino acid sequence” includes all nucleotide sequences that are degenerate versions of each other and that encode the same amino acid sequence. The phrase nucleotide sequence that -18- 51532213.1 Attorney Docket No.046483-7413WO1(03398) encodes a protein or an RNA may also include introns to the extent that the nucleotide sequence encoding the protein may in some version contain an intron(s). Unless otherwise specified, a “nucleotide sequence encoding an amino acid sequence” includes all nucleotide sequences that are degenerate versions of each other and that encode the same amino acid sequence. Nucleotide sequences that encode proteins and RNA may include introns. The term “operably linked” refers to functional linkage between a regulatory sequence and a heterologous nucleic acid sequence resulting in expression of the latter. For example, a first nucleic acid sequence is operably linked with a second nucleic acid sequence when the first nucleic acid sequence is placed in a functional relationship with the second nucleic acid sequence. For instance, a promoter is operably linked to a coding sequence if the promoter affects the transcription or expression of the coding sequence. Generally, operably linked DNA sequences are contiguous and, where necessary to join two protein coding regions, in the same reading frame. The term “overexpressed” tumor antigen or “overexpression” of a tumor antigen is intended to indicate an abnormal level of expression of a tumor antigen in a cell from a disease area like a solid tumor within a specific tissue or organ of the patient relative to the level of expression in a normal cell from that tissue or organ. Patients having solid tumors, or a hematological malignancy characterized by overexpression of the tumor antigen can be determined by standard assays known in the art. “Parenteral” administration of an immunogenic composition includes, e.g., subcutaneous (s.c.), intravenous (i.v.), intramuscular (i.m.), or intrasternal injection, or infusion techniques. The term “polynucleotide” as used herein is defined as a chain of nucleotides. Furthermore, nucleic acids are polymers of nucleotides. Thus, nucleic acids and polynucleotides as used herein are interchangeable. One skilled in the art has the general knowledge that nucleic acids are polynucleotides, which can be hydrolyzed into the monomeric “nucleotides.” The monomeric nucleotides can be hydrolyzed into nucleosides. As used herein polynucleotides include, but are not limited to, all nucleic acid sequences which are obtained by any means available in the art, including, without limitation, recombinant means, i.e., the cloning of nucleic acid sequences from a -19- 51532213.1 Attorney Docket No.046483-7413WO1(03398) recombinant library or a cell genome, using ordinary cloning technology and PCR™, and the like, and by synthetic means. As used herein, the terms “peptide,” “polypeptide,” and “protein” are used interchangeably, and refer to a compound comprised of amino acid residues covalently linked by peptide bonds. A protein or peptide must contain at least two amino acids, and no limitation is placed on the maximum number of amino acids that can comprise a protein’s or peptide’s sequence. Polypeptides include any peptide or protein comprising two or more amino acids joined to each other by peptide bonds. As used herein, the term refers to both short chains, which also commonly are referred to in the art as peptides, oligopeptides and oligomers, for example, and to longer chains, which generally are referred to in the art as proteins, of which there are many types. “Polypeptides” include, for example, biologically active fragments, substantially homologous polypeptides, oligopeptides, homodimers, heterodimers, variants of polypeptides, modified polypeptides, derivatives, analogs, fusion proteins, among others. The polypeptides include natural peptides, recombinant peptides, synthetic peptides, or a combination thereof. The term “promoter” as used herein is defined as a DNA sequence recognized by the synthetic machinery of the cell, or introduced synthetic machinery, required to initiate the specific transcription of a polynucleotide sequence. As used herein, the term “promoter/regulatory sequence” means a nucleic acid sequence which is required for expression of a gene product operably linked to the promoter/regulatory sequence. In some instances, this sequence may be the core promoter sequence and in other instances, this sequence may also include an enhancer sequence and other regulatory elements which are required for expression of the gene product. The promoter/regulatory sequence may, for example, be one which expresses the gene product in a tissue specific manner. A “constitutive” promoter is a nucleotide sequence which, when operably linked with a polynucleotide which encodes or specifies a gene product, causes the gene product to be produced in a cell under most or all physiological conditions of the cell. An “inducible” promoter is a nucleotide sequence which, when operably linked with a polynucleotide which encodes or specifies a gene product, causes the gene product -20- 51532213.1 Attorney Docket No.046483-7413WO1(03398) to be produced in a cell substantially only when an inducer which corresponds to the promoter is present in the cell. A “tissue-specific” promoter is a nucleotide sequence which, when operably linked with a polynucleotide encodes or specified by a gene, causes the gene product to be produced in a cell substantially only if the cell is a cell of the tissue type corresponding to the promoter. A “signal transduction pathway” refers to the biochemical relationship between a variety of signal transduction molecules that play a role in the transmission of a signal from one portion of a cell to another portion of a cell. The phrase “cell surface receptor” includes molecules and complexes of molecules capable of receiving a signal and transmitting signal across the plasma membrane of a cell. An example of a “cell surface receptor” is human FSHR. “Similarity” as used herein, refers to the subunit sequence identity between two polymeric molecules, e.g., between two nucleic acid molecules, such as, two DNA molecules or two RNA molecules, or between two polypeptide molecules. When a subunit position in both of the two molecules is occupied by the same monomeric subunit; e.g., if a position in each of two DNA molecules is occupied by adenine, then they are similar at that position. The similarity between two sequences is a direct function of the number of matching or similar positions; e.g., if half (e.g., five positions in a polymer ten subunits in length) of the positions in two sequences are similar, the two sequences are 50% similar; if 90% of the positions (e.g., 9 of 10), are matched or similar, the two sequences are 90% similar. “Single chain antibodies” refer to antibodies formed by recombinant DNA techniques in which immunoglobulin heavy and light chain fragments are linked to the Fv region via an engineered span of amino acids. Various methods of generating single chain antibodies are known, including those described in U.S. Pat. No.4,694,778; Bird (1988) Science 242:423-442; Huston et al. (1988) Proc. Natl. Acad. Sci. USA 85:5879- 5883; Ward et al. (1989) Nature 334:54454; Skerra et al. (1988) Science 242:1038-1041. The term “small molecule” refers to a peptide having about 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acids with the capacity to bind a target, such as a molecule, or antigen. The small molecule comprises a low molar mass, such as less than about 12 kD, 11 kD, 10 kD, 9 kD, 8 kD, 7 kD, 6 kD, 5 kD, or any molar mass therebetween or less. In -21- 51532213.1 Attorney Docket No.046483-7413WO1(03398) some embodiments, the small molecule is a small molecule extracellular domain of an affinity molecule chimeric receptor. In some embodiments, the small molecule is a small molecule binding domain of a bispecific affinity molecule. Small molecule may be characterized by their ability to bind a target and their structure. In some embodiments, the small molecule comprises at least one helix, such an alpha-helix, or two helices, three helices or more. The small molecule may also be chemically inert and withstand high temperatures, such as 85°C or higher. By the term “specifically binds,” as used herein with respect to an antibody, is meant an antibody which recognizes a specific antigen, but does not substantially recognize or bind other molecules in a sample. For example, an antibody that specifically binds to an antigen from one species may also bind to that antigen from one or more species. But such cross-species reactivity does not itself alter the classification of an antibody as specific. In another example, an antibody that specifically binds to an antigen may also bind to different allelic forms of the antigen. However, such cross reactivity does not itself alter the classification of an antibody as specific. In some instances, the terms “specific binding” or “specifically binding,” can be used in reference to the interaction of an antibody, a protein, or a peptide with a second chemical species, to mean that the interaction is dependent upon the presence of a particular structure (e.g., an antigenic determinant or epitope) on the chemical species; for example, an antibody recognizes and binds to a specific protein structure rather than to proteins generally. If an antibody is specific for epitope “A”, the presence of a molecule containing epitope A (or free, unlabeled A), in a reaction containing labeled “A” and the antibody, will reduce the amount of labeled A bound to the antibody. By the term “stimulation,” is meant a primary response induced by binding of a stimulatory molecule (e.g., a TCR/CD3 complex) with its cognate ligand thereby mediating a signal transduction event, such as, but not limited to, signal transduction via the TCR/CD3 complex. Stimulation can mediate altered expression of certain molecules, such as downregulation of TGF-beta, and/or reorganization of cytoskeletal structures, and the like. A “stimulatory molecule,” as the term is used herein, means a molecule on a T cell that specifically binds with a cognate stimulatory ligand present on an antigen presenting cell. -22- 51532213.1 Attorney Docket No.046483-7413WO1(03398) A “stimulatory ligand,” as used herein, means a ligand that when present on an antigen presenting cell (e.g., an aAPC, a dendritic cell, a B-cell, and the like) can specifically bind with a cognate binding partner (referred to herein as a “stimulatory molecule”) on a T cell, thereby mediating a primary response by the T cell, including, but not limited to, activation, initiation of an immune response, proliferation, and the like. Stimulatory ligands are well-known in the art and encompass, inter alia, an MHC Class I molecule loaded with a peptide, an anti-CD3 antibody, a super agonist anti-CD28 antibody, and a super agonist anti-CD2 antibody. The term “subject” is intended to include living organisms in which an immune response can be elicited (e.g., mammals). A “subject” or “patient,” as used therein, may be a human or non-human mammal. Non-human mammals include, for example, livestock and pets, such as ovine, bovine, porcine, canine, feline and murine mammals. Preferably, the subject is human. As used herein, a “substantially purified” cell is a cell that is essentially free of other cell types. A substantially purified cell also refers to a cell which has been separated from other cell types with which it is normally associated in its naturally occurring state. In some instances, a population of substantially purified cells refers to a homogenous population of cells. In other instances, this term refers simply to cell that have been separated from the cells with which they are naturally associated in their natural state. In some embodiments, the cells are cultured in vitro. In other embodiments, the cells are not cultured in vitro. A “target site” or “target sequence” refers to a genomic nucleic acid sequence that defines a region of a nucleic acid to which a binding molecule may specifically bind under conditions sufficient for binding to occur. As used herein, the term “T cell receptor” or “TCR” refers to a complex of membrane proteins that participate in the activation of T cells in response to the recognition of an antigen. The TCR is responsible for recognizing antigens bound to major histocompatibility complex (MHC) molecules. The TCR is composed of a heterodimer of an alpha (a) and beta (β) chain, although in some cells the TCR consists of gamma and delta (γ/δ) chains. TCRs may exist in alpha/beta and gamma/delta forms, which are structurally similar but have distinct anatomical locations and functions. Each chain is composed of two extracellular domains, a variable and constant domain. In some -23- 51532213.1 Attorney Docket No.046483-7413WO1(03398) embodiments, the TCR may be modified on any cell comprising a TCR, including, for example, a helper T cell, a cytotoxic T cell, a memory T cell, regulatory T cell, natural killer T cell, and gamma delta T cell. The term “therapeutic” as used herein means a treatment and/or prophylaxis. A therapeutic effect is obtained by suppression, remission, or eradication of a disease state. The term “transfected” or “transformed” or “transduced” as used herein refers to a process by which exogenous nucleic acid is transferred or introduced into the host cell. A “transfected” or “transformed” or “transduced” cell is one which has been transfected, transformed or transduced with exogenous nucleic acid. The cell includes the primary subject cell and its progeny. To “treat” a disease as the term is used herein, means to reduce the frequency or severity of at least one sign or symptom of a disease or disorder experienced by a subject. The phrase “under transcriptional control” or “operatively linked” as used herein means that the promoter is in the correct location and orientation in relation to a polynucleotide to control the initiation of transcription by RNA polymerase and expression of the polynucleotide. A “vector” is a composition of matter which comprises an isolated nucleic acid and which can be used to deliver the isolated nucleic acid to the interior of a cell. Numerous vectors are known in the art including, but not limited to, linear polynucleotides, polynucleotides associated with ionic or amphiphilic compounds, plasmids, and viruses. Thus, the term “vector” includes an autonomously replicating plasmid or a virus. The term should also be construed to include non-plasmid and non- viral compounds which facilitate transfer of nucleic acid into cells, such as, for example, polylysine compounds, liposomes, and the like. Examples of viral vectors include, but are not limited to, adenoviral vectors, adeno-associated virus vectors, retroviral vectors, lentiviral vectors, and the like. Ranges: throughout this disclosure, various aspects of the invention can be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to -24- 51532213.1 Attorney Docket No.046483-7413WO1(03398) 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 2.7, 3, 4, 5, 5.3, and 6. This applies regardless of the breadth of the range. Description The invention of the present disclosure is based on the finding that expression of the Sox2 gene is associated with many cancer cell types, especially cancer stem cells. Endogenous immune responses against Sox2 in cancer patients have been observed to be associated with longer survival and better disease prognosis, and often occur secondary to other treatment strategies, including chimeric antigen receptor (CAR)-T cell therapy. As such, in certain aspects, the present disclosure includes recombinant T cell receptor (TCR) alpha and beta chains which are specific for Sox2 epitopes. Also included are isolated nucleic acids encoding Sox2-specific TCR alpha and beta chains. In certain aspects, the invention also includes methods and compositions for generating a modified T cell capable of expressing a TCR specific for an epitope of Sox2 protein. In other aspects, the invention includes modified T cells and compositions comprising modified T cells which comprise recombinant, Sox2-specific TCR alpha and beta chains, which, in some embodiments, also comprise deletions in endogenous TCR-encoding genetic loci as well as methods for generating said modified T cells. The present disclosure also provides methods for treating Sox2-related diseases and conditions, especially cancers, comprising administering effective amounts of modified T cells comprising said Sox2- specific TCR alpha and beta chains. Sox2 and Cancer The stem cell transcription factor Sox2 is critical for maintaining pluripotency and self-renewal capacity of embryonic stem cells, where its normal expression contributes to the formation of several endodermal and ectodermal tissues, especially the central nervous system, anterior foregut endoderm, retina, and skin. In cancer, the expression or over-expression of Sox2 protein promotes tumor-initiating, stemness, or lineage-plasticity phenotypes in different types of cancers, including glioblastoma, non-small cell lung cancer, breast cancer, prostate cancer, and multiple myeloma (MM). By way of a non- -25- 51532213.1 Attorney Docket No.046483-7413WO1(03398) limiting example, in multiple myeloma, Sox2 is expressed in a minor subset of cancer cells (cancer stem cells), which are capable of aggressive growth. The frequency of Sox2+ myeloma cells increase during the transition from of myeloma precursor conditions (e.g., monoclonal gammopathy of undetermined significance (MGUS)) to symptomatic MM. Sox2 is also required for the persistence of residual MM after otherwise successful treatment in murine animal models. In certain embodiments, the invention of the current disclosure provides immunotherapies, particularly recombinant T cell receptors and modified T cells comprising recombinant T cell receptors specific for Sox2 protein. Multiple myeloma (MM), a cancer of bone marrow plasma cells, is the second most common hematological malignancy, with 32270 new cases and 12830 myeloma- related deaths expected in the US in 2020. Initial response rates and survival in MM have improved with the development of new therapies with nearly 90% of patients with newly diagnosed myeloma responding to first-line therapy. However, most patients, even those who achieve complete responses, eventually relapse and die of drug-resistant disease. Nearly all MM cases arise from a precursor state called monoclonal gammopathy of unknown significance (MGUS) that progresses into smoldering multiple myeloma (SMM) and finally into MM. Both MGUS and MM cells share a complex genomic landscape, suggesting that factors beyond the cancer clone such as impaired immunosurveillance or a permissive BM microenvironment may play an important role in the progression from MGUS to MM. In vitro studies demonstrated that cellular immunity against Sox2 inhibits the clonogenic growth of MGUS cells. T-cell immune responses against Sox2 in patients with are associated with decreased risk of progression to MM, suggesting that immune responses against Sox2 peptides are recognized by T cells of the host immune system and can control myeloma growth. T Cell Receptors In certain aspects, the invention of the current disclosure includes recombinant T cell receptor alpha and beta chains which can associate with each other in order to form functional recombinant T cell receptors (TCRs) specific for epitopes of Sox2 protein. In another aspect, the invention includes a method for generating a modified T cell comprising expanding a population of T cells and introducing a nucleic acid encoding -26- 51532213.1 Attorney Docket No.046483-7413WO1(03398) modified T cell receptor (TCR) alpha and beta chains with binding affinity for epitopes of Sox2 protein expressed by a target cell into the expanded T cells. In this embodiment, the T cells are capable of expressing the modified TCR. A T cell receptor is a complex of membrane proteins that participate in the activation of T cells in response to the recognition of presented antigen. Stimulation of the TCR is triggered by major histocompatibility complex molecules (MHC) or human leukocyte antigen complex molecules (HLA) on either normal cells (in the case of HLA/MHC class I) or professional antigen presenting cells (in the case of HLA/MHC class II) that present antigenic peptides to the T cells and bind to the TCR ab heterodimer to induce a series of intracellular signaling cascades. The TCR complex is generally composed of six different membrane bound proteins that form the TCR heterodimer complex. Antigen recognition is provided by the TCR alpha (α) and TCR beta (β) chains, while signal transduction is provided by a CD3δ chain, two CD3ε chains, and the CD3ζ chain. TCRs exist in alpha/beta and gamma/delta forms, which are structurally similar but have distinct anatomical locations and functions. In one embodiment, the TCR comprises a TCR alpha and beta chain, such as the nucleic acid encoding the TCR comprises a nucleic acid encoding a TCR alpha and a TCR beta chain. In another embodiment, an alpha or beta chain or both comprises at least one N- deglycosylation. Each chain is composed of two extracellular domains, a variable and constant domain. The constant domain is proximal to the cell membrane, followed by a transmembrane domain and a short cytoplasmic tail. The variable domain contributes to the determination of the particular antigen and HLA molecule to which the TCR has binding specificity. In turn, the specificity of a T cell for a unique antigen-HLA complex resides in the particular TCR expressed by the T cell. The variable domains include the highly polymorphic loops analogous to the complementarity determining regions (CDRs) of antibodies. The diversity of TCR sequences is generated via somatic rearrangement of linked variable (V), diversity (D), joining (J), and constant genes. Functional alpha and gamma chain polypeptides are formed by rearranged V-J-C regions, whereas beta and delta chains consist of V-D-J-C regions. The extracellular constant domain includes a membrane proximal region and an immunoglobulin region. -27- 51532213.1 Attorney Docket No.046483-7413WO1(03398) In one embodiment, the invention of the current disclosure comprises two TCR chains, each of which comprises a human TCR alpha or beta variable region comprising a complementarity determining region (CDR)1, a CDR2, and a CDR3. In one embodiment, the TCR alpha chain comprises a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 11 and the TCR beta chain comprises a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 12. In another embodiment, the TCR alpha chain comprises a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 13 and the TCR beta chain comprises a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 14. In an embodiment of the invention of the current disclosure, the TCR can comprise an amino acid sequence of a variable region of a TCR comprising the CDRs set forth above. In this regard, the TCR can comprise the α chain amino acid sequence of SEQ ID NO: 7, the β chain amino acid sequence of SEQ ID NO: 8, or both SEQ ID NOs: 7 and 8. Preferably, the TCR of the invention comprises the amino acid sequences of both SEQ ID NOs: 7 and 8. In another embodiment of the invention of the current disclosure, the TCR can comprise the α chain amino acid sequence of SEQ ID NO: 9, the β chain amino acid sequence of SEQ ID NO: 10, or both SEQ ID NOs: 9 and 10. Preferably, the inventive TCR of the invention comprises the amino acid sequences of both SEQ ID NOs: 9 and 10. In one embodiment, the TCR includes a wildtype TCR, a high affinity TCR, and a chimeric TCR. When the TCR is modified, it may have higher affinity for the target cell antigen than a wildtype TCR. In embodiments where the TCR is a chimeric TCR, the TCR may include chimeric domains, such as the TCR comprises a co-stimulatory signaling domain at a C’ terminal of at least one of the chains. In other embodiments, the TCR may include a modified chain, such as a modified alpha or beta chain. Such modifications may include, but are not limited to, N-deglycosylation, altered domain (such as an engineered variable region to target a specific antigen or increase affinity), addition of one or more disulfide bonds, entire or fragment of a chain derived from a different species, and any combination thereof. Also provided by the invention is a polypeptide comprising a functional portion of any of the TCRs (or functional variants thereof) disclosed herein. With respect to the -28- 51532213.1 Attorney Docket No.046483-7413WO1(03398) polypeptides of the invention, the functional portion can be any portion comprising contiguous amino acids of the TCR of which it is a part, provided that the functional portion specifically binds to an epitope of Sox2. The term “functional portion” when used in reference to a TCR refers to any part or fragment of the TCR alpha or beta chains of the invention, which retains the biological activity of the original or parent TCR alpha or beta chains of which it is a part. Functional portions encompass, for example, those parts of a TCR alpha or beta chains that retain the ability to specifically bind to an epitope of Sox2 protein (e.g., as presented on an HLA complex, for example HLA-B*07:02). In reference to the TCR of the invention, the functional portion can comprise, for instance, about 10%, 25%, 30%, 50%, 68%, 80%, 90%, 95%, or more, of the original TCR alpha or beta chains (or functional variants thereof). The functional portion can comprise additional amino acids at the amino or carboxy terminus of the portion, or at both termini, which additional amino acids are not found in the amino acid sequence of the original or parent TCR alpha or beta chains or functional variants thereof. Desirably, the additional amino acids do not interfere with the biological function of the functional portion, e.g., specifically binding to epitopes of Sox2. More desirably, the additional amino acids enhance the biological activity, as compared to the biological activity of the parent TCR or functional variant thereof. In certain embodiments of the invention of the current disclosure, the invention includes a polypeptide which comprises a first polypeptide region, a linker polypeptide, and a second polypeptide region, wherein the first and second polypeptide regions comprise TCR alpha and/or beta chains. In certain embodiments, the linker polypeptide comprises a self-cleaving polypeptide sequence. In certain preferred embodiments, the self-cleaving peptide is a 2A peptide. 2A peptides are known in the art as 12-22 amino acid-long peptides which induce ribosomal skipping during translation and share a core sequence motif of DxExNPGP. Non-binding examples of 2A peptides which could be used in polypeptides of the invention include T2A (EGRGSLLTCGDVEENPGP, SEQ ID NO: 15), P2A (ATNFSLLKQAGDVEENPGP, SEQ ID NO: 16), E2A (QCTNYALLKLAGDVESNPGP, SEQ ID NO: 17), and F2A (VKQTLNFDLLKLAGDVESNPGP, SEQ ID NO: 18). In certain preferred embodiments, the polypeptides of the current invention comprise TCR alpha and beta chains separated by T2A self-cleaving peptide sequences such that expression of the -29- 51532213.1 Attorney Docket No.046483-7413WO1(03398) polypeptide results in expression of separate TCR alpha and beta chains. It is also contemplated that any self-cleaving peptide sequence which is function in eukaryotic or mammalian cells, (e.g., T cells) would be able to be used in the polypeptides of the invention of the current disclosure. In one aspect, the invention includes a population of modified T cells comprising an exogenous nucleic acid encoding a modified T cell receptor (TCR) comprising affinity for a Sox2 protein on a target cell, wherein the population of T cells was expanded prior to introduction of the exogenous nucleic acid. Techniques for engineering and expressing T cell receptors include, but are not limited to, the production of TCR heterodimers which include the native disulphide bridge which connects the respective subunits (Garboczi, et al., (1996), Nature 384(6605): 134-41; Garboczi, et al., (1996), J Immunol 157(12): 5403-10; Chang et al., (1994), PNAS USA 91: 11408-11412; Davodeau et al., (1993), J. Biol. Chem.268(21): 15455-15460; Golden et al., (1997), J. Imm. Meth.206: 163-169; U.S. Pat. No. 6,080,840). The target cell antigen may include any epitope of Sox2 protein that may be processed and presented by major histocompability or human leukocyte antigen complexes. For example, the Sox2 epitope antigen may be associated with a particular disease state. Introduction of Nucleic Acids Methods of introducing nucleic acids into a cell include physical, biological and chemical methods. Physical methods for introducing a polynucleotide, such as RNA, into a host cell include calcium phosphate precipitation, lipofection, particle bombardment, microinjection, electroporation, and the like. RNA can be introduced into target cells using commercially available methods which include electroporation (Amaxa Nucleofector-II (Amaxa Biosystems, Cologne, Germany)), (ECM 830 (BTX) (Harvard Instruments, Boston, Mass.) or the Gene Pulser II (BioRad, Denver, Colo.), Multiporator (Eppendort, Hamburg Germany). RNA can also be introduced into cells using cationic liposome mediated transfection using lipofection, using polymer encapsulation, using peptide mediated transfection, or using biolistic particle delivery systems such as “gene guns” (see, for example, Nishikawa, et al. Hum Gene Ther., 12(8):861-70 (2001). -30- 51532213.1 Attorney Docket No.046483-7413WO1(03398) Biological methods for introducing a polynucleotide of interest into a host cell include the use of DNA and RNA vectors. Viral vectors, and especially retroviral vectors, have become the most widely used method for inserting genes into mammalian, e.g., human cells. Other viral vectors can be derived from lentivirus, poxviruses, herpes simplex virus I, adenoviruses and adeno-associated viruses, and the like. See, for example, U.S. Pat. Nos.5,350,674 and 5,585,362. Chemical means for introducing a polynucleotide into a host cell include colloidal dispersion systems, such as macromolecule complexes, nanocapsules, microspheres, beads, and lipid-based systems including oil-in-water emulsions, micelles, mixed micelles, and liposomes. An exemplary colloidal system for use as a delivery vehicle in vitro and in vivo is a liposome (e.g., an artificial membrane vesicle). Lipids suitable for use can be obtained from commercial sources. For example, dimyristyl phosphatidylcholine (“DMPC”) can be obtained from Sigma, St. Louis, MO; dicetyl phosphate (“DCP”) can be obtained from K & K Laboratories (Plainview, NY); cholesterol (“Choi”) can be obtained from Calbiochem-Behring; dimyristyl phosphatidylglycerol (“DMPG”) and other lipids may be obtained from Avanti Polar Lipids, Inc. (Birmingham, AL). Stock solutions of lipids in chloroform or chloroform/methanol can be stored at about -20 ^C. Chloroform is used as the only solvent since it is more readily evaporated than methanol. “Liposome” is a generic term encompassing a variety of single and multilamellar lipid vehicles formed by the generation of enclosed lipid bilayers or aggregates. Liposomes can be characterized as having vesicular structures with a phospholipid bilayer membrane and an inner aqueous medium. Multilamellar liposomes have multiple lipid layers separated by aqueous medium. They form spontaneously when phospholipids are suspended in an excess of aqueous solution. The lipid components undergo self-rearrangement before the formation of closed structures and entrap water and dissolved solutes between the lipid bilayers (Ghosh et al., 1991 Glycobiology 5: 505-10). However, compositions that have different structures in solution than the normal vesicular structure are also encompassed. For example, the lipids may assume a micellar structure or merely exist as nonuniform aggregates of lipid molecules. Also contemplated are lipofectamine-nucleic acid complexes. -31- 51532213.1 Attorney Docket No.046483-7413WO1(03398) Regardless of the method used to introduce exogenous nucleic acids into a host cell or otherwise expose a cell to the inhibitor of the present invention, in order to confirm the presence of the nucleic acids in the host cell, a variety of assays may be performed. Such assays include, for example, “molecular biological” assays well known to those of skill in the art, such as Southern and Northern blotting, RT-PCR and PCR; “biochemical” assays, such as detecting the presence or absence of a particular peptide, e.g., by immunological means (ELISAs and Western blots) or by assays described herein to identify agents falling within the scope of the invention. In one embodiment, a nucleic acid encoding a T cell receptor (TCR) comprising affinity for an antigen on a target cell is introduced into the T cells. The nucleic acid may be introduced by any means, such as transducing the expanded T cells, transfecting the expanded T cells, and electroporating the expanded T cells. RNA In one embodiment, the nucleic acids introduced into the T cell are RNA. In another embodiment, the RNA is mRNA that comprises in vitro transcribed RNA or synthetic RNA. The RNA is produced by in vitro transcription using a polymerase chain reaction (PCR)-generated template. DNA of interest from any source can be directly converted by PCR into a template for in vitro mRNA synthesis using appropriate primers and RNA polymerase. The source of the DNA can be, for example, genomic DNA, plasmid DNA, phage DNA, cDNA, synthetic DNA sequence or any other appropriate source of DNA. The desired template for in vitro transcription is a chimeric membrane protein. By way of example, the template encodes an antibody, a fragment of an antibody or a portion of an antibody. By way of another example, the template comprises an extracellular domain comprising a single chain variable domain of an antibody, such as anti-CD3, and an intracellular domain of a co-stimulatory molecule. In one embodiment, the template for the RNA chimeric membrane protein encodes a chimeric membrane protein comprising an extracellular domain comprising an antigen binding domain derived from an antibody to a co-stimulatory molecule, and an intracellular domain derived from a portion of an intracellular domain of CD28 and 4-1BB. PCR can be used to generate a template for in vitro transcription of mRNA which is then introduced into cells. Methods for performing PCR are well known in the art. -32- 51532213.1 Attorney Docket No.046483-7413WO1(03398) Primers for use in PCR are designed to have regions that are substantially complementary to regions of the DNA to be used as a template for the PCR. “Substantially complementary”, as used herein, refers to sequences of nucleotides where a majority or all of the bases in the primer sequence are complementary, or one or more bases are non- complementary, or mismatched. Substantially complementary sequences are able to anneal or hybridize with the intended DNA target under annealing conditions used for PCR. The primers can be designed to be substantially complementary to any portion of the DNA template. For example, the primers can be designed to amplify the portion of a gene that is normally transcribed in cells (the open reading frame), including 5' and 3' UTRs. The primers can also be designed to amplify a portion of a gene that encodes a particular domain of interest. In one embodiment, the primers are designed to amplify the coding region of a human cDNA, including all or portions of the 5' and 3' UTRs. Primers useful for PCR are generated by synthetic methods that are well known in the art. “Forward primers” are primers that contain a region of nucleotides that are substantially complementary to nucleotides on the DNA template that are upstream of the DNA sequence that is to be amplified. “Upstream” is used herein to refer to a location 5, to the DNA sequence to be amplified relative to the coding strand. “Reverse primers” are primers that contain a region of nucleotides that are substantially complementary to a double-stranded DNA template that are downstream of the DNA sequence that is to be amplified. “Downstream” is used herein to refer to a location 3' to the DNA sequence to be amplified relative to the coding strand. Chemical structures that have the ability to promote stability and/or translation efficiency of the RNA may also be used. The RNA preferably has 5' and 3' UTRs. In one embodiment, the 5' UTR is between zero and 3000 nucleotides in length. The length of 5' and 3' UTR sequences to be added to the coding region can be altered by different methods, including, but not limited to, designing primers for PCR that anneal to different regions of the UTRs. Using this approach, one of ordinary skill in the art can modify the 5' and 3' UTR lengths required to achieve optimal translation efficiency following transfection of the transcribed RNA. The 5' and 3' UTRs can be the naturally occurring, endogenous 5' and 3' UTRs for the gene of interest. Alternatively, UTR sequences that are not endogenous to the gene of interest can be added by incorporating the UTR sequences into the forward and reverse -33- 51532213.1 Attorney Docket No.046483-7413WO1(03398) primers or by any other modifications of the template. The use of UTR sequences that are not endogenous to the gene of interest can be useful for modifying the stability and/or translation efficiency of the RNA. For example, it is known that AU-rich elements in 3' UTR sequences can decrease the stability of mRNA. Therefore, 3' UTRs can be selected or designed to increase the stability of the transcribed RNA based on properties of UTRs that are well known in the art. In one embodiment, the 5' UTR can contain the Kozak sequence of the endogenous gene. Alternatively, when a 5' UTR that is not endogenous to the gene of interest is being added by PCR as described above, a consensus Kozak sequence can be redesigned by adding the 5' UTR sequence. Kozak sequences can increase the efficiency of translation of some RNA transcripts but does not appear to be required for all RNAs to enable efficient translation. The requirement for Kozak sequences for many mRNAs is known in the art. In other embodiments the 5' UTR can be derived from an RNA virus whose RNA genome is stable in cells. In other embodiments various nucleotide analogues can be used in the 3' or 5' UTR to impede exonuclease degradation of the mRNA. To enable synthesis of RNA from a DNA template without the need for gene cloning, a promoter of transcription should be attached to the DNA template upstream of the sequence to be transcribed. When a sequence that functions as a promoter for an RNA polymerase is added to the 5' end of the forward primer, the RNA polymerase promoter becomes incorporated into the PCR product upstream of the open reading frame that is to be transcribed. In one embodiment, the promoter is a T7 polymerase promoter, as described elsewhere herein. Other useful promoters include, but are not limited to, T3 and SP6 RNA polymerase promoters. Consensus nucleotide sequences for T7, T3 and SP6 promoters are known in the art. In one embodiment, the mRNA has both a cap on the 5' end and a 3' poly(A) tail which determine ribosome binding, initiation of translation and stability mRNA in the cell. On a circular DNA template, for instance, plasmid DNA, RNA polymerase produces a long concatemeric product which is not suitable for expression in eukaryotic cells. The transcription of plasmid DNA linearized at the end of the 3' UTR results in normal sized mRNA which is not effective in eukaryotic transfection even if it is polyadenylated after transcription. -34- 51532213.1 Attorney Docket No.046483-7413WO1(03398) On a linear DNA template, phage T7 RNA polymerase can extend the 3' end of the transcript beyond the last base of the template (Schenborn and Mierendorf, Nuc Acids Res., 13:6223-36 (1985); Nacheva and Berzal-Herranz, Eur. J. Biochem., 270:1485-65 (2003). The conventional method of integration of polyA/T stretches into a DNA template is molecular cloning. However, polyA/T sequence integrated into plasmid DNA can cause plasmid instability, which is why plasmid DNA templates obtained from bacterial cells are often highly contaminated with deletions and other aberrations. This makes cloning procedures not only laborious and time consuming but often not reliable. That is why a method which allows construction of DNA templates with polyA/T 3' stretch without cloning highly desirable. The polyA/T segment of the transcriptional DNA template can be produced during PCR by using a reverse primer containing a polyT tail, such as 100T tail (size can be 50-5000 T), or after PCR by any other method, including, but not limited to, DNA ligation or in vitro recombination. Poly(A) tails also provide stability to RNAs and reduce their degradation. Generally, the length of a poly(A) tail positively correlates with the stability of the transcribed RNA. In one embodiment, the poly(A) tail is between 100 and 5000 adenosines. Poly(A) tails of RNAs can be further extended following in vitro transcription with the use of a poly(A) polymerase, such as E. coli polyA polymerase (E-PAP). In one embodiment, increasing the length of a poly(A) tail from 100 nucleotides to between 300 and 400 nucleotides results in about a two-fold increase in the translation efficiency of the RNA. Additionally, the attachment of different chemical groups to the 3' end can increase mRNA stability. Such attachment can contain modified/artificial nucleotides, aptamers and other compounds. For example, ATP analogs can be incorporated into the poly(A) tail using poly(A) polymerase. ATP analogs can further increase the stability of the RNA. 5' caps also provide stability to RNA molecules. In a preferred embodiment, RNAs produced by the methods disclosed herein include a 5' cap. The 5' cap is provided using techniques known in the art and described herein (Cougot, et al., Trends in Biochem. Sci., 29:436-444 (2001); Stepinski, et al., RNA, 7:1468-95 (2001); Elango, et al., Biochim. Biophys. Res. Commun., 330:958-966 (2005)). -35- 51532213.1 Attorney Docket No.046483-7413WO1(03398) The RNAs produced by the methods disclosed herein can also contain an internal ribosome entry site (IRES) sequence. The IRES sequence may be any viral, chromosomal or artificially designed sequence which initiates cap-independent ribosome binding to mRNA and facilitates the initiation of translation. Any solutes suitable for cell electroporation, which can contain factors facilitating cellular permeability and viability such as sugars, peptides, lipids, proteins, antioxidants, and surfactants can be included. The disclosed methods can be applied to the modulation of T cell activity in basic research and therapy, in the fields of cancer, stem cells, acute and chronic infections, and autoimmune diseases, including the assessment of the ability of the genetically modified T cell to kill a target cancer cell. The methods also provide the ability to control the level of expression over a wide range by changing, for example, the promoter or the amount of input RNA, making it possible to individually regulate the expression level. Furthermore, the PCR-based technique of mRNA production greatly facilitates the design of the chimeric receptor mRNAs with different structures and combination of their domains. For example, varying of different intracellular effector/costimulatory domains on multiple chimeric receptors in the same cell allows determination of the structure of the receptor combinations which assess the highest level of cytotoxicity against multi-antigenic targets, and at the same time lowest cytotoxicity toward normal cells. One advantage of RNA transfection methods of the invention is that RNA transfection is essentially transient and a vector-free. An RNA transgene can be delivered to a lymphocyte and expressed therein following a brief in vitro cell activation, as a minimal expressing cassette without the need for any additional viral sequences. Under these conditions, integration of the transgene into the host cell genome is unlikely. Cloning of cells is not necessary because of the efficiency of transfection of the RNA and its ability to uniformly modify the entire lymphocyte population. Genetic modification of T cells with in vitro-transcribed RNA (IVT-RNA) makes use of two different strategies both of which have been successively tested in various animal models. Cells are transfected with in vitro-transcribed RNA by means of lipofection or electroporation. It is desirable to stabilize IVT-RNA using various modifications in order to achieve prolonged expression of transferred IVT-RNA. -36- 51532213.1 Attorney Docket No.046483-7413WO1(03398) Some IVT vectors are known in the literature which are utilized in a standardized manner as template for in vitro transcription and which have been genetically modified in such a way that stabilized RNA transcripts are produced. Currently protocols used in the art are based on a plasmid vector with the following structure: a 5' RNA polymerase promoter enabling RNA transcription, followed by a gene of interest which is flanked either 3' and/or 5' by untranslated regions (UTR), and a 3' polyadenyl cassette containing 50-70 A nucleotides. Prior to in vitro transcription, the circular plasmid is linearized downstream of the polyadenyl cassette by type II restriction enzymes (recognition sequence corresponds to cleavage site). The polyadenyl cassette thus corresponds to the later poly(A) sequence in the transcript. As a result of this procedure, some nucleotides remain as part of the enzyme cleavage site after linearization and extend or mask the poly(A) sequence at the 3' end. It is not clear, whether this nonphysiological overhang affects the amount of protein produced intracellularly from such a construct. RNA has several advantages over more traditional plasmid or viral approaches. Gene expression from an RNA source does not require transcription and the protein product is produced rapidly after the transfection. Further, since the RNA has to only gain access to the cytoplasm, rather than the nucleus, and therefore typical transfection methods result in an extremely high rate of transfection. In addition, plasmid-based approaches require that the promoter driving the expression of the gene of interest be active in the cells under study. In another aspect, the RNA construct is delivered into the cells by electroporation. See, e.g., the formulations and methodology of electroporation of nucleic acid constructs into mammalian cells as taught in US 2004/0014645, US 2005/0052630A1, US 2005/0070841A1, US 2004/0059285A1, US 2004/0092907A1. The various parameters including electric field strength required for electroporation of any known cell type are generally known in the relevant research literature as well as numerous patents and applications in the field. See e.g., U.S. Pat. No.6,678,556, U.S. Pat. No.7,171,264, and U.S. Pat. No.7,173,116. Apparatus for therapeutic application of electroporation are available commercially, e.g., the MedPulser™ DNA Electroporation Therapy System (Inovio/Genetronics, San Diego, Calif.), and are described in patents such as U.S. Pat. No.6,567,694; U.S. Pat. No.6,516,223, U.S. Pat. No.5,993,434, U.S. Pat. No.6,181,964, U.S. Pat. No.6,241,701, and U.S. Pat. No.6,233,482; electroporation may also be used -37- 51532213.1 Attorney Docket No.046483-7413WO1(03398) for transfection of cells in vitro as described e.g. in US20070128708A1. Electroporation may also be utilized to deliver nucleic acids into cells in vitro. Accordingly, electroporation-mediated administration into cells of nucleic acids including expression constructs utilizing any of the many available devices and electroporation systems known to those of skill in the art presents an exciting new means for delivering an RNA of interest to a target cell. In some embodiments, the RNA encoding a TCR is electroporated into the cells. In one embodiment, the RNA encoding the TCR is in vitro transcribed RNA. In some embodiments, the mRNA encoding bispecific antibodies are electroporated into the cells. In another embodiment, the mRNA encoding bispecific antibodies is in vitro transcribed mRNA. In some embodiments, the RNA encoding bispecific antibodies is electroporated into the cells. In one embodiment, the RNA encoding bispecific antibodies is in vitro transcribed RNA. In some embodiments, the RNA encoding the affinity molecule chimeric receptor or bispecific affinity molecule is electroporated into the cells. In one embodiment, the RNA encoding the affinity molecule chimeric receptor or bispecific affinity molecule is in vitro transcribed RNA. In one embodiment, the method includes electroporating an RNA encoding a TCR alpha and beta chain. The TCR alpha and beta chain can be encoded on the same or separate RNAs, such as co-electroporating an RNA encoding the TCR alpha chain and a separate RNA encoding the TCR beta chain. When the alpha and beta are encoded by separate RNAs, the RNA may be co-electroporated. In some embodiments, the method further includes electroporating a nucleic acid encoding a bispecific antibody or BiTE molecule. The bispecific antibody nucleic acid may be co-electroporated with the TCR RNA. In another embodiment, the method may further include electroporating a nucleic acid encoding a costimulatory molecule. The costimulatory molecule nucleic acid may be co-electroporated with the TCR RNA. In one embodiment, the method includes electroporating an RNA encoding the affinity molecule chimeric receptor. In another embodiment, the method further includes electroporating an RNA encoding a co-stimulatory molecule, such as CD3. The affinity -38- 51532213.1 Attorney Docket No.046483-7413WO1(03398) molecule chimeric receptor and co-stimulatory molecule can be encoded on the same or separate RNAs. When the affinity molecule chimeric receptor and co-stimulatory molecule are encoded by separate RNAs, the RNA may be co-electroporated. In another embodiment, the method includes electroporating a nucleic acid encoding a bispecific affinity molecule. The costimulatory molecule nucleic acid may also be co-electroporated with the bispecific affinity molecule nucleic acid. Nucleic Acids and Expression Vectors The present disclosure provides an isolated nucleic acid encoding a polypeptide. The nucleic acid of the present disclosure can comprise a polynucleotide sequence encoding any one of the T cell receptors or any fragments thereof disclosed herein. One aspect of the present disclosure includes an isolated nucleic acid encoding a T cell receptor that comprises an antigen-binding domain that specifically binds an epitope of human Sox2 protein presented by HLA*B7:02. In certain embodiments, the nucleic acid comprises a T cell receptor comprising an antigen binding domain comprising an alpha chain variable region that comprises three alpha chain complementarity determining regions (CDRs) and a beta chain variable region that comprises three beta chain complementarity determining regions (CDRs). The alpha chain CDR3 comprises the amino acid sequences (SEQ ID NOs: 7 or 9) and/or the beta chain CDR3 comprises the amino acid sequences (SEQ ID NOs: 8 or 10). In certain embodiments, the binding polypeptide comprises a T cell receptor or antigen-binding fragment thereof. In certain embodiments, the T cell receptor is encoded by a nucleic acid comprising a polynucleotide sequence having at least 80%, 85%, 90%, 95%, 96%, 96%, 97%, 98%, 99% identity to SEQ ID NOs: 3 or 5. In certain embodiments, the T cell receptor is encoded by a nucleic acid comprising the polynucleotide sequence set forth in SEQ ID NOs: 3 or 5. In certain embodiments, the T cell receptor is encoded by a nucleic acid consisting of the polynucleotide sequence set forth in SEQ ID NO: 3 or 5. Tolerable variations of the nucleic acid sequences will be known to those of skill in the art. For example, in some embodiments the nucleic acid encoding a T cell receptor comprises a nucleotide sequence that has at least 80%, at least 81%, at least 82%, at least -39- 51532213.1 Attorney Docket No.046483-7413WO1(03398) 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to any of the nucleotide sequences set forth in SEQ ID NOs: 3 or 5 In certain embodiments, a nucleic acid of the present disclosure comprises a first polynucleotide sequence and a second polynucleotide sequence. The first and second polynucleotide sequences may be separated by a linker. For example, in certain embodiments the alpha chain region and beta chain region of a T cell receptor are separated a linker. In certain embodiments, the nucleic acid comprises from 5’ to 3’ the first polynucleotide sequence, the linker, and the second polynucleotide sequence. In certain embodiments, the nucleic acid comprises from 5’ to 3’ the second polynucleotide sequence, the linker, and the first polynucleotide sequence. In certain embodiments, the linker sequence encodes a self-cleaving peptide sequence. In certain embodiments, the self-cleaving peptide sequence encodes a T2A peptide. Another aspect of the present disclosure provides a vector comprising any one of the isolated nucleic acids disclosed herein. In certain embodiments, the vector is selected from the group consisting of a DNA vector, an RNA vector, a plasmid, a lentiviral vector, an adenoviral vector, an adeno-associated viral vector, and a retroviral vector. In certain embodiments, the vector is an expression vector. Also provided is a host cell comprising any of the vectors or nucleic acids disclosed herein. The host cell can be of eukaryotic, prokaryotic, mammalian, or bacterial origin. Non-limiting examples of cells that can be used to express the T cell receptors disclosed herein include Human CD8+ T cells, CD4+ T cell, NK T cells, and the like. In certain embodiments, the host cell is a human CD8+ T cell. Also provided is a method for generating a modified T cell comprising introducing any one of the nucleic acids disclosed herein into a T cell. In some embodiments, the method further comprises modifying the expression of an endogenous genetic locus encoding a TCR alpha chain, beta chain, both alpha and beta chains. In certain embodiments, the modification reduces or eliminates expression of endogenous TCR alpha chains, beta chains, or alpha and beta chains. -40- 51532213.1 Attorney Docket No.046483-7413WO1(03398) In some embodiments, a nucleic acid of the present disclosure can be operably linked to a transcriptional control element, e.g., a promoter and enhancer, etc. Suitable promoter and enhancer elements are known to those of skill in the art. Modified Immune Cells In another aspect, the present disclosure provides a modified T cell or immune precursor thereof comprising an any of the nucleic acids disclosed herein. In certain embodiments, the nucleic acid encodes a recombinant TCR specific for an epitope of Sox2 protein. In certain embodiments, the T cell or precursor thereof is obtained from peripheral cells, cord blood cells, a purified population of T cells, and a T cell line. In certain embodiments, the T cell or precursor thereof is a CD8+ T cell, a CD4+ T cell, a Th1 helper T cell, a Th2 helper T cell, a Th17 helper T cell, a cytotoxic T cell, a memory T cell, a regulatory T cell, natural killer T cell, and a gamma delta T cell. In certain embodiments, the modified T cell or immune precursor thereof further comprises a modified endogenous genetic locus. In certain embodiments, the modified endogenous genetic locus encodes the TCR alpha and beta chains, and the modification reduces or eliminates expression of the TCR alpha, TCR beta, or both TCR alpha and beta chains. This modification is combined with expression of the exogenous TCR alpha and beta chains such that the only TCR expressed by the modified T cell is that encoded by the exogenous nucleic acid. In certain embodiments, the modification of the endogenous genetic locus is accomplished by way of a CRISPR or CRISPR/Cas system which edits or mutates the endogenous locus such that expression of the endogenous TCR alpha and/or beta chains is disrupted. It should be understood that any gene editing system known in art which is capable of disruption expression of endogenous TCR alpha and/or beta chain proteins can be used to generate the modified T cells of the invention, and that the skilled artisan would be able to select a gene modifying or editing system appropriate for use. The CRISPR/Cas9 system is a facile and efficient system for inducing targeted genetic alterations. Target recognition by the Cas9 protein requires a ‘seed’ sequence within the guide RNA (gRNA) and a conserved di-nucleotide containing protospacer adjacent motif (PAM) sequence upstream of the gRNA-binding region. The CRISPR/Cas9 system can thereby be engineered to cleave virtually any DNA sequence -41- 51532213.1 Attorney Docket No.046483-7413WO1(03398) by redesigning the gRNA in cell lines (such as 293T cells), primary cells, and CAR T cells. The CRISPR/Cas9 system can simultaneously target multiple genomic loci by co- expressing a single Cas9 protein with two or more gRNAs, making this system uniquely suited for multiple gene editing or synergistic activation of target genes. The Cas9 protein and guide RNA form a complex that identifies and cleaves target sequences. Cas9 is comprised of six domains: REC I, REC II, Bridge Helix, PAM interacting, HNH, and RuvC. The RecI domain binds the guide RNA, while the Bridge helix binds to target DNA. The HNH and RuvC domains are nuclease domains. Guide RNA is engineered to have a 5’ end that is complementary to the target DNA sequence. Upon binding of the guide RNA to the Cas9 protein, a conformational change occurs activating the protein. Once activated, Cas9 searches for target DNA by binding to sequences that match its protospacer adjacent motif (PAM) sequence. A PAM is a two to six nucleotide base sequence within one nucleotide downstream of the region complementary to the guide RNA. In one non-limiting example, the PAM sequence is 5’- NGG-3’. When the Cas9 protein finds its target sequence with the appropriate PAM, it melts the bases upstream of the PAM and pairs them with the complementary region on the guide RNA. Then the RuvC and HNH nuclease domains cut the target DNA after the third nucleotide base upstream of the PAM. One non-limiting example of a CRISPR/Cas system used to inhibit gene expression, CRISPRi, is described in U.S. Publication No. US20140068797. CRISPRi induces permanent gene disruption that utilizes the RNA-guided Cas9 endonuclease to introduce DNA double stranded breaks which trigger error-prone repair pathways to result in frame shift mutations. A catalytically dead Cas9 lacks endonuclease activity. When coexpressed with a guide RNA, a DNA recognition complex is generated that specifically interferes with transcriptional elongation, RNA polymerase binding, or transcription factor binding. This CRISPRi system efficiently represses expression of targeted genes. CRISPR/Cas gene disruption occurs when a guide nucleic acid sequence specific for a target gene and a Cas endonuclease are introduced into a cell and form a complex that enables the Cas endonuclease to introduce a double strand break at the target gene. In certain embodiments, the CRISPR/Cas system comprises an expression vector, such as, but not limited to, an pAd5F35-CRISPR vector. In other embodiments, the Cas -42- 51532213.1 Attorney Docket No.046483-7413WO1(03398) expression vector induces expression of Cas9 endonuclease. Other endonucleases may also be used, including but not limited to, T7, Cas3, Cas8a, Cas8b, Cas10d, Cse1, Csy1, Csn2, Cas4, Cas10, Csm2, Cmr5, Fok1, other nucleases known in the art, and any combination thereof. Sources of T Cells Prior to expansion, a source of T cells is obtained from a subject. Non-limiting examples of subjects include humans, dogs, cats, mice, rats, and transgenic species thereof. Preferably, the subject is a human. T cells can be obtained from a number of sources, including peripheral blood mononuclear cells, bone marrow, lymph node tissue, spleen tissue, umbilical cord, and tumors. In certain embodiments, any number of T cell lines available in the art, may be used. In certain embodiments, T cells can be obtained from a unit of blood collected from a subject using any number of techniques known to the skilled artisan, such as Ficoll separation. In one embodiment, cells from the circulating blood of an individual are obtained by apheresis or leukapheresis. The apheresis product typically contains lymphocytes, including T cells, monocytes, granulocytes, B cells, other nucleated white blood cells, red blood cells, and platelets. The cells collected by apheresis may be washed to remove the plasma fraction and to place the cells in an appropriate buffer or media, such as phosphate buffered saline (PBS) or wash solution lacks calcium and may lack magnesium or may lack many if not all divalent cations, for subsequent processing steps. After washing, the cells may be resuspended in a variety of biocompatible buffers, such as, for example, Ca-free, Mg-free PBS. Alternatively, the undesirable components of the apheresis sample may be removed, and the cells directly resuspended in culture media. In another embodiment, T cells are isolated from peripheral blood by lysing the red blood cells and depleting the monocytes, for example, by centrifugation through a PERCOLL™ gradient. Alternatively, T cells can be isolated from umbilical cord. In any event, a specific subpopulation of T cells can be further isolated by positive or negative selection techniques. The cord blood mononuclear cells so isolated can be depleted of cells expressing certain antigens, including, but not limited to, CD34, CD8, CD14, CD19 and CD56. Depletion of these cells can be accomplished using an isolated antibody, a biological -43- 51532213.1 Attorney Docket No.046483-7413WO1(03398) sample comprising an antibody, such as ascites, an antibody bound to a physical support, and a cell bound antibody. Enrichment of a T cell population by negative selection can be accomplished using a combination of antibodies directed to surface markers unique to the negatively selected cells. A preferred method is cell sorting and/or selection via negative magnetic immunoadherence or flow cytometry that uses a cocktail of monoclonal antibodies directed to cell surface markers present on the cells negatively selected. For example, to enrich for CD4+ cells by negative selection, a monoclonal antibody cocktail typically includes antibodies to CD14, CD20, CD11b, CD16, HLA-DR, and CD8. For isolation of a desired population of cells by positive or negative selection, the concentration of cells and surface (e.g., particles such as beads) can be varied. In certain embodiments, it may be desirable to significantly decrease the volume in which beads and cells are mixed together (i.e., increase the concentration of cells), to ensure maximum contact of cells and beads. For example, in one embodiment, a concentration of 2 billion cells/ml is used. In one embodiment, a concentration of 1 billion cells/ml is used. In a further embodiment, greater than 100 million cells/ml is used. In a further embodiment, a concentration of cells of 10, 15, 20, 25, 30, 35, 40, 45, or 50 million cells/ml is used. In yet another embodiment, a concentration of cells from 75, 80, 85, 90, 95, or 100 million cells/ml is used. In further embodiments, concentrations of 125 or 150 million cells/ml can be used. Using high concentrations can result in increased cell yield, cell activation, and cell expansion. T cells can also be frozen after the washing step, which does not require the monocyte-removal step. While not wishing to be bound by theory, the freeze and subsequent thaw step provides a more uniform product by removing granulocytes and to some extent monocytes in the cell population. After the washing step that removes plasma and platelets, the cells may be suspended in a freezing solution. While many freezing solutions and parameters are known in the art and will be useful in this context, in a non-limiting example, one method involves using PBS containing 20% DMSO and 8% human serum albumin, or other suitable cell freezing media. The cells are then frozen to -80 ^C at a rate of 1 ^ per minute and stored in the vapor phase of a liquid nitrogen storage tank. Other methods of controlled freezing may be used as well as uncontrolled freezing immediately at -20 ^C or in liquid nitrogen. -44- 51532213.1 Attorney Docket No.046483-7413WO1(03398) In one embodiment, the population of T cells is comprised within cells such as peripheral blood mononuclear cells, cord blood cells, a purified population of T cells, and a T cell line. In another embodiment, peripheral blood mononuclear cells comprise the population of T cells. In yet another embodiment, purified T cells comprise the population of T cells. In another embodiment, the T cells are isolated from cells such as peripheral blood mononuclear cells, cord blood cells, a purified population of T cells, and a T cell line. In another embodiment, the method described herein further comprises isolating a population of T cells from peripheral blood mononuclear cells, cord blood cells, a purified population of T cells, or a T cell line. Expansion of T Cells In one embodiment, expanding the T cells further includes culturing the modified electroporated or transduced T cells. In another embodiment, the source of the T cells to be modified and expanded is peripheral blood mononuclear cells. Generally, T cells are expanded by contact with a surface having attached thereto an agent that stimulates a CD3/TCR complex associated signal and a ligand that stimulates a co-stimulatory molecule on the surface of the T cells. The present invention comprises a novel method of expanding a population of modified electroporated or transduced T cells comprising culturing the electroporated or transduced population, wherein the modified electroporated or transduced T cells within the population expand at least 10-fold. Expression of the recombinant TCR alpha and beta chains of the invention allows interaction with other cells in the population to stimulate and activate expansion of the modified electroporated or transduced T cells. In one embodiment, at least one cell in the population of cells expresses CD3. Alternatively, the cells can be ex vivo expanded using a method described in U.S. Pat. No.5,199,942 (incorporated herein by reference). Expansion, such as described in U.S. Pat. No.5,199,942 can be an alternative or in addition to other methods of expansion described herein. Briefly, ex vivo culture and expansion of T cells comprises the addition to the cellular growth factors, such as those described in U.S. Pat. No.5,199,942, or other factors, such as flt3-L, IL-1, IL-2, IL-3 and c-kit ligand, for example as those described in Dudley et al., J. Immunol., 26(4):332-342, 2003, for a Rapid Expansion Protocol (REP). -45- 51532213.1 Attorney Docket No.046483-7413WO1(03398) In one embodiment, expanding the T cells comprises culturing the T cells with a factor selected from the group consisting of flt3-L, IL-1, IL-2, IL-3 and c-kit ligand. As demonstrated by the data disclosed herein, expanding the modified electroporated or transduced T cells by the methods disclosed herein can be multiplied by about 10 fold, 20 fold, 30 fold, 40 fold, 50 fold, 60 fold, 70 fold, 80 fold, 90 fold, 100 fold, 200 fold, 300 fold, 400 fold, 500 fold, 600 fold, 700 fold, 800 fold, 900 fold, 1000 fold, 2000 fold, 3000 fold, 4000 fold, 5000 fold, 6000 fold, 7000 fold, 8000 fold, 9000 fold, 10,000 fold, 100,000 fold, 1,000,000 fold, 10,000,000 fold, or greater, and any and all whole or partial integers therebetween. In one embodiment, the T cells expand in the range of about 20-fold to about 50-fold. Following culturing, the T cells can be incubated in cell medium in a culture apparatus for a period of time or until the cells reach confluency or high cell density for optimal passage before passing the cells to another culture apparatus. The culturing apparatus can be of any culture apparatus commonly used for culturing cells in vitro. A period of time can be any time suitable for the culture of cells in vitro. The T cell medium may be replaced during the culture of the T cells at any time. Preferably, the T cell medium is replaced about every 2 to 3 days. The T cells are then harvested from the culture apparatus whereupon the T cells can be used immediately or cryopreserved to be stored for use at a later time. In one embodiment, the invention includes cryopreserving the expanded T cells. The cryopreserved, expanded T cells are then thawed prior to electroporation or transduction with RNA. In another embodiment, the cryopreserved T cells are thawed prior to introducing the nucleic acid into the T cell. The culturing step as described herein (contact with agents as described herein) can be very short, for example less than 24 hours such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23 hours. The culturing step as described further herein (contact with agents as described herein) can be longer, for example 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or more days. Various terms are used to describe cells in culture. Cell culture refers generally to cells taken from a living organism and grown under controlled condition. A primary cell culture is a culture of cells, tissues or organs taken directly from an organism and before the first subculture. Cells are expanded in culture when they are placed in a growth medium under conditions that facilitate cell growth and/or division, resulting in a larger -46- 51532213.1 Attorney Docket No.046483-7413WO1(03398) population of the cells. When cells are expanded in culture, the rate of cell proliferation is typically measured by the amount of time required for the cells to double in number, otherwise known as the doubling time. Each round of subculturing is referred to as a passage. When cells are sub- cultured, they are referred to as having been passaged. A specific population of cells, or a cell line, is sometimes referred to or characterized by the number of times it has been passaged. For example, a cultured cell population that has been passaged ten times may be referred to as a P10 culture. The primary culture, i.e., the first culture following the isolation of cells from tissue, is designated P0. Following the first subculture, the cells are described as a secondary culture (P1 or passage 1). After the second subculture, the cells become a tertiary culture (P2 or passage 2), and so on. It will be understood by those of skill in the art that there may be many population doublings during the period of passaging; therefore, the number of population doublings of a culture is greater than the passage number. The expansion of cells (i.e., the number of population doublings) during the period between passaging depends on many factors, including but is not limited to the seeding density, substrate, medium, and time between passaging. In one embodiment, the cells may be cultured for several hours (about 3 hours) to about 14 days or any hourly integer value in between. Conditions appropriate for T cell culture include an appropriate media (e.g., Minimal Essential Media or RPMI Media 1640 or, X-vivo 15, (Lonza)) that may contain factors necessary for proliferation and viability, including serum (e.g., fetal bovine or human serum), interleukin-2 (IL-2), insulin, IFN-gamma, IL-4, IL-7, GM-CSF, IL-10, IL-12, IL-15, TGF-beta, and TNF-α. or any other additives for the growth of cells known to the skilled artisan. Other additives for the growth of cells include, but are not limited to, surfactant, plasmanate, and reducing agents such as N-acetylcysteine and 2-mercaptoethanol. Media can include RPMI 1640, AIM-V, DMEM, MEM, α-MEM, F-12, X-Vivo 15, and X-Vivo 20, Optimizer, with added amino acids, sodium pyruvate, and vitamins, either serum-free or supplemented with an appropriate amount of serum (or plasma) or a defined set of hormones, and/or an amount of cytokine(s) sufficient for the growth and expansion of T cells. Antibiotics, e.g., penicillin and streptomycin, are included only in experimental cultures, not in cultures of cells that are to be infused into a subject. The target cells are maintained -47- 51532213.1 Attorney Docket No.046483-7413WO1(03398) under conditions necessary to support growth, for example, an appropriate temperature (e.g., 37° C) and atmosphere (e.g., air plus 5% CO₂). The medium used to culture the T cells may include an agent that can co-stimulate the T cells. For example, an agent that can stimulate CD3 is an antibody to CD3, and an agent that can stimulate CD28 is an antibody to CD28. This is because, as demonstrated by the data disclosed herein, a cell isolated by the methods disclosed herein can be expanded approximately 10 fold, 20 fold, 30 fold, 40 fold, 50 fold, 60 fold, 70 fold, 80 fold, 90 fold, 100 fold, 200 fold, 300 fold, 400 fold, 500 fold, 600 fold, 700 fold, 800 fold, 900 fold, 1000 fold, 2000 fold, 3000 fold, 4000 fold, 5000 fold, 6000 fold, 7000 fold, 8000 fold, 9000 fold, 10,000 fold, 100,000 fold, 1,000,000 fold, 10,000,000 fold, or greater. In one embodiment, the T cells expand in the range of about 20-fold to about 50- fold, or more by culturing the electroporated population. Methods of Treatment and Use Also provided is a method for generating a modified T cell or precursor thereof, comprising modifying expression of an endogenous genetic locus encoding TCR alpha and/or beta chains and introducing into the T cell an exogenous nucleic acid encoding a T cell receptor (TCR) specific for an epitope of Sox2 protein. In certain embodiments, the modification of the endogenous locus reduces or eliminations expression of the endogenous TCR alpha chains TCR beta chains, or both TCR alpha and beta chains. In certain embodiments, the modification is accomplished by use of a CRISPR knock-out system. In certain embodiments, the T cell is obtained from peripheral cells, cord blood cells, a purified population of T cells, and a T cell line. In certain embodiments, the T cell is a CD8+ T cell, a helper T cell, a cytotoxic T cell, a memory T cell, regulatory T cell, natural killer T cell, and gamma delta T cell. The modified T cells described herein may be included in a composition for therapy. The composition may include a pharmaceutical composition and further include a pharmaceutically acceptable carrier. A therapeutically effective amount of the pharmaceutical composition comprising the modified T cells may be administered. In one aspect, the invention includes a method for stimulating a T cell-mediated immune response to a target cell or tissue in a subject that expresses Sox2 protein, comprising administering to the subject an effective amount of a modified T cell -48- 51532213.1 Attorney Docket No.046483-7413WO1(03398) comprising a nucleic acid encoding a T cell receptor (TCR) specific for an epitope of Sox2 protein. In another aspect, the invention includes a method of treating a condition in a subject related to Sox2 expression, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a modified T cell comprising a nucleic acid encoding a T cell receptor (TCR) specific for an epitope of Sox2 protein and a pharmaceutically acceptable carrier or excipient. In one embodiment of the above aspects, the modified T cells have been expanded and an RNA encoding a modified T cell receptor (TCR) comprising affinity for an epitope of Sox2 protein has been introduced into the T cells. In another embodiment, the modified T cells have been expanded, an endogenous genetic locus encoding TCR alpha and/or TCR beta chains has been modified, and an RNA encoding a modified T cell receptor (TCR) specific for an epitope of Sox2 protein has been introduced into the cells. The cells of the present invention can be administered to an animal, preferably a mammal, even more preferably a human, to treat a cancer. In addition, the cells of the present invention can be used for the treatment of any condition related to a cancer, especially the expression of Sox2 protein by various sub-populations of cancer cells that are otherwise resistant to treatment with other strategies commonly used in clinical practice (e.g., cancer stem cells). Examples of cancers include but are not limited breast cancer, prostate cancer, ovarian cancer, cervical cancer, skin cancer, pancreatic cancer, colorectal cancer, renal cancer, liver cancer, brain cancer, lymphoma, leukemia, lung cancer, thyroid cancer, and the like. In certain embodiments, the cancer is multiple myeloma or a condition that is at risk of developing into multiple myeloma, including but not limited to monoclonal gammopathy of undetermined significance. In certain embodiments, the cancer treatment regimen comprising the cells of the invention further comprises administering to the subject one or more additional therapeutic agents. In certain embodiments, the additional therapeutic agent can be a chemotherapy, a chimeric-antigen receptor (CAR) T cell, a monoclonal antibody, a biologic therapy, and a radiologic therapy or any combination thereof. In certain embodiments, the treatment regimen also includes an allogeneic or hematopoietic stem- cell transplant. In one non-limiting example, the cells of the current invention can be used to treat multiple myeloma by combination with one or more chemotherapeutic agents including, but not limited to bortezomib, lenalidomide, dexamethasone, -49- 51532213.1 Attorney Docket No.046483-7413WO1(03398) cyclophosphamide, thalidomide, lenalidomide, daratumumab, melphalan, prednisone, and any combination thereof. In another non-limiting example, the cells of the current invention can be administered with CAR-T cells specific for other cancer-related antigens including, but not limited to CD19, CD20, CD22, CD138, CD33, CD123, BCMA, PSMA, Igκ, LeY, ROR1, and any combination thereof. Cells of the invention can be administered in dosages and routes and at times to be determined in appropriate pre-clinical and clinical experimentation and trials. Cell compositions may be administered multiple times at dosages within these ranges. Administration of the cells of the invention may be combined with other methods useful to treat the desired disease or condition as determined by those of skill in the art. The cells of the invention to be administered may be autologous, allogeneic or xenogenic with respect to the subject undergoing therapy. The administration of the cells of the invention may be carried out in any convenient manner known to those of skill in the art. The cells of the present invention may be administered to a subject by aerosol inhalation, injection, ingestion, transfusion, implantation or transplantation. The compositions described herein may be administered to a patient transarterially, subcutaneously, intradermally, intratumorally, intranodally, intramedullary, intramuscularly, by intravenous (i.v.) injection, or intraperitoneally. In other instances, the cells of the invention are injected directly into a site of inflammation in the subject, a local disease site in the subject, lymph node, an organ, a tumor, and the like. The cells described herein can also be administered using any number of matrices. The present invention utilizes such matrices within the novel context of acting as an artificial lymphoid organ to support, maintain, or modulate the immune system, typically through modulation of T cells. Accordingly, the present invention can utilize those matrix compositions and formulations which have demonstrated utility in tissue engineering. Accordingly, the type of matrix that may be used in the compositions, devices and methods of the invention is virtually limitless and may include both biological and synthetic matrices. In one particular example, the compositions and devices set forth by U.S. Pat. Nos.5,980,889; 5,913,998; 5,902,745; 5,843,069; 5,787,900; or 5,626,561 are utilized, as such these patents are incorporated herein by reference in their entirety. Matrices comprise features commonly associated with being -50- 51532213.1 Attorney Docket No.046483-7413WO1(03398) biocompatible when administered to a mammalian host. Matrices may be formed from natural and/or synthetic materials. The matrices may be non-biodegradable in instances where it is desirable to leave permanent structures or removable structures in the body of an animal, such as an implant, or biodegradable. The matrices may take the form of sponges, implants, tubes, telfa pads, fibers, hollow fibers, lyophilized components, gels, powders, porous compositions, or nanoparticles. In addition, matrices can be designed to allow for sustained release of seeded cells or produced cytokine or other active agent. In certain embodiments, the matrix of the present invention is flexible and elastic, and may be described as a semisolid scaffold that is permeable to substances such as inorganic salts, aqueous fluids and dissolved gaseous agents including oxygen. A matrix is used herein as an example of a biocompatible substance. However, the current invention is not limited to matrices and thus, wherever the term matrix or matrices appears these terms should be read to include devices and other substances which allow for cellular retention or cellular traversal, are biocompatible, and are capable of allowing traversal of macromolecules either directly through the substance such that the substance itself is a semi-permeable membrane or used in conjunction with a particular semi-permeable substance. Pharmaceutical compositions Pharmaceutical compositions of the present invention may comprise a modified T cell population as described herein, in combination with one or more pharmaceutically or physiologically acceptable carriers, diluents or excipients. Such compositions may comprise buffers such as neutral buffered saline, phosphate buffered saline and the like; carbohydrates such as glucose, mannose, sucrose or dextrans, mannitol; proteins; polypeptides or amino acids such as glycine; antioxidants; chelating agents such as EDTA or glutathione; adjuvants (e.g., aluminum hydroxide); and preservatives. Compositions of the present invention are preferably formulated for intravenous administration. Pharmaceutical compositions of the present invention may be administered in a manner appropriate to the disease to be treated (or prevented). The quantity and frequency of administration will be determined by such factors as the condition of the patient, and the type and severity of the patient’s disease, although appropriate dosages may be determined by clinical trials. -51- 51532213.1 Attorney Docket No.046483-7413WO1(03398) It can generally be stated that a pharmaceutical composition comprising the modified T cells described herein may be administered at a dosage of 10⁴ to 10⁹ cells/kg body weight, preferably 10⁵ to 10⁶ cells/kg body weight, including all integer values within those ranges. T cell compositions may also be administered multiple times at these dosages. The cells can be administered by using infusion techniques that are commonly known in immunotherapy (see, e.g., Rosenberg et al., New Eng. J. of Med. 319:1676, 1988). The optimal dosage and treatment regime for a particular patient can readily be determined by one skilled in the art of medicine by monitoring the patient for signs of disease and adjusting the treatment accordingly. In certain embodiments, it may be desired to administer activated T cells to a subject and then subsequently redraw blood (or have an apheresis performed), activate T cells therefrom according to the present invention, and reinfuse the patient with these activated and expanded T cells. This process can be carried out multiple times every few weeks. In certain embodiments, T cells can be activated from blood draws of from 10 ml to 400 ml. In certain embodiments, T cells are activated from blood draws of 20 ml, 30 ml, 40 ml, 50 ml, 60 ml, 70 ml, 80 ml, 90 ml, or 100 ml. Not to be bound by theory, using this multiple blood draw/multiple reinfusion protocol, may select out certain populations of T cells. In certain embodiments of the present invention, cells expanded and modified using the methods described herein, or other methods known in the art where T cells are expanded to therapeutic levels, are administered to a patient in conjunction with (e.g., before, simultaneously or following) any number of relevant treatment modalities, including but not limited to treatment with agents such as antiviral therapy, cidofovir and interleukin-2, Cytarabine (also known as ARA-C) or natalizumab treatment for MS patients or efalizumab treatment for psoriasis patients or other treatments for PML patients. In further embodiments, the T cells of the invention may be used in combination with chemotherapy, radiation, immunosuppressive agents, such as cyclosporin, azathioprine, methotrexate, mycophenolate, and FK506, antibodies, or other immunoablative agents such as CAM PATH, anti-CD3 antibodies or other antibody therapies, Cytoxan, fludarabine, cyclosporin, FK506, rapamycin, mycophenolic acid, steroids, FR901228, cytokines, and irradiation. These drugs inhibit either the calcium dependent phosphatase calcineurin (cyclosporine and FK506) or inhibit the p70S6 kinase -52- 51532213.1 Attorney Docket No.046483-7413WO1(03398) that is important for growth factor induced signaling (rapamycin). (Liu et al., Cell 66:807-815, 1991; Henderson et al., Immun.73:316-321, 1991; Bierer et al., Curr. Opin. Immun.5:763-773, 1993). In a further embodiment, the cell compositions of the present invention are administered to a patient in conjunction with (e.g., before, simultaneously or following) bone marrow transplantation, T cell ablative therapy using either chemotherapy agents such as, fludarabine, external-beam radiation therapy (XRT), cyclophosphamide, or antibodies such as OKT3 or CAMPATH. In another embodiment, the cell compositions of the present invention are administered following B-cell ablative therapy such as agents that react with CD20, e.g., Rituxan. For example, in one embodiment, subjects may undergo standard treatment with high dose chemotherapy followed by peripheral blood stem cell transplantation. In certain embodiments, following the transplant, subjects receive an infusion of the expanded immune cells of the present invention. In an additional embodiment, expanded cells are administered before or following surgery. The dosage of the above treatments to be administered to a patient will vary with the precise nature of the condition being treated and the recipient of the treatment. The scaling of dosages for human administration can be performed according to art-accepted practices. The dose for CAMPATH, for example, will generally be in the range 1 to about 100 mg for an adult patient, usually administered daily for a period between 1 and 30 days. The preferred daily dose is 1 to 10 mg per day although in some instances larger doses of up to 40 mg per day may be used (described in U.S. Patent No.6,120,766). It should be understood that the method and compositions that would be useful in the present invention are not limited to the particular formulations set forth in the examples. The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the cells, expansion and culture methods, and therapeutic methods of the invention, and are not intended to limit the scope of what the inventors regard as their invention. The practice of the present invention employs, unless otherwise indicated, conventional techniques of molecular biology (including recombinant techniques), microbiology, cell biology, biochemistry and immunology, which are well within the purview of the skilled artisan. Such techniques are explained fully in the literature, such as, “Molecular Cloning: A Laboratory Manual”, fourth edition (Sambrook, 2012); -53- 51532213.1 Attorney Docket No.046483-7413WO1(03398) “Oligonucleotide Synthesis” (Gait, 1984); “Culture of Animal Cells” (Freshney, 2010); “Methods in Enzymology” “Handbook of Experimental Immunology” (Weir, 1997); “Gene Transfer Vectors for Mammalian Cells” (Miller and Calos, 1987); “Short Protocols in Molecular Biology” (Ausubel, 2002); “Polymerase Chain Reaction: Principles, Applications and Troubleshooting”, (Babar, 2011); “Current Protocols in Immunology” (Coligan, 2002). These techniques are applicable to the production of the polynucleotides and polypeptides of the invention, and, as such, may be considered in making and practicing the invention. Particularly useful techniques for particular embodiments will be discussed in the sections that follow. EXPERIMENTAL EXAMPLES The invention is further described in detail by reference to the following experimental examples. These examples are provided for purposes of illustration only and are not intended to be limiting unless otherwise specified. Thus, the invention should in no way be construed as being limited to the following examples, but rather, should be construed to encompass any and all variations which become evident as a result of the teaching provided herein. Without further description, it is believed that one of ordinary skill in the art can, using the preceding description and the following illustrative examples, make and utilize the compounds of the present invention and practice the claimed methods. The following working examples, therefore, specifically point out the preferred embodiments of the present invention and are not to be construed as limiting in any way the remainder of the disclosure. The materials and methods employed in the examples disclosed herein are now described. Subjects. Study approval was obtained from the Institutional Review Board of the University of Pennsylvania (number). Eligible patients were aged 18 or older; were HLA- B*07:02 positive and had stable MGUS/SMM defined as unchanged paraprotein levels over the last 6 months before their study participation and received clinical care at the Multiple Myeloma Research Clinics at the Abramson Cancer Center (Philadelphia, USA). After informed consent was obtained, approximately 50 ml of peripheral blood (PBMC) -54- 51532213.1 Attorney Docket No.046483-7413WO1(03398) was collected in heparin tubes. Peripheral blood mononuclear cells (PBMC) were isolated by Ficoll-Paque density centrifugation and stored at minus 150°C. Detection of Sox2 CD8+ T-cell responses in MGUS/SMM patients. Candidate Sox2 peptides were identified using two methods: 1) Gapped sequence alignment software “NetMHC-4.0” to predict Sox2 antigen peptides with high binding affinity to MHC class I alleles.2) Immunopeptidome analysis by targeted mass spectroscopy to identify naturally processed Sox2 peptides presented in the context of HLA-A*02:01 and HLA-B*07:02. Sox2 CD8+ responses were detected using IFN-γ ELISPOT assays. PBMC were pulsed for 12 days with Sox2 candidate peptides, media and a viral peptide mix in the presence of IL-2. Media and viral peptide-pulsed cultures served as negative and positive controls, respectively. Positive Sox2 CD8+ T cell responses were identified by comparing mean spot counts of triplicate media, Sox2-, and viral-peptide-pulsed cultures. Statistical analysis was performed using Mann-Whitney U test. Positive anti- Sox2 CD8+ T cells responses were confirmed by FACS using custom peptide/HLA multimers. Cell Cultures and Human Cell Lines. Primary Cells: Peripheral blood mononuclear cells and purified CD8+ T cells were obtained from apheresis products or whole blood donation from study subjects with identified Sox2-specific CD8+ responses via IFN-γ ELISpot. Cell Lines: 721.221 cells (HLA class I negative lymphoblastoid cell line) were obtained from the Fred Hutchinson Cancer Research Center International Histocompatibility Working Group (IHWG). K562 cells (HLA class I negative human erythroleukemia) were obtained from the American Type Culture Collection (ATCC). Jurkat E6-1 cells (Human T cell derivative) were obtained from the American Type Culture Collection (ATCC). L-363 cell were obtained from the Leibniz Institute DSMZ. These cell lines were cultured in RPMI media with 10% fetal bovine serum, L-glutamine and penicillin / streptomycin. SK-NM-C cells were obtained from the American Type Culture Collection (ATCC). This cell line was cultured in EMEM media with 10% fetal bovine serum, L-glutamine and penicillin / streptomycin. HLA Class I Genotyping and Phenotyping of Cell Lines: Tumor cell line HLA class I typing data was obtained using the TRON Cell Line Portal when available. Tumor cell lines were transduced with lentiviral particles expressing HLA class I / 2-microglobulin single-chain dimer (HLA- SCD, eGFP+) to generated HLA class I / peptides matched cell lines. HLA class I cell -55- 51532213.1 Attorney Docket No.046483-7413WO1(03398) surface expression was assessed by flow cytometry using APC-conjugated anti-human HLA-A, B, C (clone W6/32) as well as PE. Proteomic Analysis: Cell lines (K562, 721.221 and SK-NM-C cells) were expanded to 1-2 x 10⁸ total cells and HLA class I immunoprecipitation was performed as previously described using MHC class I (W6/32) antibody non-covalently linked to agarose beads (Santa Cruz Biotechnology, Dallas, TX). Peptides were eluted from HLA class I molecules using 0.1% TFA. Immunoprecipitation eluent was passed through a 10,000 Da Amicon molecular weight cut off filter (Merck Millipore) at 10,000g for 10 minutes. Filtered eluent was dried and resuspended in 100uL of 0.1% trifluoroacetic acid (TFA). After equilibrating stage tip C18 columns (Harvard Apparatus) with 200ul of acetonitrile and 200ul of 0.1% TFA, samples were loaded onto the columns for desalting. After washing with three rounds 200uL of 0.1% TFA, samples were eluted in 70% acetonitrile in 0.1% formic acid (FA) and dried. TMC-expressing monoallelic cell lines (K562 and 721.221) were analyzed on a Q-Exactive HF-X (Thermo Scientific) coupled to an Ultimate 3000 nano UHPLC system (Thermo Scientific) using a parallel reaction monitoring strategy.30 Samples were resuspended in 10uL of 0.1% TFA and 5ul was injected for each analysis. Samples were separated with an in-house packed column with ReproSil-Pur C18 AQ 3 μm resin with dimensions 75um x 20cm (Dr. Maisch GmbH, Ammerbuch, Germany) at a flow rate of 400nl/min. Using 0.1% FA as buffer A and 80% ACN 0.1% FA as buffer B, peptides were eluted with a gradient of 4% buffer B to 30% buffer B in 42 minutes, then to 65% buffer B in 6 minutes, followed by a 7- minute wash at 95% buffer B, and a 5 minute equilibration at 4% buffer B. Peptides were ionized in a Nanospray Flex Ion Source (Thermo Scientific) at 2.3kV. An MS1 scan was acquired at a resolution of 120,000, AGC target of 1e5, and maximum inject time of 50ms. An inclusion list of 34 unique ions was used to isolate and fragment target peptides at a collision energy of 28, and an MS2 scan was acquired for each using a resolution of 15,000, AGC target of 1e⁵, maximum ion inject time of 100ms, loop count of 10, and isolation window of 1.6 m/z. Results were analyzed with Skyline50 and reference spectra were used to validate fragmentation patterns when available. Spectra were manually annotated with IPSA.51 Synthetic peptides were analyzed on a Q-Exactive HF (Thermo Scientific) coupled to an Ultimate 3000 nano UHPLC system (Thermo Scientific) with data dependent acquisition. Each synthetic peptide was injected at 1pmol/μl and analyzed -56- 51532213.1 Attorney Docket No.046483-7413WO1(03398) with similar liquid chromatography conditions. An MS1 scan was acquired at a resolution of 120,000, AGC target of 3e6, maximum inject time of 32ms. Top 20 intense ions were isolated and fragmented with a dynamic exclusion of 45 seconds. For each peptide, an MS2 scan was acquired using a resolution of 15,000, AGC target of 2e5, maximum ion inject time of 32ms, and isolation window of 1.4 m/z. Ions were filtered for charges 2-5. Raw files were searched using Proteome Discoverer 2.2 (Thermo Scientific) against a database of targets with non- tryptic digestion, precursor mass tolerance of 10ppm, and fragment mass tolerance of 0.02 Da. Search results were filtered with the target decoy approach (Elias et al., 2007). Analysis of COR-L23 cell line samples were performed by MS BioWorks (Ann Arbor, MI). Data Dependent Acquisition (DDA) experiments were carried out on half of each enriched sample by nano LC-MS/MS using a Waters M-Class system interfaced to a ThermoFisher Fusion Lumos mass spectrometer. Peptides were loaded on a trapping column and eluted over a 75 μm analytical column at 350nL/min; both columns were packed with Luna C18 resin (Phenomenex). A 2 hr reverse phase gradient was employed. The mass spectrometer was operated in a combined data dependent EThcD/CID mode, with MS and MS/MS performed in the Orbitrap at 60,000 FWHM resolution and 15,000 FWHM resolution, respectively. The instrument was run with a 3s cycle for MS and MS/MS. Synthetic stable labeled peptides (New England Peptide) were added to the remaining enriched samples for targeted mass spectrometry using Parallel Reaction Monitoring (PRM). PRM experiments were performed with Waters M- Class HPLC system interfaced to a ThermoFisher Fusion Lumos mass spectrometer. Peptides were loaded on a trapping column and eluted over a 75 μm analytical column at 350 nL/min; both columns were packed with Luna C18 resin (Phenomenex). The mass spectrometer was operated in PRM mode the quadrupole operating with a 1.4 Da isolation window and with the Orbitrap operating at 15,000 FWHM. Data were collected for the target peptides Default settings were used with the following exceptions. Enzyme: None, Max peptide mass (Da): 1700, Min. peptide length for unspecific searches: 7, Protein FDR: 1, Second Peptides: True. PRM data were analyzed manually using the XCalibur QualBrowser software (ThermoFisher). Extracted ion chromatograms for each of the target peptides were generated 20ppm mass tolerance of precursor and product ions. For the calculation of Sox peptides s expressed by HLA- B*07:02, eluted and internal standard peptide peak area data was used to calculate the -57- 51532213.1 Attorney Docket No.046483-7413WO1(03398) number of moles of peptide present in the sample. This was converted to molecules by multiplying by Avogadro’s number. The result was divided by the number of input cells to give number of peptide molecules/cell. IFN- ELISPOT Assay: CD8+ T cell reactivity to peptide antigen was assessed by interferon-γ (IFN-γ) ELISPOT assay as previously described. The spot number was determined in an independent blinded fashion (ZellNet Consulting, New York, NY) using a high-resolution automated ELISPOT Reader System (Carl Zeiss, Thornwood, NY) using KS ELISPOT 4.3 software. A positive response was recorded if the number of spots in the peptide- exposed wells was two times or higher than the number of spots in the unstimulated wells and if there was a minimum of twenty (after subtraction of background spots) peptide-specific spots per 5 x 10⁵ CD8+ cells. p/HLA multimer Assay: Sox-specific CD8+ T cell frequencies were determined by staining with p-HLA dextramers (Immudex), followed by addition of APC-CD8 antibody (Invitrogen). Cells were washed, resuspended in FACS buffer containing 7AAD. Twenty- five thousand events in the CD8+ gate were collected using a hierarchical gating strategy that included FSC/SSC and excluded 7AAD-positive (dead cells). Data was acquired and analyzed using Flow-Jo software. Isolation and Validation of Sox2-specific TCRs: Sox2-specific CD8+ T cell cultures underwent antigen-specific expansion using irradiated (10,000 Rads) HLA-SCD / 4-1BBL expressing K562 cells at a 1:1 ratio. Cultures were supplemented with IL-2 (500 U/mL) 24h after initiation and every 48h thereafter until culture termination. T cells were expanded for 12-14 days, sorted to 98-99% purity by CD8 and p-HLA multimer coexpression. Cell pellets were prepared for nucleic acid isolation. TCR/TCR Sequencing: DNA was extracted using the Gentra Puregene cell kit following the manufacturer’s directions (Qiagen, Valencia, CA, Cat. No.158388). The bulk DNA TCR Vβ and Vα libraries for sequencing on the Illumina MiSeq platform were prepared using a cocktail of 23 Vβ families from framework region 2 (FR2) forward primers, and 13 Jβ region reverse primers, modified from the BIOMED2 primer series 54 and a cocktail of 39 Vα from FR3 primers and 50 Jα region reverse primers, respectively. Libraries were generated using the QIAGEN Multiplex PCR Kit and Illumina Nextera XT index kit.55 RNA was extracted using RNeasy Plus Mini Kit following the manufacturer’s directions (Qiagen, Cat. No.74134). The bulk RNA TCR Vβ and Vα libraries were prepared using -58- 51532213.1 Attorney Docket No.046483-7413WO1(03398) SMARTer® Human TCR Profiling Kit following the manufacturer’s directions (Takara Bio USA, Inc., Mountain View, CA, Cat. No.635014). Single cell was sorted into a 96- well plate and single cell sequencing libraries were prepared using SMARTer® Human scTCR a/b Profiling Kit following the manufacturer’s directions (Takara Bio USA, Inc., Cat. No.634431). Libraries were sequenced (2 x 300 bp paired end reads, MiSeq Reagent Kit v3-600 cycle, Illumina, San Diego, CA, USA: Cat. No.102-3003) on an Illumina MiSeq instrument in the Human Immunology Core Facility at the University of Pennsylvania. Data analysis: Raw sequences were quality filtered as described in Meng et al.2017 and clone assemblies were processed with MiXCR (v.3.0.7 REF Bolotin et al. 2015) and VDJtools (v1.2.1, REF Shugay 2015). Cytotoxicity Assays: ⁵¹Cr-release Assay: K562/HLA-B*07:02 cells, the myeloma cell line L-363 and the Ewing sarcoma cell line/HLA-B*07:02 cells were labeled with 25 Ci ⁵¹Cr in the presence or absence of peptide (10 ug/mL) for 1h at 37°C, washed and tested as targets in a standard 4 h ⁵¹Cr-release assay. Effector cells consisted of Sox2-specific TCR952 and TCR954 CD8+ T cells. Antigen specificity was assessed by p-HLA multimer assay as described. Assays were performed, in triplicate, at various effector: target ratios. Data was collected using a MicroBeta2 LumiJET Microplate Counter (PerkinElmer). Data is represented as percent specific lysis reported as mean +/- SD. Real Time Apoptotic Cell Death Analysis: Real time apoptotic cell death analysis (live cell imaging with cellular impedance) was performed to assess extended cytotoxic activity using the xCELLigence Real Time Cell Analysis eSight system (ACEA Biosciences). Target tumor cells were plated (1x104 cells/well) and allowed to adhere for 24 hours. Effector T cells were added at E:T ratios 5:1, 2.5:1 and 1:1, and the media was supplemented with Annexin V-CF594 (Biotium, Fremont, CA). Cell index (relative cell impedance) was monitored every 15 minutes for 5 days and normalized to the maximum cell index value immediately prior to effector-cell plating. Shaded lines reflect the mean of duplicate wells +/- SD. Concurrent time lapse video monitoring was performed with acquisition of brightfield, Green (GFP) and Red (CF-594) windows every hour. Jurkat Reporter System and TCR Antigen Specificity and Avidity: Using Cas9 protein and riboprobes as guides against TRAC and TRBC1/TRBC2, a Jurkat E6.1 TCR negative cell line was generated. To generate JASP90 reporter cells, TCR negative Jurkat -59- 51532213.1 Attorney Docket No.046483-7413WO1(03398) E6.1 cells were first transduced with lentiviral particles encoding human CD8 / mCherry / Inducible eGFP expression driven by the NFAT promoter as means to assess TCR signaling. JASP90 reporter cells were flow cytometrically sorted to purity based on TCR- (anti-human TCR/ antibody clone IP26, Biolegend, San Diego, CA), CD8+ (anti-CD8 antibody, ThermoFisher Scientific, Waltham, MA), mCherry+ expression and low basal NFAT (eGFP+) signal. The TCR and TCR chains of Sox2 TCR952 and TCR954 were expressed via lentivirus in JASP90 using the pTRPE vector to generate the J-TCR952 and J-TCR954 cell lines. These cell lines were sorted to yield a unimodal p-HLA multimer positive cell population and expanded for use in functional assays. Sorted J-TCR952 and J-TCR954 cell lines were mixed 1:1 with HLA-SCD-expressing 721.221 cells pulsed with titrated peptide concentrations (10 μM – 1 pM). After 16-20 h, cells were analyzed by flow cytometry to determine percentage of eGFP positive cells in each sample. Cells activated with PMA (50 ng/mL) and Ionomycin (750 ng/mL) were included as positive controls and data was fitted to a dose response curve by linear non-regression analysis using GraphPad Prism version 8.0. Table 1: Sequences used in the current disclosure. SEQ Name: Sequence: ID T T A G T T C A C T A T

51532213.1 Attorney Docket No.046483-7413WO1(03398) GACTTTGCATGTGCAAACGCCTTCAACAACAGCATTATTCC AGAAGACACCTTCTTCCCCAGCCCAGAAAGTTCCTGTGAT GTCAAGCTGGTCGAGAAAAGCTTTGAAACAGATACGAACC C G C G T A G T T T C T C G C C C L F I P L A Y K L T A

51532213.1 Attorney Docket No.046483-7413WO1(03398) ORF TCTATGTTTATCCAGGAAGGAGAAGATGTCTCCATGAACT GCACTTCTTCAAGCATATTTAACACCTGGCTATGGTACAAG CAGGACCCTGGGGAAGGTCCTGTCCTCTTGATAGCCTTATA T T T T T A T G A C G G C T T G A G G C A T G C C G G C G

51532213.1 Attorney Docket No.046483-7413WO1(03398) NVSQSKDSDVYITDKCVLDMRSMDFKSNSAVAWSNKSDFAC ANAFNNSIIPEDTFFPSPESSCDVKLVEKSFETDTNLNFQNL SVIGFRILLLKVAGFNLLMTLRLWSSSGGSGEGRGSLLTCGDV D T N I C L F I L A Y K L G C D T N I

-63- 51532213.1 Attorney Docket No.046483-7413WO1(03398) 13. GLE954 CAVIIPYAGGTSYGKLTF B7-9 TRA CDR3

Recent studies have demonstrated an increase in the proportion of MM cells with Sox2 expression in patients with active MM compared to MGUS and smoldering MM. To further evaluate the hypothesis that a discrete, minor subset of MM cells exhibit features of stem cells that might be important for relapse, single-cell RNAseq of bone marrow from a relapsed/refractory MM patient was conducted. MM plasma cells (PC) were identified by expression of PC-specific genes and monoclonal immunoglobulin transcript. UMAP analysis of ~700 MM cells identified a cluster of MM cells (FIG.12; cluster 3) distinguished by up-regulation of genes known to be regulated by Sox2 (based on a previously compiled index of ChIP-seq experiments). Indeed, Sox2 target genes VIM, SULF2, and CST3 were among the top 10 differentially expressed genes in cluster 3. Interestingly, cluster 3 was also distinguished from other clusters by signaling pathways typical of B lymphocytes, consistent with prior work discussed below suggesting that stem-like MM cells may resemble B lymphocytes. To assess the relationship of Sox2 expression with clinical outcomes, clinical and bulk RNAseq data on pooled CD138+ MM cells from MM patients (N=767) in the MMRF COMMPASS dataset was analyzed. Patients in the top decile of Sox2 expression had significantly inferior OS (FIG.13A); this adverse prognostic association persisted after adjusting for R-ISS stage in a multivariable model (HR 1.8, p=0.002). These results support a role for Sox2 in MM pathogenesis. In another study, an extraordinary responder to anti-CD19 CAR T cells for MM developed new anti-Sox2 immune responses post-treatment. Though MM PCs are generally CD19-negative, minor CD19+ subsets are readily apparent in most patients; moreover, CD19+ B cells can be identified in MM patients that are clonally related to the MM plasma cells. These less differentiated, CD19+ subsets of the MM clone may have enhanced clonogenic potential compared to the dominant CD19-neg PC population. A pilot clinical trial was then undertaken utilizing anti-CD19 CAR T cells (CART19) to -64- 51532213.1 Attorney Docket No.046483-7413WO1(03398) target clonogenic MM cells. Without wishing to be bound by theory, it was hypothesized that CART19 would prevent or delay relapse after a cytoreductive MM therapy. Since this study was undertaken prior to development of anti-BCMA CAR T cells, high dose melphalan + autologous stem cell transplant (ASCT) was utilized as the companion cytoreductive therapy. To distinguish the clinical effect of CART19 from the expected response to ASCT, enrollment was restricted to patients with relapsed/refractory MM who had previously undergone ASCT and relapsed within one year. Progression-free survival (PFS) after ASCT + CART19 (PFS2) to PFS after initial ASCT (PFS1) was then compared. Since PFS after second ASCT seldom, if ever, exceeds PFS, it was reasoned that PFS2 in excess of PFS1 would indicate clinical benefit from CART19. As previously reported, PFS2 substantially exceeded PFS1 in 2/10 subjects on this trial (subjects #1 and #5), most notably in subject #1 who experienced PFS2 of 479 days compared to PFS1 of 181 days. In subjects #1 and #5, disease progression post-CART19 was surprisingly clinically indolent and confined to extramedullary sites. Bone marrow in both subjects was morphologically negative for MM despite presence of very rare MM cells at <0.01% frequency by MRD flow cytometry analysis; this finding suggested MGUS-like quiescence of the marrow disease, perhaps indicating active immune surveillance of the bone marrow against relapse. Moreover, the MM in subject #1 re-entered a complete remission after single-agent therapy with daratumumab; this subject is now off-therapy and without clinical evidence of MM nearly 7 years after CART19 and >5 years after extramedullary progression; for comparison, prior to CART19, this subject progressed through 10 lines of therapy in 4 years. Since in vivo CART19 activity had dissipated in all subjects within 100 days of administration, it was hypothesized that the indolent clinical behavior of previously very aggressive MM in subjects #1 and #5 was due to secondary immune responses precipitated by CART19 cytotoxicity against clonogenic MM cells specifically in these subjects. Given data presented above on potential capability of anti-Sox2 immune responses to maintain MGUS in a clinically indolent state, anti-Sox2 immune responses in patients after ASCT + CART19 was specifically examined. As previously reported, new anti-Sox2 antibody responses were observed specifically in subjects #1 and #5 post- CART; the response was strongest in subject #1, who had the best clinical outcome (FIG. 13B). These studies also observed a robust anti-Sox2 T cell response post-CART -65- 51532213.1 Attorney Docket No.046483-7413WO1(03398) specifically in subject #1 that was ongoing at time of isolated extramedullary progression, 494 days after CART19 (FIGs.13C-D). This result was Sox2-specific and independent of general immune reconstitution, as indicated by analysis of responses to control antigens. This result was also not the consequence of jackpot activation of Sox2- specific T cells during CAR T manufacturing since the response first appeared six months after CAR T cell infusion, long after the peak expansion of infused CAR T cells, which typically occurs <28d after infusion. These results suggest that CART19 targeted rare clonogenic MM cells co-expressing CD19 and Sox2, resulting in immunogenic cell death and secondary durable immunity against Sox2- expressing clonogenic MM cells. This result further suggests that (1) Sox2-specific responses may be able to restrain not only MGUS but also clinically aggressive MM following an effective cytoreductive therapy and that (2) cellular immunotherapies can induce durable, clinically significant secondary immune responses via immunogenic cell death. Since anti-Sox2 responses emerged post-CART19 in only 2 of 10 subjects, more direct approaches to induce anti-Sox2 immunity are needed. The invention of the current disclosure includes anti-Sox2 immunotherapies that both primarily targets this clonogenic population and also stimulates durable, secondary immune responses against the clonogenic MM phenotype. Example 2: Identification and characterization of Sox2 antigens and Sox2-specific TCRs To translate the above findings into a therapy that induces anti-Sox2 immune responses, a pipeline to isolate Sox2-specific TCRs from patients was developed. Studies initially focused on TCRs restricted to the HLA class I alleles A*02:01 and B*07:02. These HLA class I alleles are carried by ~47% and ~29% of the US Caucasian population and ~25% and ~16% of the US African American population. Candidate HLA- A*02:01 and -B*07:02-restricted Sox2 peptides were computationally identified and ranked according to predicted class I binding affinity using NetMHC4.029. In parallel, studies identified Sox2 peptides as constituents of the HLA-A*02:01 and -B7*07:02 peptidome by performing targeted proteomics using HLA class I monoallelic cell lines expressing full length Sox2 protein 30. FIG.1A shows NetMHC4.0 predicted affinities for Sox2 peptides presented by HLA- B*07:02. Proteomic studies identified two candidate peptides for presentation by HLA-B*07:02 (identified as B7-4, RPMNAFMVW (SEQ ID NO: 1) and B7-9, YPQHPGLNA (SEQ ID NO: 2)) and one candidate peptide for -66- 51532213.1 Attorney Docket No.046483-7413WO1(03398) presentation by HLA-A*02:01 (identified as A2-1). FIG.1B shows representative ELISpot results from three HLA-B*07:02 patients and one HLA-A*02:01 patient with reactivity to the B7-4 and A2-1 peptides, respectively. A diagram of the workflow of these studies is presented in FIGs.7 and 2A. Isolation of Sox2-specific TCRs. For subjects in whom Sox2-specific T cells are identified in initial ELISPOT assays, additional studies are undertaken to expand Sox2-specific T cells. Sox2-peptide- specific T cells are expanded by sequential rounds of stimulation with peptide-loaded APCs, and antigen-specific T cells are isolated by cell sorting (98-99% purity) using custom HLA class I/peptide (HLA/p) multimers. FIG.14 presents representative results obtained from an HLA-B*07:02 MGUS patient in whom both B7-4- and B7-9-specific T cells were identified in initial screening. First, PBMC cultures were stimulated with peptide-pulsed autologous mature dendritic cells, followed by secondary stimulation with peptide-pulsed HLA-null K562 cells transduced with HLA- B*07:02. FIG.14A shows HLA/p multimer (tetramer) staining indicating expansion of B7-4- and B7-9-specific T cells. To validate recognition of endogenously processed and presented Sox2 peptides, secondary cultures were then stimulated with the HLA-null 721.221 lymphoma cell line transduced with HLA-B*07:02 +/- full-length Sox2 protein; FIG.4B shows positive ELISPOT responses in T cells when stimulated with Sox2-expressing 721.221 cells. Next, highly enriched peptide-specific cultures of CD8+ T cells were generated by HLA/p multimer sorting and subsequent expansion (FIG.4C; 77% for B7-4, 46% for B7- 9). TCRa/b sequencing was performed on DNA and RNA extracted from HLA/p multimer+ cell pellets. For B7-4- specific T cell responses, TCRVβ DNA sequencing showed a Vb4 family dominant clonotype (FIG.4D, top). TCRαβ RNA sequencing demonstrated this Vb4 clonotype paired with a Va21 clonotype (FIG.14D, bottom), suggesting that these two clonotypes comprise the TCRαβ that recognizes the Sox2 B7-4 peptide. Similar results were obtained from sequencing of the B7-9 HLA/p multimer+ culture. Candidate TCRαβ heterodimers are cloned into lentiviral expression vectors and transduced into J90_NFAT reporter cells to confirm proper assembly, surface expression, antigen specificity, and intracellular signaling. FIG.4E shows HLA/p multimer staining -67- 51532213.1 Attorney Docket No.046483-7413WO1(03398) of TCR-null SUPT1 cells transduced with B7-4- or B7-9-specific TCRab pairs. These results confirm expression of the transduced TCR on the cell surface and that the selected TCRab heterodimers recognize the specific Sox2 peptides in the context of HLA- B*07:02. Experiments are underway to confirm functionality of TCRs expressed in J90_NFAT reporter cells and in CRISPR-Cas9 TCR edited primary CD8+ T cells. Sequences of the cloned TCRαβ chains as a single polypeptide separated by a self- cleaving T2A peptide sequence are displayed in Table 1. Validation of Sox2 Antigen Processing and Presentation To identify processed and presented Sox2 peptides, targeted mass spectrometry was performed on monoallelic HLA class-expressing cell lines expressing full length Sox2 protein. The HLA class I negative cell lines K562 and 721.221 were engineered to express a GFP-tagged HLA class I/β2-microglobulin single-chain dimer (HLA-SCD) construct and an mCherry-tagged ubiquinated full length Sox2 protein. Monoallelic cell lines were used in order to avoid the ambiguity that arises from co-expression of multiple HLA class I alleles. Sox2-expressing monoallelic cell lines were phenotyped HLA class I expression (FIG.8A). Sox2 protein expression was confirmed by RT-PCR (FIG.8B). The monoallelic cell lines were subjected to HLA class I immunoprecipitation and peptide elution. Peptide sequence identities were determined by quadrupole – orbitrap tandem mass spectrometry (MS) using parallel reaction monitoring as previously described. MS/MS fragmentation pattern comparison for eluted and synthetic peptides confirmed the sequence identities of HLA-restricted Sox2 peptides. The HLA class I negative cell lines were engineered to express both a GFP-tagged HLA class I / β2-microglobulin single chain dimer (HLA-SCD) construct. Peptides 1 and 2 were presented in the context of the HLA-B*07:02 allele (FIG.8C). No HLA-A*02:01-restricted Sox2 peptides were identified. Determination of Sox2 peptides immunogenicity and isolation of Sox2-specific TCR Sequences To evaluate the immunogenicity of identified candidate Sox2 peptides, HLA- A*02:01+ and /or HLA-B*07:02+ patients were screened who had a diagnosis of clinically stable MGUS or SMM for at least a year. PBMCs were pulsed with candidate -68- 51532213.1 Attorney Docket No.046483-7413WO1(03398) peptides and culture for 12 days in the presence of IL-2. An IFN-γ Elispot assay was performed to identify CD8+ T cell responses. (FIG.9A) Patients with positive Sox2 reactivity underwent whole blood donation or apheresis. CD8+ T cells isolated from these patients were cocultured with autologous monocyte-derived mature dendritic cells (mDC) pulsed with candidate Sox2 peptides followed by a secondary expansion with peptide- pulsed artificial antigen presenting cells (APCs). HLA-restriction and antigen- specificity of expanded T cell populations were confirmed by p-HLA multimer staining (FIG.9B) and IFN- γ production (Elispot assay, FIG.9C). Cultures were restimulated with peptide- pulsed HLA-matched K562 to obtain enough cells for fluorescence-activated cell sorting (FACS) isolation. p-HLA Multimer+ cells were flow cytometrically sorted to >99% purity. TCRα/β sequences were determined by next-generation DNA and RNA sequencing. Two HLA-B*07:02 restricted TCRα/β pairs: TCR952 and TCR954 were isolated from one patient with SMM. The TCR952 recognize the Sox2 peptide 1 and the TCR952 recognize the Sox2 peptide 2. Example 3: Validation and functional characterization of Sox2-specific TCRs. The function of identified candidate Sox2 TCRs was characterized using a Jurkat cell-reporter system (JASP90). p-HLA multimer staining was performed on TCR engineered JASP90 reporter cells to confirm Sox2 TCR expression and antigen specificity (FIG.10A). To assess Sox2-specific TCR function, specificity and avidity, TCR-engineered JASP90 reporter cells (J-TCR) were co-cultured with HLA class I monoallelic K562 cells pulsed with cognate Sox2 synthetic peptides. TCR signaling is indicated by eGFP expression upon NFAT activation (FIG.10B). The functional avidities of each TCR were determined in peptide titration experiments. The avidities of Sox2 TCR952 and TCR954 were determined to be 42.6nM and 51.9 nM, respectively. (FIG.10C). The functional anti-tumor activity of Sox2 TCRs was evaluated using gene edited TCRαβnull primary CD8+ T cells. Engineered TCR expression was assessed by cell surface CD3, TCRαβ and p-HLA multimer staining (Fig 5a). A secondary expansion of Sox2-TCR +T cells using peptide-pulsed artificial APCs led to CD8+ T cells populations with high (50–80%) TCR expression. T cells transduced with Sox2 TCRs recognized HLA-B*07:02-positive K562 cells pulsed with cognate peptide with varying functional -69- 51532213.1 Attorney Docket No.046483-7413WO1(03398) avidity. Further evaluation of specificity and cytotoxic activity was performed. In 4hr ⁵¹Cr-release assays, TCR952 and TCR954 engineered CD8+ T cells kill HLA class I matched K562 cells pulsed with exogenous cognate Sox2 peptide but not non-pulsed target cells. The recognition of p-HLA complexes on the surface of cancer cells by Sox2 TCRs identified herein was evaluated by using a panel of Sox2-expressing cells lines of different histologies. Gene transfer of TCR954 confer lytic activity against engineered Sox2-expressing HLA class I matched myeloma L-363 tumor cells (Fig 5b and Fig 5c respectively). Furthermore, 24h co-culture with TCR954 CD8+ T cells resulted in a consistent, significant reduction in myeloma-propagating capability of Sox2-expressing L-363 cell lines (Fig 5d). Notably, TCR952 CD8+ T cells were not able to recognize Sox2- expressing cancer cells. To investigate the functional potential of TCR954 with natural endogenous of Sox2 in cancer cells, the T-cell response against sarcoma cell line SK-NM-C was assessed. Since this cell line originated from an HLA-B*07:02 negative patient, the cells were transduced to stably express the HLA*B07:02 gene. In 4h ⁵¹Cr- release assays, the cytotoxic activity of TCR954 engineered CD8+ T cells was enhanced when the tumor target cells were pre-treated with IFN-γ (Fig 5d). In vitro tumor recognition and cytotoxic activity against the sarcoma cell line SK-NM-C was then characterized via cellular impedance (Fig 5f) and live cell imaging (Fig 5g). These complimentary measurements of cell death allow for visualization of the loss of GFP- labeled tumor cells and the accumulation of Annexin V-CF594 dye over a 4d period. TCR954+ T cells promoted rapid cell death of SK-NM-C-B7 tumor cells at a 2.5:1 E:T ratio compared to non-HLA matched control tumor cells. MS/MS fragmentation pattern comparison confirmed that peptide 2 was presented in the context of the HLA-B*07:02 allele (Figure 5h). Example 4: Selected discussion Sox2 is a transcription factor that confers self-renewal and pluripotency capacity to residual cancer cells. In the studies disclosed herein a combined modality approach was undertaken in order to characterize Sox2-specific CD8+ T cell immune responses. Such responses have clinical relevance given the potential mechanistic role of Sox2 in conferring a myeloma-clonogenic phenotype to residual treatment-resistant cells. Indeed, -70- 51532213.1 Attorney Docket No.046483-7413WO1(03398) previous studies have demonstrated that Sox2 immune T-cell responses are associated with decreased risk of progression from MGUS to symptomatic multiple myeloma. Conversely, anti-Sox2 immune responses are seldom described in patients with newly diagnosed myeloma. In the studies disclosed herein, a comprehensive approach was undertaken which incorporated bioinformatic, proteomic and immunological methods to identify, characterize and validate HLA class I-restricted Sox2 peptides. The two HLA- B7*02-restricted Sox2 epitopes described herein are novel and have not been previously reported. Using the Sox2 TCRs described in this study, evidence for the immunological recognition of various Sox-expressing tumor cell lines is disclosed. These two TCRs were generated from a patient with intermediate-high risk smoldering multiple myeloma whose disease has remained stable for 7 years. In summary, and without wishing to be bound by theory, the findings of the present disclosure provide direct evidence of the clinical utility of Sox2-engineered T cells and open the path toward development of Sox2-targeted immunotherapies including vaccine and adoptive cell therapies for select patients expressing HLA*B7:02 alleles. Enumerated Embodiments The following enumerated embodiments are provided, the numbering of which is not to be construed as designating levels of importance. Embodiment 1 provides an isolated nucleic acid encoding a first polypeptide, a linker polypeptide, and a second polypeptide, wherein: a. the first polypeptide is a T cell receptor (TCR) alpha chain comprising a third complementarity determining region (CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 11 or SEQ ID NO: 13; b. the second polypeptide is a TCR beta chain comprising a third complementarity determining region (CDR3) comprising an amino acid set forth in SE ID NO: 12 or SEQ ID NO: 14; and c. the linker polypeptide is a self-cleaving polypeptide; wherein the TCR has antigenic specificity for an epitope of Sox2 protein. Embodiment 2 provides the isolated nucleic acid of claim 1, wherein the TCR comprises a TCR alpha chain comprising the amino acid sequence set forth in SEQ ID -71- 51532213.1 Attorney Docket No.046483-7413WO1(03398) NO: 7 or SEQ ID NO: 9 and a TCR beta chain comprising the amino acid sequence set forth in SEQ ID NO: 8 or SEQ ID NO: 10. Embodiment 3 provides the isolated nucleic acid of claim 1, wherein the epitope of Sox2 comprises the amino acid sequence set forth in SEQ ID NO: 1 or SEQ ID NO: 2. Embodiment 4 provides the isolated nucleic acid of claim 3, wherein the epitope of Sox2 is presented by HLA-B*07:02. Embodiment 5 provides the isolated nucleic acid of claim 1, wherein the nucleic acid comprises a nucleic acid sequence set forth in SEQ ID NO: 3 or SEQ ID NO: 5. Embodiment 6 provides the isolated nucleic acid of claim 1, wherein the nucleic acid encodes a polypeptide comprising the amino acid sequence set forth in SEQ ID NO: 4 or SEQ ID NO: 6. Embodiment 7 provides a recombinant expression vector comprising the isolated nucleic acid of any one of claims 1-6. Embodiment 8 provides a modified T cell comprising the nucleic acid of any one of claims 1-6. Embodiment 9 provides a modified T cell comprising an exogenous nucleic acid encoding a T cell receptor (TCR) specific for Sox2 protein, wherein the TCR comprises: a. an alpha chain comprising a third complementarity determining region (CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 11 or SEQ ID NO: 13; and b. a beta chain comprising a CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 12 or SEQ ID NO: 14. Embodiment 10 provides the modified T cell of any one of claims 8 or 9, wherein the T cell further comprises a modified endogenous genetic locus. Embodiment 11 provides the modified T cell of claim 10, wherein the endogenous genetic locus encodes the TCR alpha chain, beta chain, or both alpha and beta chains. Embodiment 12 provides the modified T cell of any one of claims 10 and 11, wherein the modification reduces or eliminates expression of the genes encoded by the locus. Embodiment 13 provides the modified T cell of claim 10, wherein the modification is accomplished by use of a CRISPR system. Embodiment 14 provides the modified T cell of claim 9, wherein: -72- 51532213.1 Attorney Docket No.046483-7413WO1(03398) a. the TCR alpha chain comprises an amino acid sequence set forth in SEQ ID NO: 7 or SEQ ID NO: 9; and b. the TCR beta chain comprises an amino acid sequence set forth in SEQ ID NO: 8 or SEQ ID NO: 10. Embodiment 15 provides the modified T cell of claim 9, wherein the TCR has antigenic specificity for an epitope of Sox2 comprising the amino acid sequence set forth in SEQ ID NO: 1 or SEQ ID NO: 2. Embodiment 16 provides the modified T cell of claim 15, wherein the epitope of Sox2 is presented by HLA-B*07:02. Embodiment 17 provides the modified T cell of claim 9, wherein the nucleic acid comprises the nucleic acid sequence set forth in SEQ ID NO: 3 or SEQ ID NO: 5. Embodiment 18 provides the modified T cell of claim 9, wherein the nucleic acid encodes a polypeptide comprising the amino acid sequence set forth in SEQ ID NO: 4 or SEQ ID NO: 6. Embodiment 19 provides the modified T cell of claim 9, wherein the T cell is a CD4+ T cell. Embodiment 20 provides the modified T cell of claim 9, wherein the T cell is a CD8+ T cell. Embodiment 21 provides a method for generating a modified T cell comprising: a. modifying expression of an endogenous genetic locus encoding TCR alpha and/or beta chains; and b. introducing into the T cell an exogenous nucleic acid encoding a T cell receptor (TCR) specific for an epitope of Sox2 protein, wherein the TCR comprises: an alpha chain comprising a third complementarity determining region (CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 11 or SEQ ID NO: 13; and a beta chain comprising a CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 12 or SEQ ID NO: 14; wherein the T cell is capable of expressing the TCR. -73- 51532213.1 Attorney Docket No.046483-7413WO1(03398) Embodiment 22 provides the method of claim 21, wherein the modification of the endogenous locus reduces or eliminates expression of endogenous TCR alpha or beta chains. Embodiment 23 provides the method of claim 22, wherein the modification is accomplished by a CRISPR system. Embodiment 24 provides the method of claim 21, wherein the epitope of Sox2 protein comprises the amino acid sequence set forth in SEQ ID NO: 1 or SEQ ID NO: 2. Embodiment 25 provides the method of claim 21, wherein the epitope of Sox2 protein is presented by HLA-B*07:02. Embodiment 26 provides the method of claim 21, wherein the T cell is obtained from the group consisting of peripheral blood mononuclear cells, cord blood cells, a purified population of T cells, and a T cell line. Embodiment 27 provides a method for stimulating a T cell-mediated immune response to a target cell or tissue in a subject that expresses Sox2 protein, comprising administering to the subject an effective amount of a modified T cell comprising a nucleic acid encoding a T cell receptor (TCR) specific for an epitope of Sox2 protein, wherein the TCR comprises: a. an alpha chain comprising a third complementarity determining region (CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 11 or SEQ ID NO: 13; and b. a beta chain comprising a CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 12 or SEQ ID NO: 14. Embodiment 28 provides the method of claim 27, wherein the modified T cell further comprises a modified endogenous genetic locus. Embodiment 29 provides the method of claim 27, wherein the endogenous genetic locus encodes a TCR alpha chain and/or beta chain. Embodiment 30 provides the method of claim 27, wherein the modification reduces or eliminates expression of the endogenous TCR alpha and/or beta chain. Embodiment 31 provides the method of claim 27, wherein the modification is accomplished by a CRISPR system. Embodiment 32 provides the method of claim 27, wherein the Sox 2 antigen comprises the amino acid sequence set forth in SEQ ID NO: 1 or SEQ ID NO: 2. -74- 51532213.1 Attorney Docket No.046483-7413WO1(03398) Embodiment 33 provides the method of claim 32, wherein the epitope of Sox2 is presented by HLA-B*07:02. Embodiment 34 provides the method of claim 27, wherein the target cell or tissue is a cancer cell or tissue. Embodiment 35 provides the method of claim 34, wherein the cancer is selected from the group consisting of glioblastoma, non-small cell lung cancer, breast cancer, prostate cancer, and multiple myeloma (MM). Embodiment 36 provides a method of treating a condition in a subject related to Sox2 expression, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising the modified T cell of any one of claims 8 – 20 and a pharmaceutically acceptable carrier or excipient. Embodiment 37 provides the method of claim 36, comprising administering to the subject one or more additional therapeutic agents. Embodiment 38 provides the method of claim 37, wherein the additional therapeutic agent is selected from the group consisting of chemotherapy, chimeric-antigen receptor (CAR)-T cell therapy, monoclonal antibody therapy, biologic therapy, allogeneic stem cell transplant, radiologic therapy, and any combination thereof. Embodiment 39 provides the method of claim 36, wherein the condition is cancer. Embodiment 40 provides the method of claim 39, wherein the cancer is selected from the group consisting of glioblastoma, non-small cell lung cancer, breast cancer, prostate cancer, and multiple myeloma (MM). Embodiment 41 provides a pharmaceutical composition comprising the modified T cell of claims 8-20 and a pharmaceutically acceptable carrier. Other Embodiments The disclosures of each and every patent, patent application, and publication cited herein are hereby incorporated herein by reference in their entirety. While this invention has been disclosed with reference to specific embodiments, it is apparent that other embodiments and variations of this invention may be devised by others skilled in the art without departing from the true spirit and scope of the invention. The appended claims are intended to be construed to include all such embodiments and equivalent variations. -75- 51532213.1

Claims

Attorney Docket No.046483-7413WO1(03398) CLAIMS What is claimed is: 1. An isolated nucleic acid encoding a first polypeptide, a linker polypeptide, and a second polypeptide, wherein: a. the first polypeptide is a T cell receptor (TCR) alpha chain comprising a third complementarity determining region (CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 11 or SEQ ID NO: 13; b. the second polypeptide is a TCR beta chain comprising a third complementarity determining region (CDR3) comprising an amino acid set forth in SE ID NO: 12 or SEQ ID NO: 14; and c. the linker polypeptide is a self-cleaving polypeptide; wherein the TCR has antigenic specificity for an epitope of Sox2 protein. 2. The isolated nucleic acid of claim 1, wherein the TCR comprises a TCR alpha chain comprising the amino acid sequence set forth in SEQ ID NO: 7 or SEQ ID NO: 9 and a TCR beta chain comprising the amino acid sequence set forth in SEQ ID NO: 8 or SEQ ID NO: 10. 3. The isolated nucleic acid of claim 1, wherein the epitope of Sox2 comprises the amino acid sequence set forth in SEQ ID NO: 1 or SEQ ID NO: 2. 4. The isolated nucleic acid of claim 3, wherein the epitope of Sox2 is presented by HLA-B*07:02. 5. The isolated nucleic acid of claim 1, wherein the nucleic acid comprises a nucleic acid sequence set forth in SEQ ID NO: 3 or SEQ ID NO: 5. 6. The isolated nucleic acid of claim 1, wherein the nucleic acid encodes a polypeptide comprising the amino acid sequence set forth in SEQ ID NO: 4 or SEQ ID NO: 6. -76- 51532213.1 Attorney Docket No.046483-7413WO1(03398) 7. A recombinant expression vector comprising the isolated nucleic acid of any one of claims 1-6. 8. A modified T cell comprising the nucleic acid of any one of claims 1-6. 9. A modified T cell comprising an exogenous nucleic acid encoding a T cell receptor (TCR) specific for Sox2 protein, wherein the TCR comprises: a. an alpha chain comprising a third complementarity determining region (CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 11 or SEQ ID NO: 13; and b. a beta chain comprising a CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 12 or SEQ ID NO: 14. 10. The modified T cell of any one of claims 8 or 9, wherein the T cell further comprises a modified endogenous genetic locus. 11. The modified T cell of claim 10, wherein the endogenous genetic locus encodes the TCR alpha chain, beta chain, or both alpha and beta chains. 12. The modified T cell of any one of claims 10 and 11, wherein the modification reduces or eliminates expression of the genes encoded by the locus. 13. The modified T cell of claim 10, wherein the modification is accomplished by use of a CRISPR system. 14. The modified T cell of claim 9, wherein: a. the TCR alpha chain comprises an amino acid sequence set forth in SEQ ID NO: 7 or SEQ ID NO: 9; and b. the TCR beta chain comprises an amino acid sequence set forth in SEQ ID NO: 8 or SEQ ID NO: 10. -77- 51532213.1 Attorney Docket No.046483-7413WO1(03398) 15. The modified T cell of claim 9, wherein the TCR has antigenic specificity for an epitope of Sox2 comprising the amino acid sequence set forth in SEQ ID NO: 1 or SEQ ID NO: 2. 16. The modified T cell of claim 15, wherein the epitope of Sox2 is presented by HLA-B*07:02. 17. The modified T cell of claim 9, wherein the nucleic acid comprises the nucleic acid sequence set forth in SEQ ID NO: 3 or SEQ ID NO: 5. 18. The modified T cell of claim 9, wherein the nucleic acid encodes a polypeptide comprising the amino acid sequence set forth in SEQ ID NO: 4 or SEQ ID NO: 6. 19. The modified T cell of claim 9, wherein the T cell is a CD4+ T cell. 20. The modified T cell of claim 9, wherein the T cell is a CD8+ T cell. 21. A method for generating a modified T cell comprising: a. modifying expression of an endogenous genetic locus encoding TCR alpha and/or beta chains; and b. introducing into the T cell an exogenous nucleic acid encoding a T cell receptor (TCR) specific for an epitope of Sox2 protein, wherein the TCR comprises: an alpha chain comprising a third complementarity determining region (CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 11 or SEQ ID NO: 13; and a beta chain comprising a CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 12 or SEQ ID NO: 14; wherein the T cell is capable of expressing the TCR. 22. The method of claim 21, wherein the modification of the endogenous locus reduces or eliminates expression of endogenous TCR alpha or beta chains. -78- 51532213.1 Attorney Docket No.046483-7413WO1(03398) 23. The method of claim 22, wherein the modification is accomplished by a CRISPR system. 24. The method of claim 21, wherein the epitope of Sox2 protein comprises the amino acid sequence set forth in SEQ ID NO: 1 or SEQ ID NO: 2. 25. The method of claim 21, wherein the epitope of Sox2 protein is presented by HLA-B*07:02. 26. The method of claim 21, wherein the T cell is obtained from the group consisting of peripheral blood mononuclear cells, cord blood cells, a purified population of T cells, and a T cell line. 27. A method for stimulating a T cell-mediated immune response to a target cell or tissue in a subject that expresses Sox2 protein, comprising administering to the subject an effective amount of a modified T cell comprising a nucleic acid encoding a T cell receptor (TCR) specific for an epitope of Sox2 protein, wherein the TCR comprises: a. an alpha chain comprising a third complementarity determining region (CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 11 or SEQ ID NO: 13; and b. a beta chain comprising a CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 12 or SEQ ID NO: 14. 28. The method of claim 27, wherein the modified T cell further comprises a modified endogenous genetic locus. 29. The method of claim 27, wherein the endogenous genetic locus encodes a TCR alpha chain and/or beta chain. -79- 51532213.1 Attorney Docket No.046483-7413WO1(03398) 30. The method of claim 27, wherein the modification reduces or eliminates expression of the endogenous TCR alpha and/or beta chain. 31. The method of claim 27, wherein the modification is accomplished by a CRISPR system. 32. The method of claim 27, wherein the Sox 2 antigen comprises the amino acid sequence set forth in SEQ ID NO: 1 or SEQ ID NO: 2. 33. The method of claim 32, wherein the epitope of Sox2 is presented by HLA- B*07:02. 34. The method of claim 27, wherein the target cell or tissue is a cancer cell or tissue. 35. The method of claim 34, wherein the cancer is selected from the group consisting of glioblastoma, non-small cell lung cancer, breast cancer, prostate cancer, and multiple myeloma (MM). 36. A method of treating a condition in a subject related to Sox2 expression, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising the modified T cell of any one of claims 8 – 20 and a pharmaceutically acceptable carrier or excipient. 37. The method of claim 36, comprising administering to the subject one or more additional therapeutic agents. 38. The method of claim 37, wherein the additional therapeutic agent is selected from the group consisting of chemotherapy, chimeric-antigen receptor (CAR)-T cell therapy, monoclonal antibody therapy, biologic therapy, allogeneic stem cell transplant, radiologic therapy, and any combination thereof. 39. The method of claim 36, wherein the condition is cancer. -80- 51532213.1 Attorney Docket No.046483-7413WO1(03398) 40. The method of claim 39, wherein the cancer is selected from the group consisting of glioblastoma, non-small cell lung cancer, breast cancer, prostate cancer, and multiple myeloma (MM). 41. A pharmaceutical composition comprising the modified T cell of claims 8-20 and a pharmaceutically acceptable carrier. -81- 51532213.1