WO2024233278A1 - Combined treatments of car-t cells and checkpoint inhibitors - Google Patents

Abstract

Disclosed herein are tumor-associated antigen-specific binding polypeptides. These binding polypeptides may be incorporated into chimeric antigen receptors (CARs). Also disclosed herein are methods of using these binding polypeptides and/or CARs for the treatment of, for example, a cancer. In some embodiments, the method combines a CAR with an at least one checkpoint inhibitor.

Description

BWGB.012WO PCT APPLICATION COMBINED TREATMENTS OF CAR-T CELLS AND CHECKPOINT INHIBITORS RELATED APPLICATION INFORMATION [0001] This application claims priority to U.S. Serial No. 63/500467, filed May 5, 2023. The foregoing is incorporated herein by reference in its entirety. REFERENCE TO SEQUENCE LISTING [0002] The present application is being filed along with a Sequence Listing in electronic format. The Sequence Listing is provided as a file entitled BWGB.012WO.xml, which was created and last modified on April 18, 2024 and is 219,956 bytes in size. The information in the electronic Sequence Listing is hereby incorporated by reference in its entirety. BACKGROUND OF THE INVENTION Field of the Invention [0003] Aspects of the present disclosure relate generally to tumor-associated antigen-specific binding polypeptides. These binding polypeptides can be incorporated into chimeric antigen receptor (CAR) constructs to be expressed in immune cells. These binding polypeptides and CARs may be used in the treatment of cancer. Description of the Related Art [0004] Adoptive cell therapies, such as chimeric antigen receptor (CAR) T cell therapies, have shown great promise in the treatment of cancer. CAR T cell therapies involve the use of genetically engineered T cells expressing receptors targeted to cancer-associated cell surface markers and other antigens, enabling directed killing of cancer cells while minimally affecting normal cells in a patient. For example, brexucabtagene autoleucel, tisagenlecleucel, and axicabtagene ciloleucel are FDA-approved CAR T cell therapies for CD19+ B cell lymphoma cancers. [0005] The CAR, which is made up of an extracellular antigen binding domain, a transmembrane domain, and an intracellular signaling domain, enables directed killing of cancer cells based on cell surface antigen expression while minimally affecting normal cells that are not expressing the targeted antigen. The extracellular antigen binding domain is often made up of an antibody or a binding fragment or derivative thereof, such as a single chain variable fragment (scFv) or single domain antibody (sdAb). There is a present need for improved extracellular antigen binding domains to be used in CARs for the treatment of various cancers or other diseases. SUMMARY OF THE INVENTION [0006] Some embodiments disclosed herein relate to a method of treating a cancer in a subject in need thereof. In some embodiments, the method comprises administering a CAR cell and an at least one effective dose of an at least one checkpoint inhibitor (iCPI) to the subject. In some embodiments, the CAR cell expresses the heavy chain CDR sequences shown in Table 1. In some embodiments, the CAR cell expressed heavy chain polypeptides shown in Table 2. . In some embodiments, the CAR cell is bivalent and/or multivalent. In some embodiments, the CAR cell has one target. In some embodiments, the CAR cell has more than one target. In some embodiments, the CAR cell is an immune cell. In some embodiments, the CAR cell is a TIL cell. In some embodiments, the CAR cell is a T cell or NK cell. In some embodiments, the at least one checkpoint inhibitor is an anti-PD1, an anti-PDL1, an anti- CTLA4, and/or an anti-PDNR. In some embodiments, the at least one checkpoint inhibitor is an anti-PD1. In some embodiments, the at least one checkpoint inhibitor is an anti-PDL1. In some embodiments, two checkpoint inhibitors are administered to the subject. In some embodiments, the two checkpoint inhibitors are the same checkpoint inhibitor. In some embodiments, the two checkpoint inhibitors are different checkpoint inhibitors. In some embodiments, the two checkpoint inhibitors are an anti-PD1 and an anti-PDL1. In some embodiments, the subject is mammalian and/or human. In some embodiments, the CAR cell is administered to the subject at a different time than the at least one iCPI. In some embodiments, the CAR T-cell is administered at Day 1, and the at least one iCPI is administered at a day that is between 1 and 24 weeks after Day 1. In some embodiments, the at least one iCPI is administered at 1, 2, 12, or 24 weeks after Day 1. In some embodiments, the at least one effective dose of an at least one iCPI is administered once. In some embodiments, the at least one effective dose of an at least one iCPI is administered more than once. In some embodiments, the at least one effective dose of an at least one iCPI is administered at least twice. In some embodiments, the at least one effective dose of an at least one iCPI is administered at least three times. In some embodiments, the at least one effective dose of an at least one iCPI is administered at least five times. In some embodiments, the at least one iCPI is administered at a constant dose. In some embodiments, the at least one iCPI is administered at an increasing dose. In some embodiments, the at least one iCPI is administered at a decreasing dose. In some embodiments, the at least one iCPI is administered at a dose of about 0.1, 0.25, 0.5, 0.75, 1, 2.5, 5, 7.5, 10, or any integer that is between 0.1 and 10, mg/kg. [0007] Some embodiments disclosed herein relate to a composition comprising a CAR cell and an at least one iCPI. In some embodiments, the CAR cell expresses a protein comprising a sequence with at least 80%, 85%, 90%, 95%, 97%, 99%, 100%, or any integer between 80 and 100%, identity with the CDR sequences shown in Table 1 or the heavy chain sequence shown in Table 2. In some embodiments, the CAR cell is bivalent and/or multivalent. In some embodiments, the CAR cell has one target. In some embodiments, the CAR cell has more than one target. In some embodiments, the CAR cell is an immune cell. In some embodiments, the CAR cell is a TIL cell. In some embodiments, the CAR cell is a T cell or NK cell. In some embodiments, the at least one checkpoint inhibitor is an anti-PD1, an anti- PDL1, and anti-CTLA4, and/or an anti-PDNR. In some embodiments, the composition comprises 2 iCPIs. In some embodiments, the two checkpoint inhibitors are the same checkpoint inhibitor. In some embodiments, the two checkpoint inhibitors are different checkpoint inhibitors. In some embodiments, the 2 iCPIs are an anti-PD1 and an anti-PDL1. [0008] Some embodiments disclosed herein relate to a use for a CAR cell and an at least one iCPI for treating a disease or disorder in a subject. In some embodiments, the disease or disorder is a cancer. In some embodiments, the CAR cell expresses a protein comprising a sequence with at least 80%, 85%, 90%, 95%, 97%, 99%, 100%, or any integer between 80 and 100%, identity with the CDR sequences shown in Table 1 or the heavy chain sequence shown in Table 2.. In some embodiments, the CAR cell is bivalent and/or multivalent. In some embodiments, the CAR cell has at least one target. In some embodiments, the CAR cell is an immune cell. In some embodiments, the CAR cell is a TIL cell. In some embodiments, the CAR cell is a T cell or NK cell. In some embodiments, the at least one checkpoint inhibitor is an anti-PD1, an anti-PDL1, and anti-CTLA4, and/or an anti-PDNR. In some embodiments, two checkpoint inhibitors are administered to the subject. In some embodiments, the two checkpoint inhibitors are the same checkpoint inhibitor. In some embodiments, the two checkpoint inhibitors are different checkpoint inhibitors. In some embodiments, the two iCPIs are an anti-PD1 and an anti-PDL1. [0009] Some embodiments disclosed herein relate to a method of treating a disease or disorder in a subject in need thereof, the method comprising: administering a CAR cell and an at least one effective dose of an at least one checkpoint inhibitor (iCPI) to the subject. In some embodiments, the disease or disorder is a cancer. In some embodiments, the method does not comprise lymphodepletion. In some embodiments, the CAR cell is administered to the subject by an at least one infusion. In some embodiments, the at least one infusion is more than one infusion. In some embodiments, the CAR cell expresses a protein comprising a sequence with at least 80%, 85%, 90%, 95%, 97%, 99%, 100%, or any integer between 80 and 100%, identity with the CDR sequences shown in Table 1 or the heavy chain sequence shown in Table 2. In some embodiments, the CAR cell is an immune cell. In some embodiments, the CAR cell is a TIL cell. In some embodiments, the CAR cell is a T cell or NK cell. In some embodiments, the method further comprises at least one administration of an effective dose of cetuximab. In some embodiments, the at least one checkpoint inhibitor is an anti-PD1, an anti-PDL1, an anti- CTLA4, and/or an anti-PDNR. In some embodiments, two checkpoint inhibitors are administered to the subject. In some embodiments, the two checkpoint inhibitors are the same checkpoint inhibitor. In some embodiments, the two checkpoint inhibitors are different checkpoint inhibitors. In some embodiments, the two checkpoint inhibitors are an anti-PD1 and an anti-PDL1. In some embodiments, the subject is mammalian and/or human. In some embodiments, the CAR cell is administered to the subject at a different time than the at least one iCPI. In some embodiments, the CAR T-cell is administered at Day 1, and the at least one iCPI is administered at a day that is between 1 and 24 weeks after Day 1. In some embodiments, the at least one effective dose of an at least one iCPI is administered at least once. In some embodiments, the at least one iCPI is administered at a constant dose. In some embodiments, the at least one iCPI is administered at an increasing dose. In some embodiments, the at least one iCPI is administered at a decreasing dose. In some embodiments, the at least one iCPI is administered at a dose of about 0.1, 0.25, 0.5, 0.75, 1, 2.5, 5, 7.5, 10, or any integer that is between 0.1 and 10, mg/kg. BRIEF DESCRIPTION OF THE DRAWINGS [0010] In addition to the features described above, additional features and variations will be readily apparent from the following descriptions of the drawings and exemplary embodiments. It is to be understood that these drawings depict typical embodiments and are not intended to be limiting in scope. [0011] FIG.1 depicts an exemplary alignment for the heavy chain variable domain CDRs disclosed herein. [0012] FIG. 2A shows three line graphs which show the anti-tumor efficacy of an exemplary anti-CEA6 CAR T-cell line expressing a Cap03+04-CEA6-R2-10 protein with a heavy chain sequence of SEQ ID NO: 146, against tumors in a cell line-derived xenograft (CDX) model of gastric tumor , non-small cell lung cancer (NSCLC), and pancreatic tumor. [0013] FIG. 2B show an image of a pancreatic orthotopic model of pancreatic tumors and also shows a line graph detailing the efficacy of an exemplary anti-CEA6 CAR T- cell line expressing the Cap03+04-CEA6-R2-10 protein against tumors in the pancreatic orthotopic and patient-derived colorectal cancer xenograph model. [0014] FIG. 3 is a line graph showing the results of a tumor re-challenge study showing immunological memory of an exemplary anti-CEA6 CAR T-cell line expressing the Cap03+04-CEA6-R2-10 protein that drives a secondary complete response. [0015] FIG. 4 is a line graph showing tumor volume over time in mice (n=5) after treatment of CAR T-cells with or without PD-1 treatment, as described in Example 2. DETAILED DESCRIPTION [0016] Disclosed herein are single-domain binding polypeptides that are incorporated into a chimeric antigen receptor cell. In some embodiments, the cell is an immune cell. In some embodiments, the cell is a mononuclear or a polymorphonuclear immune cell. In some embodiments, the cell is a lymphocyte and/or a leukocyte. In some embodiments, the cell is a tumor-infiltrating lymphocyte (TIL). In some embodiments, the cell is a myelocyte. In some embodiments, the cell is a B cell, a T cell, or a Natural Killer (NK cell). In some embodiments, the cell is an eosinophil, neutrophil, or monocyte. In some embodiments, the cell is a macrophage, basophil, or mast cell. In some embodiments, the cell is a memory cell, plasma cell, memory T cell, cytotoxic T cell, or helper T cell. [0017] In some embodiments, the chimeric antigen receptor cell is a chimeric antigen receptor T cell (CAR T-cell). The binding polypeptides provide specificity towards their respective tumor-associated antigens, enabling targeting of cancers expressing said tumor-associated antigens by the CAR T-cell. [0018] In some embodiments, the CAR cell is combined with an effective amount of a checkpoint inhibitor (iCPI). In some embodiments, the checkpoint inhibitor is an anti- PD1, an anti-PDL1, an anti-PDNR, or an anti PD-1 dominant negative receptor (DNR). In some embodiments, the checkpoint inhibitor is pembrolizumab. [0019] In some embodiments, the single domain binding polypeptides are single domain antibodies (sdAbs) disposed on the surface of the chimeric antigen receptor cells (e.g. CAR cell). The sdAbs may be specific for, or have binding affinity towards, one or more tumor-associated antigens. In some embodiments, the tumor-associated antigen is carcinoembryonic antigen 6 (CEACAM6, or CEA6). In some embodiments, the CAR cell expresses a protein found in Table 1 or Table 2 below. and is a specific CAR cell configured to bind to CEA6. In some embodiments, the CAR cell has multiple targets. In some embodiments, the CAR cell has two targets. In some embodiments, the CAR cell is bivalent. In some embodiments, the CAR cell is multi-valent. In some embodiments, the CAR cell comprises a sdAb that binds to CEA6. In some embodiments, the CAR cell is a T cell. In some embodiments, the CAR cell is a NK cell. [0020] Also disclosed herein are methods of treating a disease or disorder in a subject in need thereof by administering a chimeric antigen receptor cell comprising one or more of the single domain binding polypeptides disclosed herein. In some embodiments, the disease or disorder is a cancer. In some embodiments, the cancer may be breast cancer, colorectal cancer, kidney cancer, liver cancer, lung cancer, brain cancer, pancreatic cancer, bladder cancer, testicular cancer, prostate cancer, gastric cancer, a hematologic malignancy, or any combination thereof. The CAR cell may be derived from the subject for an autologous treatment. In some embodiments, the hematologic malignancy may comprise leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, hairy cell leukemia, lymphoma, Hodgkin’s disease, Non- Hodgkin lymphoma, or multiple myeloma. Alternatively, the CAR cell may be derived from the same species as the subject for an allogeneic treatment. [0021] In some embodiments, the CAR cell and the iCPI are administered at effective doses to a subject in need thereof. In some embodiments, the subject has cancer. In some embodiments, the CAR cell is administered by infusion. In some embodiments, the CAR cell is infused multiple times in the treatment of cancer. In some embodiments, a cell expressing a protein construct comprising a sequence in Table 1 or Table 2 is infused multiple times in the treatment of cancer. In some embodiments, the iCPI and the CAR cell are infused multiple times. In some embodiments, the iCPI and the cell expressing a protein construct found in Table 1 or Table 2 are infused multiple times. [0022] In some embodiments, the CAR cell is administered to a patient first, then the addition of iCPI treatment is initiated after 1, 2, 3, 4, 5, 10, 15, 20, 24, or any integer between 1 and 24 weeks following CAR cell administration. In some embodiments, the iCPI treatment is administered at 1 week following CAR cell administration. In some embodiments, the iCPI treatment is administered at 2 weeks following CAR cell administration. In some embodiments, the iCPI treatment is administered at 3 weeks following CAR cell administration. In some embodiments, the iCPI treatment is administered at 4 weeks following CAR cell administration. In some embodiments, the iCPI treatment is administered at 5 weeks following CAR cell administration. In some embodiments, the iCPI treatment is administered at 6 weeks following CAR cell administration. In some embodiments, the iCPI treatment is administered at 7 weeks following CAR cell administration. In some embodiments, the iCPI treatment is administered at 8 weeks following CAR cell administration. In some embodiments, the iCPI treatment is administered at 9 weeks following CAR cell administration. In some embodiments, the iCPI treatment is administered at 10 weeks following CAR cell administration. In some embodiments, the iCPI treatment is administered at 11 weeks following CAR cell administration. In some embodiments, the iCPI treatment is administered at 12 weeks following CAR cell administration. In some embodiments, the iCPI treatment is administered at 13 weeks following CAR cell administration. In some embodiments, the iCPI treatment is administered at 14 weeks following CAR cell administration. In some embodiments, the iCPI treatment is administered at 15 weeks following CAR cell administration. In some embodiments, the iCPI treatment is administered at 20 weeks following CAR cell administration. In some embodiments, the iCPI treatment is administered at 22 weeks following CAR cell administration. In some embodiments, the iCPI treatment is administered at 24 weeks following CAR cell administration. In some embodiments, the iCPI treatment is administered every other week following CAR cell administration. In some embodiments, the iCPI treatment is administered every 2 weeks following CAR cell administration. In some embodiments, the iCPI treatment is administered every 3 weeks following CAR cell administration. In some embodiments, the iCPI treatment is administered every 4 weeks following CAR cell administration. In some embodiments, the iCPI treatment is administered every 5 weeks following CAR cell administration. In some embodiments, the iCPI treatment is administered every 6 weeks following CAR cell administration. In some embodiments, the iCPI treatment is administered every 7 weeks following CAR cell administration. In some embodiments, the iCPI treatment is administered every 8 weeks following CAR cell administration. In some embodiments, the iCPI treatment is administered every 9 weeks following CAR cell administration. In some embodiments, the iCPI treatment is administered every 10 weeks following CAR cell administration. In some embodiments, the iCPI treatment is administered every 11 weeks following CAR cell administration. In some embodiments, the iCPI treatment is administered every 12 weeks following CAR cell administration. In some embodiments, the CAR cell is administered at least once. In some embodiments, the CAR cell is administered more than once. In some In some embodiments, iCPI treatment is administered at least once. In some embodiments, the iCPI treatment is administered more than once. In some embodiments, the iCPI treatment is administered at a fixed dose. In some embodiments, the iCPI treatment is administered at a dose that is about 0.1, 0.25, 0.5, 0.75, 1, 2.5, 5, 7.5, 10, or any integer that is between 0.1 and 10, mg/kg. In some embodiments, the iCPI treatment is administered at an escalating dose. In some embodiments, the iCPI treatment is administered at a decreasing dose. [0023] In some embodiments, the method does not comprise a lymphodepletion step. The term “lymphodepletion” as used herein is given its standard scientific meaning, and thus refers to a short course of chemotherapy administered to a subject in order to kill their T cells before, after, or during immunotherapy. [0024] In some embodiments, the CAR cell is administered to the subject by an at least one infusion. In some embodiments, the at least one infusion is more than one infusion. In some embodiments, the at least one infusion is administered 2, 3, 4, 5, 10, 20, 25, 30, 40, 50, 100, or any integer that is between 2 and 100, times. [0025] In some embodiments, the method of any one of the embodiments disclosed herein further comprises a drug-mediated kill switch. In some embodiments, the drug is an antibody. In some embodiments, the drug is a monoclonal antibody. In some embodiments, the drug is an epidermal growth factor receptor (EGFR) inhibitor. In some embodiments, the drug is cetuximab. In some embodiments, the drug is avelumab. In some embodiments, the dug is necitumumab. In some embodiments, the drug is panitumumab. Definitions [0026] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which the claimed subject matter belongs. It is to be understood that the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of any subject matter claimed. [0027] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. [0028] The articles “a” and “an” are used herein to refer to one or to more than one (for example, at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element. [0029] By “about” is meant a quantity, level, value, number, frequency, percentage, dimension, size, amount, weight or length that varies by as much as 30, 25, 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1% to a reference quantity, level, value, number, frequency, percentage, dimension, size, amount, weight or length. [0030] Throughout this specification, unless the context requires otherwise, the words “comprise,” “comprises,” and “comprising” will be understood to imply the inclusion of a stated step or element or group of steps or elements but not the exclusion of any other step or element or group of steps or elements. By “consisting of” is meant including, and limited to, whatever follows the phrase “consisting of.” Thus, the phrase “consisting of” indicates that the listed elements are required or mandatory, and that no other elements may be present. By “consisting essentially of” is meant including any elements listed after the phrase and limited to other elements that do not interfere with or contribute to the activity or action specified in the disclosure for the listed elements. Thus, the phrase “consisting essentially of” indicates that the listed elements are required or mandatory, but that other elements are optional and may or may not be present depending upon whether or not they materially affect the activity or action of the listed elements. [0031] The term “% w/w” or “% wt/wt” means a percentage expressed in terms of the weight of the ingredient or agent over the total weight of the composition multiplied by 100. Sequences [0032] The terms “nucleic acid” or “nucleic acid molecule” as used herein refers to polynucleotides, such as deoxyribonucleic acid (DNA) or ribonucleic acid (RNA), oligonucleotides, fragments generated by the polymerase chain reaction (PCR), and fragments generated by any of ligation, scission, endonuclease action, and exonuclease action. Nucleic acid molecules can be composed of monomers that are naturally-occurring nucleotides (such as DNA and RNA), or analogs of naturally-occurring nucleotides (e.g., enantiomeric forms of naturally-occurring nucleotides), or a combination of both. Nucleic acid monomers can be linked by phosphodiester bonds or analogs of such linkages. A nucleic acid or nucleic acids can be contained in a nucleic acid vector or nucleic acid construct (e.g. plasmid, virus, bacteriophage, cosmid, fosmid, phagemid, bacterial artificial chromosome (BAC), yeast artificial chromosome (YAC), or human artificial chromosome (HAC)) that can be used for amplification and/or expression of the nucleic acid or nucleic acids in various biological systems. Typically, the vector or construct will also contain elements including but not limited to promoters, enhancers, terminators, inducers, ribosome binding sites, translation initiation sites, start codons, stop codons, polyadenylation signals, origins of replication, cloning sites, multiple cloning sites, restriction enzyme sites, epitopes, reporter genes, selection markers, antibiotic selection markers, targeting sequences, peptide purification tags, or accessory genes, or any combination thereof. [0033] A nucleic acid or nucleic acid molecule can comprise one or more sequences encoding different peptides, polypeptides, or proteins. These one or more sequences can be joined in the same nucleic acid or nucleic acid molecule adjacently, or with extra nucleic acids in between, e.g. linkers, repeats or restriction enzyme sites, or any other sequence that is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 150, 200, or 300 bases long, or any length in a range defined by any two of the aforementioned lengths. The term “downstream” on a nucleic acid as used herein refers to a sequence being after the 3’-end of a previous sequence, on the strand containing the encoding sequence (sense strand) if the nucleic acid is double stranded. The term “upstream” on a nucleic acid as used herein refers to a sequence being before the 5’-end of a subsequent sequence, on the strand containing the encoding sequence (sense strand) if the nucleic acid is double stranded. The term “grouped” on a nucleic acid as used herein refers to two or more sequences that occur in proximity either directly or with extra nucleic acids in between, e.g. linkers, repeats, or restriction enzyme sites, or any other sequence that is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 150, 200, or 300 bases long, or any length in a range defined by any two of the aforementioned lengths, but generally not with a sequence in between that encodes for a functioning or catalytic polypeptide, protein, or protein domain. [0034] The term “codon optimized” regarding a nucleic acid as used herein refers to the substitution of codons of the nucleic acid to enhance or maximize translation in a host of a particular species without changing the polypeptide sequence based on species-specific codon usage biases and relative availability of each aminoacyl-tRNA in the target cell cytoplasm. Codon optimization and techniques to perform such optimization is known in the art. Those skilled in the art will appreciate that gene expression levels are dependent on many factors, such as promoter sequences and regulatory elements. In this aspect, many synthetic genes can be designed to increase their protein expression level. [0035] The terms “peptide”, “polypeptide”, and “protein” as used herein refers to macromolecules comprised of amino acids linked by peptide bonds. The numerous functions of peptides, polypeptides, and proteins are known in the art, and include but are not limited to enzymes, structure, transport, defense, hormones, or signaling. Peptides, polypeptides, and proteins are often, but not always, produced biologically by a ribosomal complex using a nucleic acid template, although chemical syntheses are also available. By manipulating the nucleic acid template, peptide, polypeptide, and protein mutations such as substitutions, deletions, truncations, additions, duplications, or fusions of more than one peptide, polypeptide, or protein can be performed. These fusions of more than one peptide, polypeptide, or protein can be joined in the same molecule adjacently, or with extra amino acids in between, e.g. linkers, repeats, epitopes, or tags, or any other sequence that is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 150, 200, or 300 bases long, or any length in a range defined by any two of the aforementioned lengths. The term “downstream” on a polypeptide as used herein refers to a sequence being after the C-terminus of a previous sequence. The term “upstream” on a polypeptide as used herein refers to a sequence being before the N-terminus of a subsequent sequence. [0036] In some embodiments, the nucleic acid or peptide sequences presented herein and used in the examples are functional in various biological systems including but not limited to humans, mice, rats, monkeys, primates, cats, dogs, rabbits, E. coli, yeast, and mammalian cells. In other embodiments, nucleic acid or peptide sequences sharing at least or lower than 0%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% similarity, or any percentage within a range defined by any two of the aforementioned percentages similarity to the nucleic acid or peptide sequences presented herein and used in the examples can also be used with no effect on the function of the sequences in biological systems. As used herein, the term “similarity” refers to a nucleic acid or peptide sequence having the same overall order of nucleotide or amino acids, respectively, as a template nucleic acid or peptide sequence with specific changes such as substitutions, deletions, repetitions, or insertions within the sequence. In some embodiments, two nucleic acid sequences sharing as low as 0%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% similarity can encode for the same polypeptide by comprising different codons that encode for the same amino acid during translation. [0037] As disclosed herein, sequences having a percent homology to any of the sequences disclosed herein are envisioned and may be used. The term “% homology” refers to the degree of conservation between two sequences when considering their three-dimensional structure. For example, homology between two protein sequences may be dependent on structural motifs, such as beta strands, alpha helices, and other folds, as well as their distribution throughout the sequence. Homology may be determined through structural determination, either empirically or in silico. In some embodiments, any sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence homology to any of the sequences disclosed herein may be used. In some embodiments, any sequence having at least 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 substitutions, deletions, or additions relative to any of the sequences disclosed herein, which may or may not affect the overall percent homology, may be used. [0038] As applied herein, sequences having a certain “percent similarity” or “percent identity” to any of the sequence disclosed herein are envisioned and may be used. In some embodiments, these sequences may include peptide sequences, nucleic acid sequences, CDR sequences, variable region sequences, or heavy or light chain sequences. As understood in the art with respect to peptide sequences, “similarity” refers to the comparison of amino acids based on their properties, including but not limited to size, polarity, charge, pK, aromaticity, hydrogen bonding properties, or presence of functional groups (e.g. hydroxyl, thiol, amine, carboxyl, and the like). The term “% similarity” refers to the percentage of units (i.e. amino acids) that are the same between two or more sequences relative to the length of the sequence. When the two or more sequences being compared are the same length, the percent similarity will be respective that length. When two or more sequences being compared are different lengths, deletions and/or insertions may be introduced to obtain the best alignment. The similarity of two amino acids may dictate whether a certain substitution is conservative or non-conservative. Methods of determining the conservativeness of an amino acid substitution are generally known in the art and may involve substitution matrices. Commonly used substitution matrices include BLOSUM45, BLOSUM62, BLOSUM80, PAM100, PAM120, PAM160, PAM200, PAM250, but other substitution matrices or approaches may be used as considered appropriate by the skilled person. A certain substitution matrix may be preferential over the others when considering aspects such as stringency, conservation and/or divergence of related sequences (e.g. within the same species or broader), and length of the sequences in question. As used herein, a peptide sequence having a certain percent similarity to another sequence will have up to that percent of amino acids that are either identical or an acceptable substitution as governed by the method of similarity determination used. In some embodiments, a sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence similarity to any of the sequences disclosed herein may be used. In some embodiments, any sequence having at least 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 similar substitutions relative to any of the sequences disclosed herein may be used. As applied to antibody sequences, these similar substitutions may apply to antigen-binding regions (i.e. CDRs) or regions that do not bind to antigens or are only secondary to antigen binding (i.e. framework regions). [0039] As applied herein, sequences having a certain “percent identity” to any of the sequence disclosed herein are envisioned and may be used. The term to “percent identity” refers to the percent similarity between two or more sequences. In some embodiments, any sequence having at least 60%, 70%, 80%, 85%, 90%, 95%, 99%, 100%, or any integer that is between 60 and 100% identity, to any of the sequences disclosed herein may be used. [0040] The term “consensus sequence” as used herein with regard to sequences refers to the generalized sequence representing all of the different combinations of permissible amino acids at each location of a group of sequences. A consensus sequence may provide insight into the conserved regions of related sequences where the unit (e.g. amino acid or nucleotide) is the same in most or all of the sequences, and regions that exhibit divergence between sequences. In the case of antibodies, the consensus sequence of a CDR may indicate amino acids that are important or dispensable for antigen binding. It is envisioned that consensus sequences may be prepared with any of the sequences provided herein, and the resultant various sequences derived from the consensus sequence can be validated to have similar effects as the template sequences. Antigen Binding Molecules and Antibodies [0041] As used herein, the term "antibody" denotes the meaning ascribed to it by one of skill in the art, and further it is intended to include any polypeptide chain-containing molecular structure with a specific shape that fits to and recognizes an epitope, where one or more non-covalent binding interactions stabilize the complex between the molecular structure and the epitope. [0042] The term "antibody library" refers to a collection of antibodies and/or antibody fragments displayed for screening and/or combination into full antibodies. The antibodies and/or antibody fragments may be displayed on a ribosome; on a phage; or on a cell surface, in particular a yeast cell surface. [0043] The term "compete," as used herein with regard to an antibody or binding polypeptide, means that a first antibody or binding polypeptide, or an antigen-binding portion thereof, binds to an epitope in a manner sufficiently similar to the binding of a second antibody or binding polypeptide, or an antigen-binding portion thereof, such that the result of binding of the first antibody or binding polypeptide with its cognate epitope is detectably decreased in the presence of the second antibody or binding polypeptide compared to the binding of the first antibody or binding polypeptide in the absence of the second antibody or binding polypeptide. The alternative, where the binding of the second antibody or binding polypeptide to its epitope is also detectably decreased in the presence of the first antibody or binding polypeptide, can, but need not be the case. Regardless of the mechanism by which such competition occurs (e.g., steric hindrance, conformational change, or binding to a common epitope, or portion thereof), the skilled artisan would appreciate, based upon the teachings provided herein, that such competing antibodies or binding polypeptides are encompassed and can be useful for the methods disclosed herein. [0044] An antibody or binding polypeptide that "preferentially binds" or "specifically binds" (used interchangeably herein) to an epitope is a term well understood in the art, and methods to determine such specific or preferential binding are also well known in the art. A molecule is said to exhibit "specific binding" or "preferential binding" if it reacts or associates more frequently, and/or more rapidly, and/or with greater duration and/or with greater affinity with a particular cell or substance than it does with alternative cells or substances. An antibody or binding polypeptide "specifically binds" or "preferentially binds" to a target if it binds with greater affinity, and/or avidity, and/or more readily, and/or with greater duration than it binds to other substances. [0045] The term “humanized” as applies to a non-human (e.g. rodent or primate) antibodies are hybrid immunoglobulins, immunoglobulin chains or fragments thereof which contain minimal sequence derived from non-human immunoglobulin. [0046] The term “single domain binding polypeptide” or “single domain antibody” (sdAb) as used herein refers to a single peptide strand (e.g. not bound to another peptide strand with disulfide bonds) comprising an intact immunoglobulin domain or other protein fold which can recognize antigens. Single domain binding polypeptides or sdAbs may be derived from typical heavy or light immunoglobulin chains, such as from human, or from alternative sources such as dromedaries (e.g. VHH) and cartilaginous fish (e.g. VNAR). In some embodiments, the single domain binding polypeptide or sdAb comprises one, two, or three complementarity determining regions (CDRs). In some embodiments, the single domain binding polypeptide or sdAb comprises one, two, or three of a CDR1, CDR2, and CDR3. [0047] Unless otherwise specified, the complementarity determining regions (CDRs) disclosed herein follow the IMGT definition. However, the CDRs, either separately or within the context of the variable domains, can also be interpreted by Kabat, Chothia, or other definitions as understood by those of skill in the art. [0048] The term "single-chain variable fragment" (scFv) as used herein is a fusion protein comprising the variable regions of the heavy (VH) and light chains (VL) of an immunoglobulin, in which the VH and VL are covalently linked to form a VH:VL heterodimer. The VH and VL are either joined directly or joined by a peptide-encoding linker, which connects the N-terminus of the VH with the C-terminus of the VL, or the C-terminus of the VH with the N-terminus of the VL. The linker is usually rich in glycine for flexibility, as well as serine or threonine for solubility. Despite removal of the constant regions and the introduction of a linker, scFv proteins retain the specificity of the original immunoglobulin. Single chain Fv polypeptide antibodies can be expressed from a nucleic acid including VH- and VL-encoding sequences. In some embodiments, the VH and VL of the scFv each comprises one, two, or three CDRs. In some embodiments, the VH and VL of the scFv each comprises one, two, or three of a CDR1, CDR2, and CDR3. [0049] In certain embodiments, definitive delineation of a CDR and identification of residues comprising the binding site of an antibody or binding polypeptide is accomplished by solving the structure of the antibody or binding polypeptide and/or solving the structure of the antibody-ligand complex. In certain embodiments, that can be accomplished by any of a variety of techniques known to those skilled in the art, such as X-ray crystallography. In certain embodiments, various methods of analysis can be employed to identify or approximate the CDR regions. In certain embodiments, various methods of analysis can be employed to identify or approximate the CDR regions. Examples of such methods include, but are not limited to, the Kabat definition, the Chothia definition, the IMGT approach (Lefranc et al., 2003) Dev Comp Immunol. 27:55-77), computational programs such as Paratome (Kunik et al., 2012, Nucl Acids Res. W521-4), the AbM definition, and the conformational definition. [0050] The Kabat definition is a standard for numbering the residues in an antibody and is typically used to identify CDR regions. See, e.g., Johnson & Wu, 2000, Nucleic Acids Res., 28: 214-8. The Chothia definition is similar to the Kabat definition, but the Chothia definition takes into account positions of certain structural loop regions. See, e.g., Chothia et al., 1986, J. Mol. Biol., 196: 901-17; Chothia et al., 1989, Nature, 342: 877-83. The AbM definition uses an integrated suite of computer programs produced by Oxford Molecular Group that model antibody structure. See, e.g., Martin et al., 1989, Proc Natl Acad Sci (USA), 86:9268-9272; "AbM.TM., A Computer Program for Modeling Variable Regions of Antibodies," Oxford, UK; Oxford Molecular, Ltd. The AbM definition models the tertiary structure of an antibody from primary sequence using a combination of knowledge databases and ab initio methods, such as those described by Samudrala et al., 1999, "Ab Initio Protein Structure Prediction Using a Combined Hierarchical Approach," in PROTEINS, Structure, Function and Genetics Suppl., 3:194-198. The contact definition is based on an analysis of the available complex crystal structures. See, e.g., MacCallum et al., 1996, J. Mol. Biol., 5:732- 45. In another approach, referred to herein as the "conformational definition" of CDRs, the positions of the CDRs may be identified as the residues that make enthalpic contributions to antigen binding. See, e.g., Makabe et al., 2008, Journal of Biological Chemistry, 283:1156- 1166. Still other CDR boundary definitions may not strictly follow one of the above approaches, but will nonetheless overlap with at least a portion of the Kabat CDRs, although they may be shortened or lengthened in light of prediction or experimental findings that particular residues or groups of residues do not significantly impact antigen binding. As used herein, a CDR may refer to CDRs defined by any approach known in the art, including combinations of approaches. The methods used herein may utilize CDRs defined according to any of these approaches. For any given embodiment containing more than one CDR, the CDRs may be defined in accordance with any of Kabat, Chothia, extended, IMGT, Paratome, AbM, and/or conformational definitions, or a combination of any of the foregoing. Antigen binding polypeptides [0051] In addition to entire immunoglobulins (or their recombinant counterparts), immunoglobulin fragments or “binding fragments” comprising the epitope binding site (e.g., Fab', F(ab')2, single-chain variable fragment (scFv), diabody, minibody, nanobody, single- domain antibody (sdAb), VHH fragments, VNAR fragments, or other fragments) are useful as antibody moieties in the present invention. Such antibody fragments may be generated from whole immunoglobulins by ricin, pepsin, papain, or other protease cleavage. Minimal immunoglobulins may be designed utilizing recombinant immunoglobulin techniques. For instance "Fv" immunoglobulins for use in the present invention may be produced by linking a variable light chain region to a variable heavy chain region via a peptide linker (e.g., poly- glycine or another sequence which does not form an alpha helix or beta sheet motif). Nanobodies or single-domain antibodies can also be derived from alternative organisms, such as dromedaries, camels, llamas, alpacas, sharks, or cartilaginous fish. In some embodiments, antibodies can be conjugates, e.g. pegylated antibodies, drug, radioisotope, or toxin conjugates. Monoclonal antibodies directed against a specific epitope, or combination of epitopes, will allow for the targeting and/or depletion of cellular populations expressing the marker. [0052] The term “single-domain antibody” (sdAb) as used herein refers to a single peptide strand (e.g. not bound to another peptide strand with disulfide bonds) comprising an intact immunoglobulin domain or other protein fold which can recognize antigens. sdAbs may be derived from typical heavy or light immunoglobulin chains, such as from human, or from alternative sources such as dromedaries (e.g. VHH) and cartilaginous fish (e.g. VNAR). [0053] Disclosed herein are carcinoembryonic antigen 6 (carcinoembryonic antigen-related cell adhesion molecule 6; CEA6; CEACAM6) binding polypeptides. In some embodiments, the CEA6 binding polypeptides comprise an immunoglobulin heavy chain variable domain comprising a CDR-H1, CDR-H2, and CDR-H3. In some embodiments, the CDR-H1 comprises a sequence having at least 90%, 95%, 99%, or 100% sequence identity to a sequence selected from SEQ ID NOs: 1-43. In some embodiments, CDR-H2 comprises a sequence having at least 90%, 95%, 99%, or 100% sequence identity to a sequence selected from SEQ ID NOs: 44-86. In some embodiments, the CDR-H3 comprises a sequence having at least 90%, 95%, 99%, or 100% sequence identity to a sequence selected from SEQ ID NOs: 87-129. In some embodiments, the CDR-H1 comprises a sequence having at least 90%, 95%, 99%, or 100% sequence identity to a sequence selected from SEQ ID NOs: 1-43, the CDR-H2 comprises a sequence having at least 90%, 95%, 99%, or 100% sequence identity to a sequence selected from SEQ ID NOs: 44-86, and the CDR-H3 comprises a sequence having at least 90%, 95%, 99%, or 100% sequence identity to a sequence selected from SEQ ID NOs: 87-129. [0054] In some embodiments of the CEA6 binding polypeptides: 1) the CDR-H1 comprises the sequence of SEQ ID NO: 1, the CDR-H2 comprises the sequence of SEQ ID NO: 44, and the CDR-H3 comprises the sequence of SEQ ID NO: 87; 2) the CDR-H1 comprises the sequence of SEQ ID NO: 2, the CDR-H2 comprises the sequence of SEQ ID NO: 45, and the CDR-H3 comprises the sequence of SEQ ID NO: 88; 3) the CDR-H1 comprises the sequence of SEQ ID NO: 3, the CDR-H2 comprises the sequence of SEQ ID NO: 46, and the CDR-H3 comprises the sequence of SEQ ID NO: 89; 4) the CDR-H1 comprises the sequence of SEQ ID NO: 4, the CDR-H2 comprises the sequence of SEQ ID NO: 47, and the CDR-H3 comprises the sequence of SEQ ID NO: 90; 5) the CDR-H1 comprises the sequence of SEQ ID NO: 5, the CDR-H2 comprises the sequence of SEQ ID NO: 48, and the CDR-H3 comprises the sequence of SEQ ID NO: 91; 6) the CDR-H1 comprises the sequence of SEQ ID NO: 6, the CDR-H2 comprises the sequence of SEQ ID NO: 49, and the CDR-H3 comprises the sequence of SEQ ID NO: 92; 7) the CDR-H1 comprises the sequence of SEQ ID NO: 7, the CDR-H2 comprises the sequence of SEQ ID NO: 50, and the CDR-H3 comprises the sequence of SEQ ID NO: 93; 8) the CDR-H1 comprises the sequence of SEQ ID NO: 8, the CDR-H2 comprises the sequence of SEQ ID NO: 51, and the CDR-H3 comprises the sequence of SEQ ID NO: 94; 9) the CDR-H1 comprises the sequence of SEQ ID NO: 9, the CDR-H2 comprises the sequence of SEQ ID NO: 52, and the CDR-H3 comprises the sequence of SEQ ID NO: 95; 10) the CDR-H1 comprises the sequence of SEQ ID NO: 10, the CDR-H2 comprises the sequence of SEQ ID NO: 53, and the CDR-H3 comprises the sequence of SEQ ID NO: 96; 11) the CDR-H1 comprises the sequence of SEQ ID NO: 11, the CDR-H2 comprises the sequence of SEQ ID NO: 54, and the CDR-H3 comprises the sequence of SEQ ID NO: 7; 12) the CDR-H1 comprises the sequence of SEQ ID NO: 12, the CDR-H2 comprises the sequence of SEQ ID NO: 55, and the CDR-H3 comprises the sequence of SEQ ID NO: 98; 13) the CDR-H1 comprises the sequence of SEQ ID NO: 13, the CDR-H2 comprises the sequence of SEQ ID NO: 56, and the CDR-H3 comprises the sequence of SEQ ID NO: 99; 14) the CDR-H1 comprises the sequence of SEQ ID NO: 14, the CDR-H2 comprises the sequence of SEQ ID NO: 57, and the CDR-H3 comprises the sequence of SEQ ID NO: 100; 15) the CDR-H1 comprises the sequence of SEQ ID NO: 15, the CDR-H2 comprises the sequence of SEQ ID NO: 58, and the CDR-H3 comprises the sequence of SEQ ID NO: 101; 16) the CDR-H1 comprises the sequence of SEQ ID NO: 16, the CDR-H2 comprises the sequence of SEQ ID NO: 59, and the CDR-H3 comprises the sequence of SEQ ID NO: 102; 17) the CDR-H1 comprises the sequence of SEQ ID NO: 17, the CDR-H2 comprises the sequence of SEQ ID NO: 60, and the CDR-H3 comprises the sequence of SEQ ID NO: 103; 18) the CDR-H1 comprises the sequence of SEQ ID NO: 18, the CDR-H2 comprises the sequence of SEQ ID NO: 61, and the CDR-H3 comprises the sequence of SEQ ID NO: 104; 19) the CDR-H1 comprises the sequence of SEQ ID NO: 19, the CDR-H2 comprises the sequence of SEQ ID NO: 62, and the CDR-H3 comprises the sequence of SEQ ID NO: 105; 20) the CDR-H1 comprises the sequence of SEQ ID NO: 20, the CDR-H2 comprises the sequence of SEQ ID NO: 63, and the CDR-H3 comprises the sequence of SEQ ID NO: 106; 21) the CDR-H1 comprises the sequence of SEQ ID NO: 21, the CDR-H2 comprises the sequence of SEQ ID NO: 64, and the CDR-H3 comprises the sequence of SEQ ID NO: 107; 22) the CDR-H1 comprises the sequence of SEQ ID NO: 22, the CDR-H2 comprises the sequence of SEQ ID NO: 65, and the CDR-H3 comprises the sequence of SEQ ID NO: 108; 23) the CDR-H1 comprises the sequence of SEQ ID NO: 23, the CDR-H2 comprises the sequence of SEQ ID NO: 66, and the CDR-H3 comprises the sequence of SEQ ID NO: 109; 24) the CDR-H1 comprises the sequence of SEQ ID NO: 24, the CDR-H2 comprises the sequence of SEQ ID NO: 67, and the CDR-H3 comprises the sequence of SEQ ID NO: 110; 25) the CDR-H1 comprises the sequence of SEQ ID NO: 25, the CDR-H2 comprises the sequence of SEQ ID NO: 68, and the CDR-H3 comprises the sequence of SEQ ID NO: 111; 26) the CDR-H1 comprises the sequence of SEQ ID NO: 26, the CDR-H2 comprises the sequence of SEQ ID NO: 69, and the CDR-H3 comprises the sequence of SEQ ID NO: 112; 27) the CDR-H1 comprises the sequence of SEQ ID NO: 27, the CDR-H2 comprises the sequence of SEQ ID NO: 70, and the CDR-H3 comprises the sequence of SEQ ID NO: 113; 28) the CDR-H1 comprises the sequence of SEQ ID NO: 28, the CDR-H2 comprises the sequence of SEQ ID NO: 71, and the CDR-H3 comprises the sequence of SEQ ID NO: 114; 29) the CDR-H1 comprises the sequence of SEQ ID NO: 29, the CDR-H2 comprises the sequence of SEQ ID NO: 72, and the CDR-H3 comprises the sequence of SEQ ID NO: 115; 30) the CDR-H1 comprises the sequence of SEQ ID NO: 30, the CDR-H2 comprises the sequence of SEQ ID NO: 73, and the CDR-H3 comprises the sequence of SEQ ID NO: 116; 31) the CDR-H1 comprises the sequence of SEQ ID NO: 31, the CDR-H2 comprises the sequence of SEQ ID NO: 74, and the CDR-H3 comprises the sequence of SEQ ID NO: 117; 32) the CDR-H1 comprises the sequence of SEQ ID NO: 32, the CDR-H2 comprises the sequence of SEQ ID NO: 75, and the CDR-H3 comprises the sequence of SEQ ID NO: 118; 33) the CDR-H1 comprises the sequence of SEQ ID NO: 33, the CDR-H2 comprises the sequence of SEQ ID NO: 76, and the CDR-H3 comprises the sequence of SEQ ID NO: 119; 34) the CDR-H1 comprises the sequence of SEQ ID NO: 34, the CDR-H2 comprises the sequence of SEQ ID NO: 77, and the CDR-H3 comprises the sequence of SEQ ID NO: 120; 35) the CDR-H1 comprises the sequence of SEQ ID NO: 35, the CDR-H2 comprises the sequence of SEQ ID NO: 78, and the CDR-H3 comprises the sequence of SEQ ID NO: 121; 36) the CDR-H1 comprises the sequence of SEQ ID NO: 36, the CDR-H2 comprises the sequence of SEQ ID NO: 79, and the CDR-H3 comprises the sequence of SEQ ID NO: 122; 37) the CDR-H1 comprises the sequence of SEQ ID NO: 37, the CDR-H2 comprises the sequence of SEQ ID NO: 80, and the CDR-H3 comprises the sequence of SEQ ID NO: 123; 38) the CDR-H1 comprises the sequence of SEQ ID NO: 38, the CDR-H2 comprises the sequence of SEQ ID NO: 81, and the CDR-H3 comprises the sequence of SEQ ID NO: 124; 39) the CDR-H1 comprises the sequence of SEQ ID NO: 39, the CDR-H2 comprises the sequence of SEQ ID NO: 82, and the CDR-H3 comprises the sequence of SEQ ID NO: 125; 40) the CDR-H1 comprises the sequence of SEQ ID NO: 40, the CDR-H2 comprises the sequence of SEQ ID NO: 83, and the CDR-H3 comprises the sequence of SEQ ID NO: 126; 41) the CDR-H1 comprises the sequence of SEQ ID NO: 41, the CDR-H2 comprises the sequence of SEQ ID NO: 84, and the CDR-H3 comprises the sequence of SEQ ID NO: 127; 42) the CDR-H1 comprises the sequence of SEQ ID NO: 42, the CDR-H2 comprises the sequence of SEQ ID NO: 85, and the CDR-H3 comprises the sequence of SEQ ID NO: 128; or 43) the CDR-H1 comprises the sequence of SEQ ID NO: 43, the CDR-H2 comprises the sequence of SEQ ID NO: 86, and the CDR-H3 comprises the sequence of SEQ ID NO: 129. [0055] In some embodiments, the CEA6 binding polypeptide comprise an immunoglobulin heavy chain variable domain comprising a CDR-H1, CDR-H2, and CDR-H3, where one or more of these CDRs are defined by a consensus sequence. The consensus sequences provided herein have been derived from the alignments of CDRs depicted in FIG. 1. However, it is envisioned that alternative alignments may be done (e.g. using global or local alignment, or with different algorithms, such as Hidden Markov Models, seeded guide trees, Needleman-Wunsch algorithm, or Smith-Waterman algorithm, or other known methods) and as such, alternative consensus sequences can be derived (including those done with a subset of the sequences provided herein). [0056] In some embodiments, the CDR-H1 is defined by the formula X1X2X3X4X5X6X7X8, where X1 is G; X2 is F, R, S, or Y; X3 is I or T; X4 is F, G, L, S, or Y; X5 is D, G, N, or S; X6 is D, F, I, L, N, S, T, or Y; X7 is D, N, or Y; X8 is D, F, H, L, P, T, V, or Y. In some embodiments, the CDR-H1 comprises a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to this consensus sequence. In some embodiments, the CDR-H1 comprises a sequence having 0, 1, 2, 3, 4, 5, or 6 substitutions from this consensus sequence. [0057] In some embodiments, the CDR-H2 is defined by the formula X1X2X3X4X5X6X7X8X9X10, where X1 is no amino acid, S, or T; X2 is I; X3 is N, S, or T; X4 is R, S, T, or W; X5 is D, F, I, L, S, T, or Y; X6 is A, D, G, or S; X7 is A, D, G, or S; X8 is I or S; X9 is T; X10 is no amino acid or Y. In some embodiments, the CDR-H2 comprises a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to this consensus sequence. In some embodiments, the CDR-H2 comprises a sequence having 0, 1, 2, 3, 4, 5, or 6 substitutions from this consensus sequence. [0058] In some embodiments, the CDR-H3 is defined by the formula X1X2X3X4X5X6X7X8X9X10X11X12X13X14X15X16X17X18X19X20X21X22X23X24 X25X26X27X28X29X30X31X32X33, where X1 is no amino acid or A; X2 is no amino acid, A, or V; X3 is no amino acid, A, G, M, Q, S, T, or V; X4 is no amino acid, A, D, E, G, I, M, N, R, S, V, or Y; X5 is no amino acid, A, E, K, M, R, S, T, V, or W; X6 is no amino acid, A, E, M, P, S, or V; X7 is no amino acid, A, F, I, M, P, W, or Y; X8 is no amino acid, D, I, K, L, S, T, or V; X9 is no amino acid, A, K, Q, T, or V; X10 is no amino acid, A, D, E, or S; X11 is no amino acid, A, I, L, R, V, or Y; X12 is no amino acid, A, E, G, L, P, S, or T; X13 is no amino acid, D, G, I, L, N, P, Q, S, T, or V; X14 is no amino acid, A, E, F, H, K, L, M, P, Q, R, T, V, or Y; X15 is no amino acid, A, D, H, I, L, M, P, Q, R, S, T, or V; X16 is no amino acid, A, D, E, H, L, S, T, V, W, or Y; X17 is no amino acid, E, F, G, H, L, M, N, Q, S, T, or Y; X18 is no amino acid, A, D, G, H, K, M, N, Q, R, S, V, or Y; X19 is no amino acid, F, H, Q, or Y; X20 is no amino acid, D, N, Q, S, or Y; X21 is no amino acid, A, G, or Y; X22 is no amino acid, W, or Y; X23 is no amino acid, A, or R; X24 is no amino acid, H, or S; X25 is no amino acid, D, or G; X26 is no amino acid, E, or K; X27 is no amino acid, I, or T; X28 is no amino acid, F, or R; X29 is no amino acid or Y; X30 is no amino acid or Y; X31 is no amino acid or Y; X32 is no amino acid, N, or S; X33 is no amino acid or Y. [0059] In some embodiments, the CDR-H3 comprises a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to this consensus sequence. In some embodiments, the CDR-H3 comprises a sequence having 0, 1, 2, 3, 4, 5, or 6 substitutions from this consensus sequence. [0060] In some embodiments of the CEA6 binding polypeptides, the heavy chain variable domain comprises an amino acid sequence having at least 90%, 95%, 99%, or 100% sequence identity to any sequence selected from SEQ ID NOs: 130-172. [0061] In some embodiments, the CEA6 binding polypeptide is humanized. In some embodiments, the CEA6 binding polypeptide is a single domain antibody (sdAb). [0062] In some embodiments, the CEA6 binding polypeptide binds to CEA6 with a dissociation constant (KD) of less than 1 nM, 2 nM, 5 nM, 10 nM, 15 nM, 20 nM, 30 nM, 40 nM, 50 nM, 60 nM, 70 nM, 80 nM, 90 nM, 100 nM, 200 nM, 300 nM, 400 nM, 500 nM, 600 nM, 700 nM, 800 nM, 900 nM, or 1000 nM, or any KD within a range defined by any two of the aforementioned KD. [0063] The binding polypeptides disclosed herein may be obtained from an antibody library. In some embodiments, the antibody library is an immune antibody library, a naïve antibody library, a synthetic antibody library, or a semi-synthetic antibody library. In some embodiments, the antibody library comprises antibodies derived from human, or antibodies that are not immunogenic in humans, or both. In some embodiments, the antibody library comprises antibodies that are humanized, e.g. from mouse, rat, guinea pig, rabbit, cat, dog, cow, horse, sheep, goat, horse, donkey. In some embodiments, the antibody library comprises single domain antibodies (sdAb), nanobodies, VHH fragments, VNAR fragments, single-chain variable fragments (scFv), camelid antibodies, or cartilaginous fish antibodies, or any combination thereof. One exemplary library that can be used is a fully humanized, synthetic, sdAb library, but any other antibody library that can be prepared or is available can be used for the methods disclosed herein. In some embodiments, the antibody library comprises sdAb. In some embodiments, the antibody library comprises at least 100, 500, 1000, 2000, 3000, 4000, 5000, 6000, 7000, 8000, 9000, 10000, 20000, 30000, 40000, 50000, 60000, 70000, 80000, 90000, 100000, 500000, or 1000000 unique antibodies, or any number of antibodies within a range defined by any two of the aforementioned number of antibodies. [0064] Antibody libraries may be generated computationally or using machine learning processes. An exemplary method of generating an antibody library computationally includes modifying a universal VHH framework with synthetic diversity in one or more complementary determining regions (CDRs), such as CDR1, CDR2, or CDR3, or any combination thereof. The diversity of the CDRs are introduced by randomizing the library of sequences encoding for the antibodies with degenerate codons. For example, an NNK codon library can be employed, where the NNK codon comprises N (25% mix of A/T/C/G) and K (50% mix of T/G). In some embodiments, the NNK codon library is constructed with all possible amino acids, or with some amino acids (e.g. cysteine) and stop codon combinations excluded. Other degenerate codon mixes can be substituted for said NNK codon library with minimal experimentation. In other embodiments, the antibody library can be generated using a trimer codon mix, which improves balanced representation of sense codons while reducing the chance of stop codons, improving efficiency of antibody generation and testing. In some embodiments, artificial intelligence-based prediction can be used to randomize specific binding pockets of the antibodies using available binding models or structure data. [0065] In some embodiments, panning the antibody library comprises screening for the candidate binding polypeptides by phage display, yeast display, bacterial display, ribosome display, or mRNA display, or any combination thereof. In some embodiments, panning the antibody library comprises one or more rounds of selection, wherein the candidate binding polypeptides are selected for specificity towards a cancer-associated antigen (e.g. CEA6) or cells or tissues displaying the cancer-associated antigen. In some embodiments, the candidate binding polypeptides are selected under conditions including but not limited to tumor microenvironment-like conditions, immunosuppressive conditions, low or high pH, low or high oxygen concentrations, low or high temperatures, low or high viscosity, or any combination thereof, or for specificity towards modified or derivative forms of the one or more cancer-associated antigens. In some embodiments, the immunosuppressive conditions may comprise the presence of tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), tumor-associated neutrophils (TANs), cancer-associated fibroblasts (CAFs), or other immunosuppressive cells, or the presence of adenosine, or both. [0066] In some embodiments, the chimeric antigen receptor cells are from a cell line (e.g. Jurkat). In some embodiments, the chimeric antigen receptor cells are derived from a subject. In some embodiments, the subject has a cancer. In some embodiments, the subject has a cancer, and that cancer expresses any one or more of the cancer-associated antigens disclosed herein (e.g., CEA6). In some embodiments, the cancer is breast cancer, colorectal cancer, kidney cancer, liver cancer, lung cancer, brain cancer, pancreatic cancer, bladder cancer, testicular cancer, prostate cancer, gastric cancer, ovarian cancer, head and neck cancer, gallbladder cancer, a hematologic malignancy, or any combination thereof. In some embodiments, the hematologic malignancy may comprise leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, hairy cell leukemia, lymphoma, Hodgkin’s disease, Non-Hodgkin lymphoma, or multiple myeloma. In some embodiments, the subject is a mammal, such as a human, cat, dog, mouse, rat, hamster, rodent, cow, pig, horse, goat, sheep, donkey, or monkey. In some embodiments, the subject is a human. Chimeric Antigen Receptors (CARs) [0067] Also disclosed herein are chimeric antigen receptors (CARs) comprising any one or more of the CEA6 binding polypeptides disclosed herein. [0068] The term “chimeric antigen receptor (CAR)” as used herein refers to engineered biological receptors that confers an artificial specificity in an immune cell towards a certain antigen, such as a tumor-associated antigen. An exemplary immune cell in which CARs can be used are T cells, but it is envisioned that CARs can be engineered into any amenable cytotoxic immune cell, including but not limited to T cells, Natural Killer (NK) cells, Natural Killer T (NKT) cells, dendritic cells, or macrophages. In this aspect, any disclosure pertaining to CAR T cells can also be applied to other immune cells comprising CARs. At their core, CARs comprise an extracellular antigen-recognizing domain (e.g. tumor receptor ligand, or antibody), hinge, transmembrane, and intracellular signaling domain (endodomain). Different combinations of these CAR components may result in different specificities and efficacy against certain cancer antigens. [0069] In some embodiments, the CAR comprises at least two single domain binding polypeptides and the CAR is a multivalent CAR. In some embodiments, the CAR comprises two single domain binding polypeptides and the CAR is a bivalent CAR. In some embodiments, the CAR comprises three single domain binding polypeptides and the CAR is a trivalent CAR. [0070] In some embodiments, the CAR further comprises one or more signal peptides, linkers with various lengths and composition, hinges, transmembrane domains, costimulatory domains, signaling domains, cytoplasmic domains, functionality signals, proliferation signals, anti-exhaustion signals, anti-inhibitory receptors, tumor/cancer homing proteins, or regulatory molecules, or any combination thereof. In some embodiments, the hinges comprise CD3ζ, CD4, CD8 or CD28 hinges, or computationally designed synthetic hinges with various lengths. In some embodiments, the transmembrane domains comprise CD3ζ, CD4, CD8 or CD28 transmembrane domains, or computationally designed synthetic transmembrane domains. In some embodiments, the costimulatory domains comprise CD8, CD28, ICOS, 4-1BB, OX40 (CD134), CD27, CD40, CD40L, TLR or other TNFR superfamily member or Ig superfamily member costimulatory domains, or other signaling via cytoplasmic domains of IL-2Rβ, IL-15R-α, MyD88, or CD40 or any other Toll-like receptor or IL-1 receptor signaling pathway members. [0071] In some embodiments, the CARs disclosed herein are constructed by assembling CAR expression constructs from nucleic acids encoding for any one of the single domain binding polypeptides disclosed herein and a mixture of compatible nucleic acids encoding for different CAR modules. In some embodiments, different combinations of CARs are produced for use in a CAR library for screening for CAR efficacy (in vitro or in vivo). In some embodiments, unique CARs are produced separately. In some embodiments, the CARs are specific for one target. In some embodiments, the CARs are specific for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 targets. In some embodiments, the CARs are bi-specific or tri-specific. [0072] To construct any one of CARs disclosed herein, the nucleic acids encoding for the single domain binding polypeptides identified by panning of the antibody library are assembled into CAR expression constructs with other CAR modules. In some embodiments, the CAR expression constructs are assembled using multi-fragment assembly reactions known in the art. One exemplary method of assembling CAR expression constructs involves using Type IIS restriction enzymes to generate nucleic acid fragments with compatible overhang sequences and ligating the nucleic acid fragments with a ligase. As Type IIS restriction enzymes cleave outside of their recognition sites, multiple compatible nucleic acid fragments may be prepared simultaneously. In other embodiments, the CAR expression constructs can be assembled by overlap extension PCR. It is envisioned that any other method of assembling nucleic acid constructs from more than one nucleic acid fragment can be employed. In some embodiments, the different CAR modules comprise signal peptides, linkers, hinges, transmembrane domains, costimulatory domains, activation domains, signaling domains, cytoplasmic domains, functionality signals, proliferation signals, anti-exhaustion signals, anti- inhibitor receptors, cancer homing proteins, or regulatory molecules, or any combination thereof. Some exemplary hinges comprise CD8 hinge, CD28 hinge, IgG1 hinge, or IgG4 hinge. Some exemplary transmembrane domains comprise CD3ζ transmembrane domain, CD8α transmembrane domain, CD4 transmembrane domain, CD28 transmembrane domain, or ICOS transmembrane domain. Some exemplary costimulatory domains comprise CD8 costimulatory domain, CD28 costimulatory domain, 4-1BB costimulatory domain, OX40 (CD134) costimulatory domain, ICOS costimulatory domain, CD27 costimulatory domain, CD40 costimulatory domain, CD40L costimulatory domain, TLR costimulatory domains, MYD88- CD40 costimulatory domain, or KIR2DS2 costimulatory domain. In some embodiments, the different CAR modules are derived from CD8, CD28, 4-1BB, CD3ζ, or any combination thereof. The CAR may also be modified with various additions, including but not limited to cytokines, chemokines, cytokine receptors, chemokine receptors, antigen receptors or ligands, antibodies, or enzymes. Nucleic Acids [0073] Also disclosed herein are nucleic acids that encode for a polypeptide. In some embodiments, the polypeptide is a binding polypeptide. In some embodiments, the polypeptide is a single domain binding polypeptide. In some embodiments, the polypeptide is any one of the single domain binding polypeptides disclosed herein. In some embodiments, the polypeptide comprises a sequence having at least 90%, 95%, 99%, or 100% sequence identity to: any one of the CEA5 single domain binding polypeptides disclosed herein, any one of the CEA6 single domain binding polypeptides disclosed herein, any one of the MSLN single domain binding polypeptides disclosed herein, any one of the EPCAM single domain binding polypeptides disclosed herein, any one of the GPC3 single domain binding polypeptides disclosed herein, or any one of the FAP single domain binding polypeptides disclosed herein, or any combination thereof, including two or more of the binding polypeptides disclosed herein. [0074] Any one of the nucleic acids that encode for a binding polypeptide can be prepared by recombinant DNA technology, synthetic chemistry techniques, or a combination thereof. For example, sequences of nucleic acids encoding for the binding polypeptide may be cloned into an expression vector using standard molecular techniques known in the art. Sequences can be obtained from other vectors encoding the desired protein sequence, from PCR-generated fragments using respective template nucleic acids, or by assembly of synthetic oligonucleotides encoding the desired sequences. In some embodiments, the expression vector may be a CAR expression vector, in which it is provided to an immune cell so that it expressed the CAR. In some embodiments, the expression vector may be an expression vector suited for large scale antibody or binding polypeptide production, from which the peptide products can be isolated for further use. [0075] Expression of binding polypeptides or CARs may be confirmed by nucleic acid or protein assays known in the art. For example, the presence of transcribed mRNA of binding polypeptides or CARs can be detected and/or quantified by conventional hybridization assays (e.g. Northern blot analysis), amplification procedures (e.g. RT-PCR), SAGE (U.S. Pat. No. 5,695,937), and array-based technologies (see e.g. U.S. Pat. Nos. 5,405,783, 5,412,087 and 5,445,934), using probes complementary to any region of a polynucleotide that encodes for the binding polypeptides or CARs. Expression of the binding polypeptides or CARs can also be determined by examining the expressed peptide. A variety of techniques are available in the art for protein analysis. They include but are not limited to radioimmunoassays, ELISA (enzyme linked immunoradiometric assays), “sandwich” immunoassays, immunoradiometric assays, in situ immunoassays (using e.g., colloidal gold, enzyme or radioisotope labels), western blot analysis, immunoprecipitation assays, immunofluorescent assays, and SDS- PAGE. Methods of Use or Treatment [0076] As used herein, the terms “individual(s)”, “subject(s)” and “patient(s)” mean any mammal. In some embodiments, the mammal is a human. In some embodiments, the mammal is a non-human. None of the terms require or are limited to situations characterized by the supervision (e.g. constant or intermittent) of a health care worker (e.g. a doctor, a registered nurse, a nurse practitioner, a physician’s assistant, an orderly or a hospice worker). [0077] As used herein, the terms “treating” or “treatment” (and as well understood in the art) means an approach for obtaining beneficial or desired results in a subject's condition, including clinical results. Beneficial or desired clinical results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, diminishment of the extent of a disease, stabilizing (i.e., not worsening) the state of disease, prevention of a disease's transmission or spread, delaying or slowing of disease progression, amelioration or palliation of the disease state, diminishment of the reoccurrence of disease, and remission, whether partial or total and whether detectable or undetectable. “Treating” and “treatment” as used herein also include prophylactic treatment. Treatment methods comprise administering to a subject a therapeutically effective amount of an active agent. The administering step may consist of a single administration or may comprise a series of administrations. The compositions are administered to the subject in an amount and for a duration sufficient to treat the subject. The length of the treatment period depends on a variety of factors, such as the severity of the condition, the age and genetic profile of the subject, the concentration of active agent, the activity of the compositions used in the treatment, or a combination thereof. It will also be appreciated that the effective dosage of an agent used for the treatment or prophylaxis may increase or decrease over the course of a particular treatment or prophylaxis regime. Changes in dosage may result and become apparent by standard diagnostic assays known in the art. In some instances, chronic administration may be required. [0078] The terms “effective amount” or “effective dose” as used herein refers to that amount of a recited composition or compound that results in an observable designated effect. Actual dosage levels of active ingredients in an active composition of the presently disclosed subject matter can be varied so as to administer an amount of the active composition or compound that is effective to achieve the designated response for a particular subject and/or application. The selected dosage level can vary based upon a variety of factors including, but not limited to, the activity of the composition, formulation, route of administration, combination with other drugs or treatments, severity of the condition being treated, and the physical condition and prior medical history of the subject being treated. In some embodiments, a minimal dose is administered, and dose is escalated in the absence of dose- limiting toxicity to a minimally effective amount. Determination and adjustment of an effective dose, as well as evaluation of when and how to make such adjustments, are contemplated herein. [0079] The term “administering” includes enteral, oral administration, topical contact, administration as a suppository, parenteral, intra-arteriole, intravenous, intraperitoneal, intramuscular, intralesional, intrathecal, intranasal, intraventricular, intradermal, intracranial, parenteral, subdermal, or subcutaneous administration, or the implantation of a slow-release device, e.g., a mini-osmotic pump, to a subject. Administration is by any route, including parenteral and transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal). Parenteral administration includes, e.g., intravenous, intramuscular, intra-arteriole, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial. Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, etc. By “co- administer” it is meant that a first compound described herein is administered at the same time, just prior to, or just after the administration of a second compound described herein. [0080] As used herein, the term "therapeutic target" refers to a gene or gene product that, upon modulation of its activity (e.g., by modulation of expression, biological activity, and the like), can provide for modulation of the disease phenotype. As used throughout, "modulation" is meant to refer to an increase or a decrease in the indicated phenomenon (e.g., modulation of a biological activity refers to an increase in a biological activity or a decrease in a biological activity). [0081] As used herein, the term “standard of care”, “best practice” and “standard therapy” refers to the treatment that is accepted by medical practitioners to be an appropriate, proper, effective, and/or widely used treatment for a certain disease. The standard of care of a certain disease depends on many different factors, including the biological effect of treatment, region or location within the body, patient status (e.g. age, weight, gender, hereditary risks, other disabilities, secondary conditions), toxicity, metabolism, bioaccumulation, therapeutic index, dosage, and other factors known in the art. Determining a standard of care for a disease is also dependent on establishing safety and efficacy in clinical trials as standardized by regulatory bodies such as the US Food and Drug Administration, International Council for Harmonisation, Health Canada, European Medicines Agency, Therapeutics Goods Administration, Central Drugs Standard Control Organization, National Medical Products Administration, Pharmaceuticals and Medical Devices Agency, Ministry of Food and Drug Safety, and the World Health Organization. The standard of care for a disease may include but is not limited to surgery, radiation, chemotherapy, targeted therapy, or immunotherapy. [0082] Also disclosed herein are methods of treating a cancer in a subject in need thereof. In some embodiments, the methods comprise administering a chimeric antigen receptor cell to the subject. In some embodiments, the methods comprise administering any one of the chimeric antigen receptor cells disclosed herein. In some embodiments, the chimeric antigen receptor cell expresses and/or comprises any one of the CEA6 single domain binding polypeptides disclosed herein. In some embodiments, the chimeric antigen receptor cell is a CAR T-cell. In some embodiments, the chimeric antigen receptor cell is a CAR NK cell. In some embodiments, the chimeric antigen receptor cell is a CAR Tumor Infiltrating Lymphocte (TIL) cell. In some embodiments, the chimeric antigen receptor cell is derived from the subject and is autologous to the subject. In some embodiments, the chimeric antigen receptor cell is allogeneic to the subject. In some embodiments, the chimeric antigen receptor cell is from a cell line (e.g. Jurkat). In some embodiments, the subject is a mammal, such as a human, cat, dog, mouse, rat, hamster, rodent, cow, pig, horse, goat, sheep, donkey, or monkey. In some embodiments, the subject is a human. In some embodiments, the cancer is breast cancer, colorectal cancer, kidney cancer, liver cancer, lung cancer, brain cancer, pancreatic cancer, bladder cancer, testicular cancer, prostate cancer, gastric cancer, a hematologic malignancy, or any combination thereof. In some embodiments, the chimeric antigen receptor cell is administered parenterally. [0083] In some embodiments, the chimeric antigen receptor cell is administered once per day, twice per day, three times per day or more. In some embodiments, the chimeric antigen receptor cell is administered daily, every day, every alternate day, five days a week, once a week, every other week, two weeks per month, three weeks per month, once a month, twice a month, three times per month, or more. In some embodiments, the immune cell is administered for at least 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 18 months, 2 years, 3 years, or more. [0084] In some embodiments, the amount of a given agent that correspond to such an amount varies depending upon factors such as the particular compound, the severity of the disease, the identity (e.g., weight) of the subject or host in need of treatment, but nevertheless is routinely determined in a manner known in the art according to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the route of administration, and the subject or host being treated. In some instances, the desired dose is conveniently presented in a single dose or as divided doses administered simultaneously (or over a short period of time) or at appropriate intervals, for example as two, three, four or more sub-doses per day. [0085] The ranges for administration are merely suggestive, as the number of variables in regard to an individual treatment regime is large, and considerable excursions from these recommended values are not uncommon. Such dosages is altered depending on a number of variables, not limited to the activity of the compound used, the disease or condition to be treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the practitioner. [0086] In some embodiments, toxicity and therapeutic efficacy of such therapeutic regimens are determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, the determination of the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between the toxic and therapeutic effects is the therapeutic index and it is expressed as the ratio between LD50 and ED50. Compounds exhibiting high therapeutic indices are preferred. The data obtained from cell culture assays and animal studies are used in formulating a range of dosage for use in human. The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50 with minimal toxicity. The dosage varies within this range depending upon the dosage form employed and the route of administration utilized. Checkpoint Inhibitors (iCPI) [0087] Some embodiments of the present disclosure relate to a method of treatment for cancer, comprising administering at least one checkpoint inhibitor. In some embodiments, at least two checkpoint inhibitors are administered. In some embodiments, the at least two checkpoint inhibitors are administered at the same time. In some embodiments, the at least two checkpoint inhibitors are administered at different times. [0088] A “checkpoint inhibitor” is a molecule, drug, and/or composition that is functional in inhibiting at least one immune checkpoint. An “immune checkpoint” is a regulator of the immune system in a subject. Non-limiting examples of stimulatory checkpoint molecules include CD27, CD28, CD40, CD122, CD137, OX40, GITR, and ICOS. Non- limiting examples of inhibitory checkpoint molecules include A2AR, A2BR, B7-H3, B7-H4, BTLA, CTLA-4, IDO, KIR, LAG3, NOX2, PD-1, PD-L1, PD-L2, TIM-3, VISTA, SIGLEC7, and the PD-1 dominant negative receptor (DNR). [0089] In some embodiments, the cancer in a subject may avoid targeting by the immune system by altering the function of immune checkpoint targets. Checkpoint inhibitors function to block this altered activity, thus restoring normal immune function. Consequently, cancer cells are predicted to be more susceptible to the immune system in patients that are under checkpoint inhibitor treatment. [0090] Non-limiting examples of checkpoint inhibitors (iCPI) include iplimumab, pembrolizumab, nivolumab, atezolizumab, avelumab, durvalumab, cemiplimab, tremelimumab, relatlimab, opdualag, and spartalizumab. EXAMPLES [0091] Some aspects of the embodiments discussed above are disclosed in further detail in the following examples, which are not in any way intended to limit the scope of the present disclosure. Those in the art will appreciate that many other embodiments also fall within the scope of the invention, as it is described herein above and in the claims. Example 1. Exemplary anti-CEA6 CAR T-cell lines are effective against cancers [0092] An exemplary anti-CEA6 CAR T-cell line expressing a Cap03+04-CEA6- R2-10 protein was tested in in vivo NSG mouse models. In a cell line-derived xenograft model, administration of a population of T-cells expressing the Cap03+04-CEA6-R2-10 protein resulted in dramatic clearance of the xenograft for gastric, non-small cell lung cancer, and pancreatic tumors whereas tumor growth in control mice progressed (FIG. 2A). In an orthotopic pancreatic cancer model, robust clearance of the pancreatic tumor (as detected by luciferase luminescence) resulted from 23 days of treatment, whereas control mice exhibited no reduction in tumor size (FIG. 2B). In a patient-derived xenograph (PDX) of colorectal cancer, mice treated with the T-cellsexhibited clearance of the tumor as early as 42 days. [0093] A tumor re-challenge study using the anti-CEA6 CAR T-cell line expressing Cap03+04-CEA6-R2-10 was performed and the results are shown in FIG. 3. An initial CAR T-cell infusion was administered to a pancreatic tumor model at day 0. While control mice exhibited unrestrained tumor growth, mice administered with the T-cells exhibited undetectable tumor volume as early as day 19. At day 87, where the presence of T- cells expressing the Cap03+04-CEA6-R2-10 protein was detected to be approximately 100 cells per 100 µL of blood, a second tumor was engrafted into the same mice. A rapid re- expansion of the anti-CEA6 CAR T-cells was observed, and the re-engrafted tumor, which reached a peak volume at approximately day 107, was completely cleared at around day 120. This shows that the administered T-cells remained persistent for a significant amount of time and is capable of driving a secondary complete response. Example 2. Combinatorial treatment of CAR T-cells and Checkpoint Inhibitors are effective against cancers in mice [0094] A cell-line derived xenograft (CDX) model of NSG mice were engrafted with an N87 cancel cell line over-expressing the PDL-1 receptor at a high level constitutively. On day 1, the animals (n=5) were infused via intravenous (IV) injections with CAR T cells when the tumor on each mouse was at least 100 mm3 on average. The mice were then injected with anti-PD1 via intraperitoneal (IP) injections on days 5, 10, 15, 20, and 25. The anti-PD1 administered was Nivolumab, Anti-PD1 Ab, Human, Cat# A2002, Size:20mg, and was administered at 250 μg/injection. The effect of the CAR-T cells with or without anti-PD1 treatment on tumor volume is as shown in FIG. 4. Example 3. Combinatorial treatment of CAR T-cells and Checkpoint Inhibitors are effective against cancers in humans [0095] An anti-CEA6 CAR T-cell line expressing one of the sequences shown in Table 1 or Table 2 will be administered to a human cancer patient via infusion. After 2, 12, and 24 weeks, the patient will be further administered an effective dose of the checkpoint inhibitor Pembrolizumab (for a total of 3 doses). The immune response of the patient to the infused T-cells will be monitored over this 24 week period. The T cell therapy with is predicted to be more effective in the presence of the checkpoint inhibitor than therapy in a patient treated with the T-cells in a patient without a checkpoint inhibitor drug. [0096] While various aspects and embodiments have been disclosed herein, other aspects and embodiments will be apparent to those skilled in the art. The various aspects and embodiments disclosed herein are for purposes of illustration and are not intended to be limiting, with the true scope and spirit being indicated by the following claims. [0097] All references cited herein, including but not limited to published and unpublished applications, patents, and literature references, are incorporated herein by reference in their entirety and are hereby made a part of this specification. To the extent publications and patents or patent applications incorporated by reference contradict the disclosure contained in the specification, the specification is intended to supersede and/or take precedence over any such contradictory material.

Table 1. Sequence List [0098] CEA6 Heavy Chain CDR sequences SEQ SEQ SEQ Name CDR-H1 ID CDR-H2 ID CDR-H3 ID NO NO NO 0 ^{1 2 3} 4 ₅ 6 ^{7 8} 9 0

SEQ SEQ SEQ Name CDR-H1 ID CDR-H2 ID CDR-H3 ID NO NO NO 1 2 ³ 4 5 6 7 8 9 0 1 2 3 4 5 6 7 _{8 9}

[0099] Table 2. CEA6 Heavy Chain Polypeptide Sequences SEQ D : 0

SEQ Name Heavy Chain Variable Domain Sequence ID NO: 1 2 3 4 5 6 7 8 9 0 1 2 3 4 5 6 7

SEQ Name Heavy Chain Variable Domain Sequence ID NO: 8 9 0 1 2 3 4 5 6 7 8 9 0 1 2 3 4

SEQ Name Heavy Chain Variable Domain Sequence ID NO: 5 6 7 8 9 0 1 2

Claims

WHAT IS CLAIMED IS: 1. A method of treating a cancer in a subject in need thereof, the method comprising: administering a CAR cell and an at least one effective dose of an at least one checkpoint inhibitor (iCPI) to the subject.

2. The method of claim 1, wherein the CAR cell expresses a protein having heavy chain CDRs from Table 1 or a heavy chain polypeptide from Table 2.

3. The method of claim 1 or 2, wherein the CAR cell is bivalent and/or multivalent.

4. The method of any one of claims 1-3, wherein the CAR cell has one target.

5. The method of any one of claims 1-3, wherein the CAR cell has more than one target.

6. The method of any one of claims 1-5, wherein the CAR cell is an immune cell.

7. The method of claim 6, wherein the CAR cell is a TIL cell.

8. The method of claim 6 or 7, wherein the CAR cell is a T cell or NK cell.

9. The method of any one of claims 1-8, wherein the at least one checkpoint inhibitor is an anti-PD1, an anti-PDL1, an anti-CTLA4, and/or an anti-PDNR.

10. The method of claim 9, wherein the at least one checkpoint inhibitor is an anti- PD1.

11. The method of claim 9, wherein the at least one checkpoint inhibitor is an anti- PDL1.

12. The method of any one of claims 1-11, wherein two checkpoint inhibitors are administered to the subject.

13. The method of claim 12, wherein the two checkpoint inhibitors are the same checkpoint inhibitor.

14. The method of claim 12, wherein the two checkpoint inhibitors are different checkpoint inhibitors.

15. The method of claim 12 or 14, wherein the two checkpoint inhibitors are an anti-PD1 and an anti-PDL1.

16. The method of any one of claims 1-15, wherein the subject is mammalian and/or human.

17. The method of any one of claims 1-16, wherein the CAR cell is administered to the subject at a different time than the at least one iCPI.

18. The method of claim 17, wherein the CAR T-cell is administered at Day 1, and the at least one iCPI is administered at a day that is between 1 and 24 weeks after Day 1.

19. The method of claim 18, wherein the at least one iCPI is administered at 1, 2, 12, or 24 weeks after Day 1.

20. The method of any one of claims 1-19, wherein the at least one effective dose of an at least one iCPI is administered once.

21. The method of any one of claims 1-19, wherein the at least one effective dose of an at least one iCPI is administered more than once.

22. The method of any one of claims 1-19, wherein the at least one effective dose of an at least one iCPI is administered at least twice.

23. The method of any one of claims 1-19, wherein the at least one effective dose of an at least one iCPI is administered at least three times.

24. The method of any one of claims 1-19, wherein the at least one effective dose of an at least one iCPI is administered at least five times.

25. The method of any one of claims 21-24, wherein the at least one iCPI is administered at a constant dose.

26. The method of any one of claims 21-24, wherein the at least one iCPI is administered at an increasing dose.

27. The method of any one of claims 21-24, wherein the at least one iCPI is administered at a decreasing dose.

28. The method of any one of claims 1-27, wherein the at least one iCPI is administered at a dose of about 0.1, 0.25, 0.5, 0.75, 1, 2.5, 5, 7.5, 10, or any integer that is between 0.1 and 10, mg/kg.

29. A composition comprising a CAR cell and an at least one iCPI.

30. The composition of claim 11, wherein the CAR cell expresses a heavy chain CDR protein from Table 1 or a heavy chain polypeptide from Table 2.

31. The composition of claim 29 or 30, wherein the CAR cell is bivalent and/or multivalent.

32. The composition of any one of claims 29-31, wherein the CAR cell has one target.

33. The composition of any one of claims 29-32, wherein the CAR cell has more than one target.

34. The composition of any one of claims 29-33, wherein the CAR cell is an immune cell.

35. The composition of claim 34, wherein the CAR cell is a TIL cell.

36. The composition of claim 34 or 35, wherein the CAR cell is a T cell or NK cell.

37. The composition of any one of claims 29-36, wherein the at least one checkpoint inhibitor is an anti-PD1, an anti-PDL1, and anti-CTLA4, and/or an anti-PDNR.

38. The composition of any one of claims 29-37, wherein the composition comprises 2 iCPIs.

39. The composition of claim 38, wherein the two checkpoint inhibitors are the same checkpoint inhibitor.

40. The composition of claim 38, wherein the two checkpoint inhibitors are different checkpoint inhibitors.

41. The composition of claim 38 or 40, wherein the 2 iCPIs are an anti-PD1 and an anti-PDL1.

42. A use for a CAR cell and an at least one iCPI for treating a cancer in a subject.

43. The use of claim 42, wherein the CAR cell expresses a heavy chain CDR protein from Table 1 or a heavy chain polypeptide from Table 2.

44. The use of claim 42 or 43, wherein the CAR cell is bivalent and/or multivalent.

45. The use of any one of claims 42-44, wherein the CAR cell has at least one target.

46. The use of any one of claims 42-45, wherein the CAR cell is an immune cell.

47. The use of claim 46, wherein the CAR cell is a TIL cell.

48. The use of claim 46 or 47, wherein the CAR cell is a T cell or NK cell.

49. The use of any one of claims 42-48, wherein the at least one checkpoint inhibitor is an anti-PD1, an anti-PDL1, and anti-CTLA4, and/or an anti-PDNR.

50. The use of any one of claims 42-49, wherein two checkpoint inhibitors are administered to the subject.

51. The use of claim 50, wherein the two checkpoint inhibitors are the same checkpoint inhibitor.

52. The use of claim 50, wherein the two checkpoint inhibitors are different checkpoint inhibitors.

53. The use of claim 50 or 52, wherein the two iCPIs are an anti-PD1 and an anti- PDL1.

54. A method of treating a disease or disorder in a subject in need thereof, the method comprising: administering a CAR cell and an at least one effective dose of an at least one checkpoint inhibitor (iCPI) to the subject.

55. The method of claim 54, wherein the disease or disorder is a cancer.

56. The method of any one of claims 54-55, wherein the CAR cell is administered to the subject by an at least one infusion.

57. The method of any one of claims 54-56, wherein the method does not comprise lymphodepletion.

58. The method of claim 57, wherein the at least one infusion is more than one infusion.

59. The method of any one of claims 54-58, wherein the CAR cell expresses a heavy chain CDR protein from Table 1 or a heavy chain polypeptide from Table 2.

60. The method of any one of claims 54-59, wherein the CAR cell is an immune cell.

61. The method of any one of claims 54-60, wherein the CAR cell is a TIL cell.

62. The method of any one of claims 54-61, wherein the CAR cell is a T cell or NK cell.

63. The method of any one of claims 54-62, further comprising at least one administration of an effective dose of cetuximab.

64. The method of any one of claims 54-63, wherein the at least one checkpoint inhibitor is an anti-PD1, an anti-PDL1, an anti-CTLA4, and/or an anti-PDNR.

65. The method of any one of claims 54-64, wherein two checkpoint inhibitors are administered to the subject.

66. The method of claim 65, wherein the two checkpoint inhibitors are the same checkpoint inhibitor.

67. The method of claim 65, wherein the two checkpoint inhibitors are different checkpoint inhibitors.

68. The method of claim 65 or 67, wherein the two checkpoint inhibitors are an anti-PD1 and an anti-PDL1.

69. The method of any one of claims 54-68, wherein the subject is mammalian and/or human.

70. The method of any one of claims 54-69, wherein the CAR cell is administered to the subject at a different time than the at least one iCPI.

71. The method of claim 70, wherein the CAR T-cell is administered at Day 1, and the at least one iCPI is administered at a day that is between 1 and 24 weeks after Day 1.

72. The method of any one of claims 54-71, wherein the at least one effective dose of an at least one iCPI is administered at least once.

73. The method of any one of claims 54-72, wherein the at least one iCPI is administered at a constant dose.

74. The method of any one of claims 54-72, wherein the at least one iCPI is administered at an increasing dose.

75. The method of any one of claims 54-72, wherein the at least one iCPI is administered at a decreasing dose.

76. The method of any one of claims 54-75, wherein the at least one iCPI is administered at a dose of about 0.1, 0.25, 0.5, 0.75, 1, 2.5, 5, 7.5, 10, or any integer that is between 0.1 and 10, mg/kg.

77. The method of claim 56, wherein the infusion is intravenous, intraperitoneal, or intramural.