T cell receptors and methods of use thereof

Abstract

This invention relates to recombinant T-cell receptors capable of binding to the NY-ESO-1 antigenic determinant and nucleic acid molecules encoding such recombinant T-cell receptors. In some embodiments, the nucleic acid molecules further comprise a second nucleotide sequence, wherein the second nucleotide sequence or a polypeptide encoded by the second nucleotide sequence inhibits the expression of endogenous TCRs. Other embodiments of the invention relate to vectors comprising the nucleic acid molecule and cells comprising the recombinant TCR, the nucleic acid molecule, or the vector. Other embodiments of the invention relate to methods of using the invention. In some embodiments, these methods include treating cancer in an individual of need.

Description

[Technical Field] This invention provides a recombinant T-cell receptor ("TCR") that specifically binds to human NY-ESO-1 and its uses. [Previous Technology] Immunotherapy has emerged as a key tool in the fight against a variety of diseases, including cancer. T-cell therapy is at the forefront of immunotherapy development, and the receptive transfer of anti-tumor T cells has been shown to induce clinical responses in cancer patients. Although many T-cell therapies target mutated tumor antigens, the vast majority of neoantigens are not common to each patient but are unique. The number of potential non-mutated antigens exceeds that of mutated antigens by several orders of magnitude. Elucidating T-cell antigenic determinants derived from shared antigens can facilitate the robust development of effective and safe receptive T-cell therapies readily available to a large population of cancer patients. However, the absolute number of non-mutated antigens and the high polymorphism of HLA genes may have hindered a comprehensive analysis of the specificity of anti-tumor T-cell responses to non-mutated antigens. This invention provides novel antigenic determinants of the non-mutant antigen NY-ESO-1 and TCRs capable of specifically binding to these antigenic determinants. These novel antigenic determinants are associated with specific HLA alleles. The use of these tumor-responsive HLA-restricted NY-ESO-1 TCRs supports the applicability of broadened anti-NY-ESO-1 TCR gene therapy, particularly in immuno-oncology. [Summary of the Invention] Certain embodiments of the present invention relate to a nucleic acid molecule comprising (i) a first nucleotide sequence encoding a recombinant T-cell receptor (TCR) or its antigen-binding portion ("anti-NY-ESO-1 TCR") that specifically binds to human NY-ESO-1; and (ii) a second nucleotide sequence, wherein the second nucleotide sequence or a polypeptide encoded by the second nucleotide sequence inhibits the expression of endogenous TCR, wherein the anti-NY-ESO-1 TCR cross-competitively binds to human NY-ESO-1 with a reference TCR comprising an α chain and a β chain, wherein the α chain comprises an amino acid sequence as listed in SEQ ID NO: 1 and the β chain comprises an amino acid sequence as listed in SEQ ID NO: 2. Certain embodiments of the present invention relate to a nucleic acid molecule comprising (i) a first nucleotide sequence encoding a recombinant T-cell receptor (TCR) specifically binding to human NY-ESO-1 or its antigen-binding portion (“anti-NY-ESO-1 TCR”); and (ii) a second nucleotide sequence, wherein the second nucleotide sequence or a polypeptide encoded by the second nucleotide sequence inhibits the expression of endogenous TCR, wherein the anti-NY-ESO-1 TCR binds to the same or overlapping antigenic determinants of human NY-ESO-1 as a reference TCR, the reference TCR comprising an α chain and a β chain, wherein the α chain comprises an amino acid sequence as listed in SEQ ID NO: 1 and the β chain comprises an amino acid sequence as listed in SEQ ID NO: 2. In some embodiments, the anti-NY-ESO-1 TCR binds to the antigenic determinant of NY-ESO-1, which consists of an amino acid sequence as listed in SEQ ID NO: 13. In some embodiments, the antigenic determinant is complexed with an HLA class I molecule. In some embodiments, the HLA class I molecule is the HLA-B*07 allele. In some embodiments, the HLA class I molecule is selected from the HLA-B*07:02 allele, HLA-B*07:03 allele, HLA-B*07:04 allele, HLA-B*07:05 allele, and HLA-B*07:06 allele. In some embodiments, the HLA class I molecule is the HLA-B*07:02 allele. In some embodiments, the anti-NY-ESO-1 TCR comprises an α chain and a β chain, wherein the α chain includes a variable region containing α chain CDR1, α chain CDR2, and α chain CDR3; and wherein the β chain includes a variable domain containing β chain CDR1, β chain CDR2, and β chain CDR3; wherein the α chain CDR3 includes an amino acid sequence as listed in SEQ ID NO: 7. In some embodiments, the β chain CDR3 of the anti-NY-ESO-1 TCR includes an amino acid sequence as listed in SEQ ID NO: 10. In some embodiments, the anti-NY-ESO-1 TCR comprises an α chain and a β chain, wherein the α chain includes a variable region containing α chain CDR1, α chain CDR2, and α chain CDR3; and wherein the β chain includes a variable domain containing β chain CDR1, β chain CDR2, and β chain CDR3; wherein the β chain CDR3 of the anti-NY-ESO-1 TCR comprises an amino acid sequence as listed in SEQ ID NO: 10. In some embodiments, the α chain CDR3 of the anti-NY-ESO-1 TCR comprises an amino acid sequence as listed in SEQ ID NO: 7. In some embodiments, the α-chain CDR1 of the anti-NY-ESO-1 TCR comprises the amino acid sequence as listed in SEQ ID NO: 5. In some embodiments, the β-chain CDR1 of the anti-NY-ESO-1 TCR comprises the amino acid sequence as listed in SEQ ID NO: 8. In some embodiments, the α-chain CDR2 of the anti-NY-ESO-1 TCR comprises the amino acid sequence as listed in SEQ ID NO: 6. In some embodiments, the β-chain CDR2 of the anti-NY-ESO-1 TCR comprises the amino acid sequence as listed in SEQ ID NO: 9. In some embodiments, the α-chain variable domain of the anti-NY-ESO-1 TCR comprises an amino acid sequence of the variable domain present in the amino acid sequence listed in SEQ ID NO: 1. In some embodiments, the β-chain variable domain of the anti-NY-ESO-1 TCR comprises an amino acid sequence of the variable domain present in the amino acid sequence listed in SEQ ID NO: 2. In some embodiments, the α-chain of the anti-NY-ESO-1 TCR further includes a constant region, wherein the constant region is different from the endogenous constant region of the α-chain. In some embodiments, the α-chain constant region further includes an amino acid sequence that is at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identical to the constant region present in the amino acid sequence listed in SEQ ID NO: 1. In some embodiments, the α-chain constant region includes an amino acid sequence that comprises at least one, at least two, at least three, at least four, or at least five amino acid substitutions relative to the constant region present in the amino acid sequence listed in SEQ ID NO: 1. In some embodiments, the β-chain of the anti-NY-ESO-1 TCR further includes a constant region, wherein the constant region is different from the endogenous constant region of the β-chain. In some embodiments, the β-chain of the anti-NY-ESO-1 TCR further comprises a constant region, wherein the β-chain constant region comprises an amino acid sequence having at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity with the constant region present in the amino acid sequence listed in SEQ ID NO: 2. In some embodiments, the β-chain constant region comprises an amino acid sequence having at least one, at least two, at least three, at least four, or at least five amino acid substitutions relative to the constant region present in the amino acid sequence listed in SEQ ID NO: 2. In some embodiments, the α-chain of the anti-NY-ESO-1 TCR comprises an amino acid sequence as listed in SEQ ID NO: 1. In some embodiments, the β chain of the anti-NY-ESO-1 TCR comprises an amino acid sequence as listed in SEQ ID NO: 2. In some embodiments, the second nucleotide sequence is one or more siRNAs that reduce the expression of the endogenous TCR. In some embodiments, one or more siRNAs are complementary to a target sequence within a nucleotide sequence encoding a constant region of an endogenous TCR. In some embodiments, one or more siRNAs comprise one or more nucleotide sequences selected from the group consisting of SEQ ID NO: 53-56. In some embodiments, the second nucleotide sequence encodes Cas9. In some embodiments, the anti-NY-ESO-1 TCR comprises an α-chain constant region, a β-chain constant region, or both; and wherein the α-chain constant region, the β-chain constant region, or both comprise an amino acid sequence having at least one, at least two, at least three, at least four, or at least five substituted amino acid sequences relative to the corresponding amino acid sequence of the endogenous TCR within the target sequence. Certain aspects of this invention relate to a vector comprising the nucleic acid molecules disclosed herein. In some embodiments, the vector is a viral vector, a mammalian vector, or a bacterial vector. In some embodiments, the vector is a retroviral vector. In some embodiments, the vector is selected from the group consisting of: adenovirus vectors, lentiviruses, Sendai virus vectors, baculovirus vectors, Epstein-Barr viral vectors, multivacuolar papillomavirus vectors, vaccinia virus vectors, herpes simplex virus vectors, hybrid vectors, and adeno-associated virus (AAV) vectors. In some embodiments, the vector is a lentivirus. Certain aspects of this invention relate to a T-cell receptor (TCR) or its antigen-binding portion, which includes the α-chain variable domain of the anti-NY-ESO-1 TCR disclosed herein and the β-chain variable domain of the anti-NY-ESO-1 TCR disclosed herein. In some embodiments, a recombinant T-cell receptor (TCR) specifically binding to human NY-ESO-1 or its antigen-binding portion (“anti-NY-ESO-1 TCR”) cross-competitively binds to human NY-ESO-1 with a reference TCR; wherein the reference TCR comprises an α chain and a β chain, and wherein the α chain comprises an amino acid sequence as listed in SEQ ID NO: 1 and the β chain comprises an amino acid sequence as listed in SEQ ID NO: 2; and wherein the anti-NY-ESO-1 TCR comprises an α chain and a β chain, wherein the α chain comprises a constant region, and wherein the β chain comprises a constant region; wherein (i) the α chain constant region comprises an amino acid sequence having at least one, at least two, at least three, at least four, or at least five amino acid substitutions relative to the constant region present in the amino acid sequence listed in SEQ ID NO: 1, or (ii) the β ... The constant region present in the amino acid sequence of 2 has an amino acid sequence with at least 1, at least 2, at least 3, at least 4, or at least 5 amino acid substitutions. Certain embodiments of the present invention relate to a recombinant T-cell receptor (TCR) or its antigen-binding portion (“anti-NY-ESO-1 TCR”) that specifically binds to human NY-ESO-1, binding to the same or overlapping antigenic determinants of human NY-ESO-1 as a reference TCR; wherein the reference TCR comprises an α chain and a β chain, and wherein the α chain comprises an amino acid sequence as listed in SEQ ID NO: 1 and the β chain comprises an amino acid sequence as listed in SEQ ID NO: 2; and wherein the anti-NY-ESO-1 TCR comprises an α chain and a β chain, wherein the α chain comprises a constant region, and wherein the β chain comprises a constant region; wherein (i) the α chain constant region comprises an amino acid sequence having at least one, at least two, at least three, at least four, or at least five amino acid substitutions relative to the constant region present in the amino acid sequence listed in SEQ ID NO: 1, or (ii) the β ... The constant region present in the amino acid sequences listed in 2 has an amino acid sequence with at least one, at least two, at least three, at least four, or at least five amino acid substitutions. In some embodiments, the anti-NY-ESO-1 TCR binds to the antigenic determinant of NY-ESO-1 consisting of the amino acid sequences listed in SEQ ID NO: 13. In some embodiments, the antigenic determinant is complexed with an HLA class I molecule. In some embodiments, the HLA class I molecule is an HLA-A, HLA-B, HLA-C, HLA-E, HLA-F, or HLA-G allele. In some embodiments, the HLA class I molecule is the HLA-B*07 allele. In some embodiments, the HLA class I molecule is selected from the HLA-B*07:02, HLA-B*07:03, HLA-B*07:04, HLA-B*07:05, and HLA-B*07:06 alleles. In some embodiments, the HLA class I molecule is the HLA-B*07:02 allele. In some embodiments, the α chain of the anti-NY-ESO-1 TCR includes variable domains containing α chain CDR1, α chain CDR2, and α chain CDR3; and the β chain of the anti-NY-ESO-1 TCR includes variable domains containing β chain CDR1, β chain CDR2, and β chain CDR3; wherein the α chain CDR3 of the anti-NY-ESO-1 includes an amino acid sequence as listed in SEQ ID NO: 7. In some embodiments, the β chain CDR3 of the anti-NY-ESO-1 TCR includes an amino acid sequence as listed in SEQ ID NO: 10. In some embodiments, the α chain of the anti-NY-ESO-1 TCR includes variable domains containing α chain CDR1, α chain CDR2, and α chain CDR3; and the β chain of the anti-NY-ESO-1 TCR includes variable domains containing β chain CDR1, β chain CDR2, and β chain CDR3; wherein the β chain CDR3 of the anti-NY-ESO-1 TCR includes an amino acid sequence as listed in SEQ ID NO: 10. In some embodiments, the α chain CDR3 of the anti-NY-ESO-1 TCR includes an amino acid sequence as listed in SEQ ID NO: 7. In some embodiments, the α-chain CDR1 of the anti-NY-ESO-1 TCR comprises the amino acid sequence as listed in SEQ ID NO: 5. In some embodiments, the β-chain CDR1 of the anti-NY-ESO-1 TCR comprises the amino acid sequence as listed in SEQ ID NO: 8. In some embodiments, the α-chain CDR2 of the anti-NY-ESO-1 TCR comprises the amino acid sequence as listed in SEQ ID NO: 6. In some embodiments, the β-chain CDR2 of the anti-NY-ESO-1 TCR comprises the amino acid sequence as listed in SEQ ID NO: 9. In some embodiments, the α-chain variable domain of the anti-NY-ESO-1 TCR comprises an amino acid sequence of the variable domain present in the amino acid sequence listed in SEQ ID NO: 1. In some embodiments, the β-chain variable domain of the anti-NY-ESO-1 TCR comprises an amino acid sequence of the variable domain present in the amino acid sequence listed in SEQ ID NO: 2. In some embodiments, the α-chain constant region comprises an amino acid sequence that is at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identical to the amino acid sequence present in the constant region listed in SEQ ID NO: 1. In some embodiments, the β-chain constant region comprises an amino acid sequence that is at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identical to the amino acid sequence present in the constant region listed in SEQ ID NO: 2. In some embodiments, the α chain of the anti-NY-ESO-1 TCR comprises an amino acid sequence as listed in SEQ ID NO: 1. In some embodiments, the β chain of the anti-NY-ESO-1 TCR comprises an amino acid sequence as listed in SEQ ID NO: 2. Certain embodiments of the present invention relate to a bispecific TCR comprising a first antigen-binding domain and a second antigen-binding domain, wherein the first antigen-binding domain comprises the TCR disclosed herein or its antigen-binding portion, or the TCR disclosed herein or its antigen-binding portion. In some embodiments, the first antigen-binding domain comprises a single-chain variable fragment ("scFv"). In some embodiments, the second antigen-binding domain specifically binds to proteins expressed on the surface of T cells. In some embodiments, the second antigen-binding domain specifically binds to CD3. In some embodiments, the second antigen-binding domain comprises scFv. In some embodiments, the first antigen-binding domain and the second antigen-binding domain are covalently linked or associated. In some embodiments, the first antigen-binding domain and the second antigen-binding domain are linked by peptide bonds. Certain embodiments of the present invention relate to a cell comprising the nucleic acid molecule disclosed herein, the vector disclosed herein, the TCR disclosed herein, the recombinant TCR disclosed herein, or the bispecific TCR disclosed herein. In some embodiments, the cell further expresses CD3. In some embodiments, the cell is selected from the group consisting of T cells, natural killer (NK) cells, natural killer T (NKT) cells, or ILC cells. Certain aspects of this invention relate to a method for treating cancer in an individual in need, the method comprising delivering to the individual the cells disclosed herein. In some embodiments, the cancer is selected from the group consisting of: melanoma, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, uterine cancer, ovarian cancer, rectal cancer, anal cancer, gastric cancer, testicular cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease. Diseases, non-Hodgkin's lymphoma (NHL), primary mediastinal large B-cell lymphoma (PMBC), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), transformed follicular lymphoma, splenic marginal zone lymphoma (SMZL), esophageal cancer, small bowel cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, chronic or acute leukemia, acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia (ALL) (including non-T-cell ALL), chronic lymphocytic leukemia (CLL), childhood solid tumors, lymphocytic lymphoma, bladder cancer, kidney or ureter cancer, renal pelvis cancer, central nervous system (CNS) sarcoma, primary CNS lymphoma, tumor angiogenesis, spinal axis tumors, brainstem glioma, pituitary adenoma, Kaposi's sarcoma. Sarcoma), epidermoid carcinoma, squamous cell carcinoma, T-cell lymphoma, environmentally induced cancers (including those induced by asbestos), other B-cell malignancies, and combinations thereof. In some embodiments, the cancer is recurrent or refractory. In some embodiments, the cancer is locally advanced. In some embodiments, the cancer is advanced. In some embodiments, the cancer is metastatic. In some embodiments, the cell line is obtained from an individual. In some embodiments, the cell line is obtained from a donor other than the individual. In some embodiments, the individual is pretreated before cell administration. In some embodiments, pretreatment includes administering chemotherapy, interleukins, proteins, small molecules, or any combination thereof to the individual. In some embodiments, pretreatment includes administering interleukins. In some embodiments, pretreatment includes administering IL-2, IL-4, IL-7, IL-9, IL-15, IL-21, or any combination thereof. In some embodiments, pretreatment includes administering a pretreatment agent selected from the group consisting of cyclophosphamide, fludarabine, vitamin C, AKT inhibitors, ATRA, rapamycin, or any combination thereof. In some embodiments, pretreatment includes administering cyclophosphamide, fludarabine, or both. Certain embodiments of the present invention relate to a method for engineering cells targeting an antigen, the method comprising transducing cells collected from an individual requiring T-cell therapy using the nucleic acids or vectors disclosed herein. In some embodiments, the cells targeting the antigen further express CD3. In some embodiments, the cells are T cells or natural killer (NK) cells. Some aspects of the present invention relate to an HLA class I molecule complexed with a peptide, wherein the HLA class I molecule comprises an α1 domain, an α2 domain, an α3 domain and a β2m, and wherein the peptide is composed of an amino acid sequence as listed in SEQ ID NO: 14. In some embodiments, HLA class I molecules are HLA-A, HLA-B, HLA-C, HLA-E, HLA-F, or HLA-G. In some embodiments, HLA class I molecules are HLA-B. In some embodiments, HLA class I molecules are the HLA-B*07 allele. In some embodiments, HLA class I molecules are selected from the HLA-B*07:02 allele, HLA-B*07:03 allele, HLA-B*07:04 allele, HLA-B*07:05 allele, and HLA-B*07:06 allele. In some embodiments, HLA class I molecules are the HLA-B*07:02 allele. In some embodiments, HLA class I molecules are the HLA-B*07:03 allele. In some embodiments, HLA class I molecules are monomers. In some embodiments, HLA class I molecules are dimers. In some embodiments, HLA class I molecules are trimers. In some embodiments, HLA class I molecules are tetramers. In some embodiments, HLA class I molecules are pentamers. Certain aspects of this invention relate to an antigen-presenting cell (APC) containing the HLA class I molecules disclosed herein. In some embodiments, the HLA class I molecules are expressed on the surface of the APC. Some aspects of the present invention relate to a method for enriching a target population of T cells obtained from a human individual, the method comprising contacting the T cells with an HLA class I molecule or an APC disclosed herein, wherein, after contact, the enriched population of T cells contains a higher number of T cells capable of binding HLA class I molecules compared to the number of T cells capable of binding HLA class I molecules before contact. Some aspects of the present invention relate to a method for enriching a target population of T cells obtained from a human individual, the method comprising contacting the T cells in vitro with a peptide, wherein the peptide consists of an amino acid sequence as listed in SEQ ID NO: 13, wherein after contact, the enriched population of T cells contains a higher number of T cells capable of targeting tumor cells compared to the number of T cells capable of targeting tumor cells before contact. In some embodiments, the T cells obtained from a human individual are tumor-infiltrating lymphocytes (TILs). Some aspects of the present invention relate to a method for treating a tumor in an individual in need, the method comprising administering to the individual the enriched population of T cells disclosed herein. Some aspects of the present invention relate to a method for enhancing cytotoxic T cell-mediated cancer cell targeting in an individual suffering from cancer, the method comprising administering to the individual a peptide having an amino acid sequence as listed in SEQ ID NO: 13. Some aspects of the present invention relate to a cancer vaccine comprising a peptide having an amino acid sequence as listed in SEQ ID NO: 13. Certain embodiments of the present invention relate to a method for selecting T cells capable of targeting tumor cells, the method comprising contacting a population of isolated T cells in vitro with a peptide, wherein the peptide comprises an amino acid sequence as listed in SEQ ID NO: 11. In some embodiments, the T cells are tumor-infiltrating lymphocytes (TILs).

Implementation Method

Claims

1. A nucleic acid molecule comprising: a nucleotide sequence encoding a recombinant T-cell receptor (TCR) or its antigen-binding portion (“anti-NY-ESO-1 TCR”) of a human NY-ESO-1 specifically binding to an antigenic determinant composed of an amino acid sequence as listed in SEQ ID NO: 13, wherein the antigenic determinant is complexed with the HLA class I molecule HLA-B*07 allele, wherein the anti-NY-ESO-1 TCR comprises an α chain and a β chain, wherein the α chain comprises a variable domain containing α chain CDR1, α chain CDR2 and α chain CDR3; and wherein the β chain comprises a variable domain containing β chain CDR1, β chain CDR2 and β chain CDR3; and wherein (a) the β chain CDR3 of the anti-NY-ESO-1 TCR comprises an amino acid sequence as listed in SEQ ID NO: 10; (b) the β chain CDR2 of the anti-NY-ESO-1 TCR comprises an amino acid sequence as listed in SEQ ID NO:

10. (c) The amino acid sequence listed in NO: 9; (d) The amino acid sequence listed in SEQ ID NO: 8 of the β chain CDR1 of the anti-NY-ESO-1 TCR; (e) The amino acid sequence listed in SEQ ID NO: 7 of the α chain CDR3 of the anti-NY-ESO-1 TCR; (f) The amino acid sequence listed in SEQ ID NO: 5 of the α chain CDR1 of the anti-NY-ESO-1 TCR.

2. The nucleic acid molecule of claim 1, wherein the HLA class I molecule HLA-B*07 allele is selected from the following: HLA-B*07:01 allele, HLA-B*07:02 allele, HLA-B*07:03 allele, HLA-B*07:04 allele, HLA-B*07:05 allele and HLA-B*07:06 allele.

3. The nucleic acid molecule of claim 1, wherein (i) the α-chain variable domain of the anti-NY-ESO-1 TCR contains the amino acid sequence of the variable domain present in the amino acid sequence listed in SEQ ID NO: 1; (ii) the β-chain variable domain of the anti-NY-ESO-1 TCR contains the amino acid sequence of the variable domain present in the amino acid sequence listed in SEQ ID NO: 2; or (iii) both of (i) and (ii).

4. The nucleic acid molecule of claim 3, wherein the α chain of the anti-NY-ESO-1 TCR further comprises a constant region, wherein the constant region of the α chain comprises an amino acid sequence having at least 85% sequence identity with the constant region present in the amino acid sequence listed in SEQ ID NO:

1.

5. The nucleic acid molecule of claim 3, wherein the β chain of the anti-NY-ESO-1 TCR further comprises a constant region, wherein the constant region of the β chain comprises an amino acid sequence having at least 85% sequence identity with the constant region present in the amino acid sequence listed in SEQ ID NO:

2.

6. The nucleic acid molecule of any one of claims 1 to 5, wherein (i) the α chain of the anti-NY-ESO-1 TCR contains an amino acid sequence as listed in SEQ ID NO: 1; (ii) the β chain of the anti-NY-ESO-1 TCR contains an amino acid sequence as listed in SEQ ID NO: 2; or (iii) both of (i) and (ii).

7. A vector comprising a nucleic acid molecule as claimed in any one of claims 1 to 6.

8. A cell comprising a nucleic acid molecule as claimed in any one of claims 1 to 6, or a vector as claimed in claim 7.

9. The cells of claim 8, wherein the cell line is selected from T cells, natural killer (NK) cells, natural killer T (NKT) cells and ILC cells.

10. Use of the cells of claim 8 or 9 in the manufacture of a medicament for treating cancer in an individual in need, wherein, The cancer contains one or more tumor cells that express NY-ESO-1.

11. Use of cells as claimed in claim 8 or 9 in the manufacture of a medicament for treating melanoma in an individual in need.

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