METHOD OF TREATMENT OF CANCER OR TUMOUR

Abstract

The present invention relates to a method of treating, preventing or delaying the progression of cancer and/or tumour in a subject comprising administering to the subject a treatment regimen comprising an effective amount of modified immunoresponsive cells expressing or presenting a heterologous T-cell receptor (TCR) having the property of binding to MAGE A4

Claims

1. A method of treating, preventing or delaying the progression of cancer and/or tumour in a subject comprising administering to the subject a treatment regimen comprising an effective amount of modified immunoresponsive cells expressing or presenting a heterologous T-cell receptor (TCR) which binds a peptide antigen of MAGE A4 comprising GVYDGREHTV, SEQ ID NO: 2, wherein the cancer and/or tumour is gastroesophageal cancer and/or tumour.

2. (canceled)

3. The method according to claim 1, wherein (a) the heterologous TCR binds specifically and/or selectively to the peptide antigen; (b) the peptide antigen is associated with gastroesophageal cancer and/or tumour and/or is presented by tumour and/or cancer cell or tissue; (c) the cancer and/or tumour is a MAGE A4 expressing cancer and/or tumour, and/or expresses MAGE A4 or peptide antigen thereof or a peptide antigen of MAGE A4 comprising GVYDGREHTV, SEQ ID NO: 2; and/or (d) the peptide antigen is complexed with a peptide presenting molecule, optionally major histocompatibility complex (MHC) or human leukocyte antigen (HLA), optionally class I or class II, optionally wherein the peptide presenting molecule is HLA-A*02, optionally selected from HLA*02, HLA-A*02:01, HLA-A*02:02, HLA-A*02:03, HLA-A*02:04, HLA-A*02:05, HLA-A*02:06, HLA-A*02:642 or HLA-A*02:07, preferably HLA-A*02:01 or HLA-A*02.

4-7. (canceled)

8. The method of claim 1, wherein the heterologous TCR binds specifically and/or selectively to the peptide antigen and/or the peptide presenting molecule and/or complex thereof.

9. The method according to claim 1 wherein the peptide antigen is presented independently of a peptide presenting molecule.

10. The method according to claim 1, wherein the heterologous TCR comprises a TCR alpha chain variable domain and a TCR beta chain variable domain, wherein: (i) the alpha chain variable domain comprises CDRs having the sequences VSPFSN (αCDR1), SEQ ID NO:11 or amino acids 48-53 of SEQ ID NO:5, or sequence having at least 50% sequence identity thereto, LTFSEN (αCDR2), SEQ ID NO:12 or amino acids 71-76 of SEQ ID NO:5, or sequence having at least 50% sequence identity thereto, and CVVSGGTDSWGKLQF (αCDR3), SEQ ID NO:13 or amino acids 111-125 of SEQ ID NO:5, or sequence having at least 50% sequence identity thereto, and (ii) the beta chain variable domain comprises CDRs having the sequences KGHDR (βCDR1), SEQ ID NO:14 or amino acids 46-50 of SEQ ID NO:7, or sequence having at least 50% sequence identity thereto, SFDVKD (βCDR2), SEQ ID NO:15 or amino acids 68-73 of SEQ ID NO:7, or sequence having at least 50% sequence identity thereto, and CATSGQGAYEEQFF (βCDR3), SEQ ID NO:16 or amino acids 110-123 of SEQ ID NO:7 or sequence having at least 50% sequence identity thereto.

11. The method according to claim 1, wherein the heterologous TCR comprises a TCR in which (a) the alpha chain variable domain comprises an amino acid sequence that has at least 80%, identity to SEQ ID NO:9, and/or the beta chain variable domain comprising an amino acid sequence that has at least 80% identity to SEQ ID NO:10, (b) the alpha chain variable domain comprises an amino acid sequence comprising SEQ ID NO:9, and/or the beta chain variable domain comprises SEQ ID NO:10, (c) the alpha chain comprises an amino acid sequence that has at least 80%, identity to SEQ ID NO:5, and/or the beta chain comprising an amino acid sequence that has at least 80% identity to SEQ ID NO:6, or (d) the alpha chain comprises an amino acid sequence comprising SEQ ID NO:5, and/or the beta chain comprises an amino acid sequence comprising SEQ ID NO:6.

12. The method according to claim 1, wherein the modified immunoresponsive cells expressing or presenting a heterologous TCR further express or present a heterologous co-receptor, optionally wherein the heterologous co-receptor is a CD8 co-receptor, optionally wherein the heterologous CD8 co-receptor is heterodimer or homodimer, a CD8αβ heterodimer or a CD8αα homodimer, and/or the heterologous CDS co-receptor comprises any one of; (a) a CDR 1 of at least 80% sequence identity to amino acid sequence VLLSNPTSG, SEQ ID NO: 17, CDR 2 of at least 80% sequence identity to amino acid sequence YLSQNKPK SEQ ID NO: 18 and CDR 3 of at least 80% sequence identity amino acid sequence LSNSIM SEQ ID NO:19, (b) a CDR 1 of amino acid sequence VLLSNPTSG, SEQ ID NO:17, CDR 2 of amino acid sequence YLSQNKPK SEQ ID NO:18 and CDR 3 of amino acid sequence LSNSIM SEQ ID NO:19, (c) an amino acid sequence having at least 80% sequence identity to amino acids number 22 to 235 of SEQ ID NO: 3, or 22 to 135 of SEQ ID NO: 3, or (d) an amino acid sequence having 100% sequence identity to amino acids number 22 to 235 of sequence of SEQ ID NO: 3, or 22 to 135 of SEQ ID NO: 3.

13-14. (canceled)

15. The method according to claim 1, wherein the modified immunoresponsive cells expressing or presenting a heterologous TCR further express or present a heterologous co-stimulatory ligand, optionally 4-1BBL or CD80.

16. The method of claim 1, wherein the modified immunoresponsive cells are (a) B cells, T cells or natural killer (NK) cells, (b) T cells, optionally CD4.sup.+ T cells and/or CD8.sup.+ T cells, or (c) a population of CD4+ T cells; or CD8+ T cells, or a mixed population of CD4+ T cells and CD8+ T cells.

17. (canceled)

18. The method of claim 1, wherein the modified immunoresponsive cells are administered continuously or intermittently.

19. The method of claim 1, wherein the modified immunoresponsive cells are administered as multiple doses or is administered as a single dose, optionally wherein the single or multiple doses are administered in one or more dosing cycles, optionally wherein the dose may be a fixed dose or a variable dose.

20. (canceled)

21. The method according to claim 1 wherein the the modified immunoresponsive cells are administered at a dose of between about 500 million to about 1 billion cells, about 2 billion to about 5 billion cells or about 6 billion to about 10 billion cells.

22. The method according to claim 1 wherein the modified immunoresponsive cells are administered as; (a) a single dose in each of one or more dosing cycles, (b) one or more doses in each of one or more dosing cycles, (c) a single dose on the first day of each of one or more dosing cycles, (d) one or more doses in each of one or more dosing cycles, at least one dose being on the first day of each cycle, (e) one or more doses in each of one or more dosing cycles, at least one dose being on the first day of each cycle, (f) a single dose.

23-28. (canceled)

29. The method according to claim 1 wherein, the subject is intolerant to a standard of care treatment, optionally systemic platinum-based chemotherapy treatment.

30. The method according to claim 1 wherein the gastroesophageal cancer and/or tumour has been previously unsuccessfully treated with a standard of care treatment, optionally systemic platinum-based chemotherapy treatment, or previously unsuccessfully treated with any of surgery (resection), radiation therapy, targeted therapy, immunotherapy or chemotherapy or concomitant chemotherapy with surgery (resection), radiation therapy, radiation therapy targeted therapy, checkpoint inhibitor or immunotherapy.

31. (canceled)

32. The method according to claim 1 wherein the subject has or wherein the gastroesophageal cancer and/or tumour is; primary cancer, secondary cancer, relapsed cancer or refractory cancer or recurrent cancer or locally recurrent cancer or metastatic cancer, non-resectable cancer or locally confined, cancer with no surgical or radiotherapy option or inoperable cancer optionally wherein the cancer is not amenable to transplant or loco-regional therapy, and/or wherein the gastroesophageal cancer and/or tumour is any of esophageal squamous-cell carcinoma (ESCC), esophageal adenocarcinoma (EAC), esophagogastric junction cancer, carcinoma adenocarcinoma or tumour (EGJ) or stomach or gastric cancer, carcinoma or tumour, optionally metastatic and/or advanced and/or locally advanced and/or recurrent ESCC, EAC, EGJ or stomach or gastric cancer, carcinoma or tumour.

33. (canceled)

34. The method according to claim 1 wherein prior to administration of the modified immunoresponsive cells expressing or presenting a heterologous T-cell receptor (TCR) the subject undergoes lymphodepleting chemotherapy, optionally wherein the lymphodepleting chemotherapy comprises administration of cyclophosphamide and fludarabine optionally at a dose of 500 mg/m2/d×3 d cyclophosphamide and 20 mg/m2/d×3 d fludarabine or at a dose of 600 mg/m2/d×3 d cyclophosphamide and 30 mg/m2/d×4 d, and/or the lymphodepleting chemotherapy is administered 7 to 5 or 7 to 4 days prior to administration of the modified immunoresponsive cells expressing or presenting a heterologous T-cell receptor (TCR).

35-36. (canceled)

37. The method according to claim 1 wherein the subject has not received prior treatment for cancer and/or tumour.

38. The method according to claim 1, wherein the subject has received prior cancer and/or tumour treatment and/or has failed to respond to prior cancer and/or tumour treatment, optionally wherein the prior treatment is for gastroesophageal cancer and/or tumour, optionally wherein the prior treatment comprises systemic and/or local therapy, optionally any one or more of surgery, radiation therapy cryotherapy, laser therapy, topical therapy and/or systemic therapy, for example any one or more of chemotherapy, hormonal therapy, targeted drugs, targeted chemotherapy, or immunotherapy, wherein the prior treatment optionally comprises: (a) a PD-L1 binding antagonist or PD-1 binding antagonist, optionally wherein the PD-1 axis binding antagonist or PD-L1 binding antagonist is an antibody; (b) an Epidermal Growth Factor Receptor Antagonist, optionally any of Cetuximab, erlotinib, gefitinib or afatinib or a vascular endothelial growth factor (VEGF) inhibitor such as for example ramucirumab or bevacizumab or an EGFR inhibitor antibody, such as panitumumab or cetuximab or a human hepatocyte growth factor HGF and/or Met inhibitor, such as onartuzumab or rilotumumab; (c) chemotherapy comprising a platinum compound, optionally selected from any of Lipoplatin, Cisplatin, Carboplatin, Oxaliplatin, Nedaplatin, Triplatin tetranitrate, Phenanthriplatin, Satraplatin, Picoplatin; (d) chemotherapy comprising a chemotherapeutic agent selected from any of, methotrexate, capecitabine, taxane, anthracycline, paclitaxel, docetaxel, paclitaxel protein bound particles, doxorubicine, epirubicine, 5-fluorouracil, cyclophosphamide, afatinib, vincristine, etoposide or combinations thereof; or (e) chemotherapy comprising a chemotherapeutic agent selected from any of, FEC: 5-fluorouracil, epirubicine, cyclophosphamide; FAC: 5-fluorouracil, doxorubicine, cyclophosphamide; AC: doxorubicine, cyclophosphamide; EC: epirubicine, cyclophosphamide.

39-46. (canceled)

47. The method according to claim 1 wherein the treatment effectively extends or improves: (a) progression free survival, (b) time to progression, (c) duration of response, (d) overall survival, (e) objective response or objective response rate, (f) overall response or overall response rate, (g) partial response or partial response rate, (h) complete response or complete response rate; (i) stable disease rate or median stable disease (j) median progression free survival, (k) median time to progression, (l) median duration of response, (m) median overall survival; (n) median objective response or median objective response rate, (o) median overall response or median overall response rate, (p) median partial response or median partial response rate, (q) median complete response or median complete response, or (r) median stable disease rate or median stable disease, in comparison to a placebo treatment or in comparison to prior to treatment or in comparison to without treatment or in comparison to treatment comprising a standard of care, optionally systemic platinum-based chemotherapy treatment.

Description

FIGURES

[0279] FIG. 1. CT scan (computed tomography scan) data demonstrating a >42% decrease in target lesions in esophagogastric junction (EGJ) cancer at a 12 week period following MAGE-A4 CD8 T-cell infusion for the cohort subject receiving around a 10 billion cell infusion.

[0280] FIG. 2. Table of tumour response for esophagogastric junction (EGJ) cancer following MAGE-A4 CD8 T-cell infusion, showing the % change reduction from baseline lesion SLC i.e. percent changes in sum of diameters in target lesions measurement (Sum of Diameters=Sum of the long diameters for non-nodal lesions and short axis for nodal lesions), responses evaluated by RECIST v1.1.

EXAMPLES

Example 1—a Phase I Open Label, Clinical Trial Evaluating the Safety and Anti-Tumour

[0281] Activity of Autologous T Cells Expressing Enhanced TCRs Specific for MAGE-A4, MAGE-A4 CD8 TCR in HLA-A2+ subjects with MAGE-A4 positive esophagogastric junction (EGJ) cancer, gastric cancer.

[0282] Methods

[0283] The following presents an in human study of genetically engineered ADP-A2M4CD8 SPEAR T-cells in subjects with HLA-A*02 and MAGE-A4 positive inoperable locally advanced or metastatic tumors for esophagogastric junction (EGJ) cancer, gastric cancer.

[0284] Disease was histologically or cytogenetically confirmed and/or measurable disease recorded according to RECIST v1.1 criteria. Subjects who were eligible based on HLA type and who met MAGE-A4 criteria were screened for general health, performance status and disease stage. Following Screening, subjects meeting all eligibility criteria underwent leukapheresis to obtain cells for the manufacture of autologous MAGE-A4 CD8 TCR bearing T-cells.

[0285] Eligible subjects had an ECOG Performance Status 0-1, adequate organ function and measurable disease required prior to lymphodepletion and:

[0286] (a) Subject is positive for at least one HLA-A*02 inclusion allele.

[0287] (b) Subject has inoperable or metastatic (advanced) of the esophageal (squamous or adenocarcinoma), esophagogastric Junction (EGJ), or gastric cancer.

[0288] (c) Subject may have received a fluoropyrimidine (e.g. fluorouracil or capecitabine) and/or platinum regimen

[0289] (d) Subject cancer and/or tumour may have Her2neu amplification but have failed (progressive disease or unacceptable toxicity) or refused trastuzumab.

[0290] (e) Subject may have received no more than three prior systemic regimens.

[0291] (b) Subject has histologically or cytologically confirmed diagnosis of metastatic (advanced) of the esophageal (squamous or adenocarcinoma), esophagogastric Junction (EGJ), or gastric cancer.

[0292] Exclusion of subjects is based primarily on HLA-A genotype ie if: Subject is positive for any HLA-A*02 allele other than: one of the inclusion alleles, HLA-A*02:07P or HLA-A*02 null alleles (HLA-A*02:07P or HLA-A*02 null alleles are both alleles with low activity, so if these allele's are the subject's only 02 allele then they would not be eligible). Excluded subjects additionally include those with symptomatic CNS metastases or active autoimmune or immune mediated disease, or infection.

[0293] Following leukapheresis the cells are subsequently transduced with the MAGE-A4 CD8 TCR T cells (SEQ ID NO: 5, 7+SEQ ID NO: 3) specific for MAGE-A4 antigen (particularly the specific MAGE-A4 antigenic peptide SEQ ID NO:2) and the cells expanded and cryopreserved for later use. Once the MAGE-A4 CD8 TCR T cells were available, subjects underwent lymphodepleting chemotherapy with cyclophosphamide plus fludarabine on Days −7 to −5, or Days −7 to −4 followed by infusion of transduced cells on Day 1.

[0294] Three subject cohorts were treated dosing with between 100 million to 5 billion transduced cells respectively with no dose escalation:

[0295] 100 mn cell dose, (cyclophosphamide: 500 mg/m.sup.2/d)×3 d; (fludarabine: 20 mg/m.sup.2/d)×3 d

[0296] 1 bn cell dose, (cyclophosphamide: 500 mg/m.sup.2/d)×3 d; (fludarabine: 20 mg/m.sup.2/d)×3 d

[0297] 5 bn cell dose, (cyclophosphamide: 600 mg/m.sup.2/d)×3 d; (fludarabine: 30 mg/m.sup.2/d)×4 d

[0298] Subjects are hospitalised for 7 days following infusion and monitored for safety, T-cell persistence, cytokine production with CT and MRI performed at weeks 4, 8, 16, 24 and 3 monthly thereafter until disease progression or early interventional withdrawal, long term follow up annually is planned for a 15 year period.

[0299] A subject will be considered completing the interventional phase of the study when he/she has received T-cell infusion and then progressed or died prior to disease progression. Optionally a second T-cell infusion may be given, and they will remain in the interventional phase of the study until they have further progression of disease. Once progression is established, no further efficacy assessments are performed other than overall survival. All subjects completing from the interventional portion of the study will enter the long-term follow-up (LTFU) phase for observation of delayed adverse events (AEs) during the 15 years post-infusion in accordance with FDA and EMA regulations. This study will be considered complete when the last living subject has completed LTFU.

[0300] To evaluate the safety and tolerability of MAGE-A4 CD8 TCR T cells the incidence of dose limiting toxicities (DLTs) is monitored, determination is made of optimally tolerated dose range, adverse events (AEs), and Serious Adverse Events (SAEs); laboratory assessments, including chemistry, haematology, and coagulation; and cardiac assessments, including ECG and cardiac Troponin.

[0301] During the study MAGE-A4 is evaluated as a biomarker for tumour MAGE-A4 expression, and antitumor activity. This is performed to correlate the level of antigen expression in tumour level at Baseline, and post MAGE-A4 CD8 TCR T cell infusion. Post-therapy MAGE-A4 expression in tumour over time is assessed to determine tumour immunity or resistance to MAGE-A4 CD8 TCR T cells. Additionally, circulating cytokines were measured and evaluated for association with cytokine release syndrome (CRS) and other adverse events (AEs). Additionally post MAGE-A4 CD8 TCR T cell infusion, transduced cell persistence is assessed by determination of serum level persistence of MAGE-A4 CD8 TCR engineered T-cell as measured by MAGE-A4 TCR vector copy number and MAGE-A4 CD8 TCR transduced T-cell number. Mean expression of specific surface markers on gene-modified T cells in subject blood and tumour were measured by fluorescence intensity. Killing profile and cytokine profile of genetically modified T cells were evaluated using flow cytometry in blood and tumour. Biomarkers of subject sample including polymorphisms in cytokine genes and cytokine production.

[0302] To evaluate anti-tumour activity of MAGE-A4 CD8 TCR T cells the following endpoints are monitored by RECIST v1.1; Overall Response Rate (ORR) defined as the proportion of subjects with a confirmed complete response (CR) or partial response (PR). Additional endpoints are monitored for duration of response (DoR), duration of stable disease (SD), progression free survival (PFS), overall survival (OS). Evaluation was made of the efficacy of the treatment by assessment of duration of response and assessment of overall survival. Also assessed were intervals for

[0303] (a) the date of first T cell infusion dose and first documented evidence of CR or PR and evaluation of the efficacy of the treatment by assessment of time to first response.

[0304] (b) the date of first documented evidence of CR or PR until first documented disease progression or death due to any cause.

[0305] (c) the date of first documented evidence of stable disease (SD) until first documented disease progression or death due to any cause.

[0306] (d) the date of first T cell infusion and the earliest date of disease, progression or death due to any cause.

[0307] (e) between the date of first T cell infusion and date of death due to any cause.

[0308] Evaluation of the efficacy of the treatment by Number and % of subjects having any Long Term Follow Up Adverse Events (AEs), malignancy, neurologic disorder, rheumatologic or other autoimmune disorder, hematologic disorder, infections.

[0309] Subjects were additionally monitored for safety and tolerability response through laboratory assessments including chemistry, hematology and coagulation, and anti-MAGE-A4 TCR antibodies, adverse events (AE), including serious adverse events (SAEs), dose limiting toxicities (DLT) NCI CTCAE and optimally tolerated dose range and evaluation of persistence of genetically modified T cells in the periphery and retention of heterologous TCR expression in the T cells PBMCs using PCR-based assay.

[0310] Results

[0311] The data in FIG. 1 represent the CT scans of 31-year-old man with stage 4 adenocarcinoma of the GEJ, which is HER2 negative, the subject had received prior unsuccessful chemotherapy, targeted therapy and immunotherapy regimens (Ramucirumab+Paclitaxel, Atezolizumab+BL-8040, FLOT/FOLFIRI chemotherapy). The subject had moderate MAGE-A4 expression at baseline (IHC 3+) and large disease burden; baseline lesion SLD was 66 cm and the subject was provided a first infusion of ˜10 billion MAGE-A4 CD8 TCR T cells, adverse reaction was minimal and consistent with those typically experienced by cancer patients undergoing cytotoxic chemotherapy and/or cancer immunotherapy. The tumour showed a greater than 42% decrease at 8 weeks by RECIST 1.1 and by sum of diameters in target lesions over the measured period of weeks following the date of T cell infusion. This progressed to greater than 51% decrease at week 18 see as shown in FIG. 2. The data confirms the 18 week efficacy of response in terms of tumour size reduction (51% reduction) for esophagogastric Junction (EGJ) cancer treatment. Data is shown for aortocaval lymph nodes, equivalent data were obtained by CT for periportal lymph nodes, ascites & nonmeaurable peritoneal mets, equivalent reductions from baseline were observed as for aortocaval lymph nodes.

[0312] Over the period of 8 to 12 weeks post infusion the absolute concentration of transduced lymphocyctes comprising MAGE-A4 CD8 TCR T cells was retained at a high level (46-53%) showing durability of the therapeutic T cells.

TABLE-US-00001 Sequences MAGE A4 SEQ ID NO: 1, MSSEQKSQHC KPEEGVEAQE EALGLVGAQA PTTEEQEAAV SSSSPLVPGT LEEVPAAESA GPPQSPQGAS ALPTTISFTC WRQPNEGSSS QEEEGPSTSP DAESLFREAL SNKVDELAHF LLRKYRAKEL VTKAEMLERV IKNYKRCFPV IFGKASESLK MIFGIDVKEV DPASNTYTLV TCLGLSYDGL LGNNQIFPKT GLLIIVLGTI AMEGDSASEE EIWEELGVMG VYDGREHTVY GEPRKLLTQD WVQENYLEYR QVPGSNPARY EFLWGPRALA ETSYVKVLEH VVRVNARVRI AYPSLREAAL LEEEEGV MAGE A4 peptide SEQ ID NO: 2, GVYDGREHTV (CD8α)CDRs bold underlined, signal sequence italic underlined SEQ ID NO: 3; MALPVTALLLPLALLLHAARPSQFRVSPLDRTWNLGETVELKCQVLLSNPTSGCSWLFQPRGAAASPT FLLYLSQNKPKAAEGLDTQRFSGKRLGDTFVLTLSDFRRENEGYYFCSALSNSIMYFSHFVPVFLPAK PTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITL YCNHRNRRRVCKCPRPVVKSGDKPSLSARYV (CD8α) SEQ ID NO: 4; ATGGCCTTACCAGTGACCGCCTTGCTCCTGCCGCTGGCCTTGCTGCTCCACGCCGCCAGGCCGAGCCA GTTCCGGGTGTCGCCGCTGGATCGGACCTGGAACCTGGGCGAGACAGTGGAGCTGAAGTGCCAGGTGC TGCTGTCCAACCCGACGTCGGGCTGCTCGTGGCTCTTCCAGCCGCGCGGCGCCGCCGCCAGTCCCACC TTCCTCCTATACCTCTCCCAAAACAAGCCCAAGGCGGCCGAGGGGCTGGACACCCAGCGGTTCTCGGG CAAGAGGTTGGGGGACACCTTCGTCCTCACCCTGAGCGACTTCCGCCGAGAGAACGAGGGCTACTATT TCTGCTCGGCCCTGAGCAACTCCATCATGTACTTCAGCCACTTCGTGCCGGTCTTCCTGCCAGCGAAG CCCACCACGACGCCAGCGCCGCGACCACCAACACCGGCGCCCACCATCGCGTCGCAGCCCCTGTCCCT GCGCCCAGAGGCGTGCCGGCCAGCGGCGGGGGGCGCAGTGCACACGAGGGGGCTGGACTTCGCCTGTG ATATCTACATCTGGGCGCCCTTGGCCGGGACTTGTGGGGTCCTTCTCCTGTCACTGGTTATCACCCTT TACTGCAACCACAGGAACCGAAGACGTGTTTGCAAATGTCCCCGGCCTGTGGTCAAATCGGGAGACAA GCCCAGCCTTTCGGCGAGATACGTCGGTTCAAGAGCTAAAAGAAGTGGTAGTGGTGCCCCTGTGA (MAGE A4 TCR α chain) CDRs bold underlined SEQ ID NO: 5; MKKHLTTFLVILWLYFYRGNGKNQVEQSPQSLIILEGKNCTLQCNYTVSPFSNLRWYKQDTGRGPVSL TILTFSENTKSNGRYTATLDADTKQSSLHITASQLSDSASYICVVSGGTDSWGKLQFGAGTQVVVTPD IQNPDPAVYQLRDSKSSDKSVCLFTDFDSQTNVSQSKDSDVYITDKTVLDMRSMDFKSNSAVAWSNKS DFACANAFNNSIIPEDTFFPSPESSCDVKLVEKSFETDTNLNFQNLSVIGFRILLLKVAGFNLLMTLR LWSSGSRAKR (MAGE A4 TCR α chain coding sequence) SEQ ID NO: 6; ATGAAGAAGCACCTGACCACCTTTCTCGTGATCCTGTGGCTGTACTTCTACCGGGGCAACGGCAAGAA CCAGGTGGAACAGAGCCCCCAGAGCCTGATCATCCTGGAAGGCAAGAACTGCACCCTGCAGTGCAACT ACACCGTGTCCCCCTTCAGCAACCTGCGGTGGTACAAGCAGGACACCGGCAGAGGCCCTGTGTCCCTG ACCATCCTGACCTTCAGCGAGAACACCAAGAGCAACGGCCGGTACACCGCCACCCTGGACGCCGATAC AAAGCAGAGCAGCCTGCACATCACCGCCAGCCAGCTGAGCGATAGCGCCAGCTACATCTGCGTGGTGT CCGGCGGCACAGACAGCTGGGGCAAGCTGCAGTTTGGCGCCGGAACACAGGTGGTCGTGACCCCCGAC ATCCAGAACCCTGACCCTGCCGTGTACCAGCTGCGGGACAGCAAGAGCAGCGACAAGAGCGTGTGCCT GTTCACCGACTTCGACAGCCAGACCAACGTGTCCCAGAGCAAGGACAGCGACGTGTACATCACCGACA AGACCGTGCTGGACATGCGGAGCATGGACTTCAAGAGCAATAGCGCCGTGGCCTGGTCCAACAAGAGC GACTTCGCCTGCGCCAACGCCTTCAACAACAGCATTATCCCCGAGGACACATTCTTCCCAAGCCCCGA GAGCAGCTGCGACGTCAAGCTGGTGGAAAAGAGCTTCGAGACAGACACCAACCTGAACTTCCAGAACC TGAGCGTGATCGGCTTCAGAATCCTGCTGCTGAAGGTGGCCGGCTTCAACCTGCTGATGACCCTGAGA CTGTGGTCCAGCGGCAGCCGGGCCAAGAGA (MAGE A4 TCR β chain) CDRs bold underlined SEQ ID NO: 7; MASLLFFCGAFYLLGTGSMDADVTQTPRNRITKTGKRIMLECSQTKGHDRMYWYRQDPGLGLRLIYYS FDVKDINKGEISDGYSVSRQAQAKFSLSLESAIPNQTALYFCATSGQGAYEEQFFGPGTRLTVLEDLK NVFPPEVAVFEPSEAEISHTQKATLVCLATGFYPDHVELSWWVNGKEVHSGVSTDPQPLKEQPALNDS RYCLSSRLRVSATFWQNPRNHFRCQVQFYGLSENDEWTQDRAKPVTQIVSAEAWGRADCGFTSESYQQ GVLSATILYEILLGKATLYAVLVSALVLMAMVKRKDSRG (MAGE A4 TCR β chain coding sequence) SEQ ID NO: 8; ATGGCCAGCCTGCTGTTCTTCTGCGGCGCCTTCTACCTGCTGGGCACCGGCTCTATGGATGCCGACGT GACCCAGACCCCCCGGAACAGAATCACCAAGACCGGCAAGCGGATCATGCTGGAATGCTCCCAGACCA AGGGCCACGACCGGATGTACTGGTACAGACAGGACCCTGGCCTGGGCCTGCGGCTGATCTACTACAGC TTCGACGTGAAGGACATCAACAAGGGCGAGATCAGCGACGGCTACAGCGTGTCCAGACAGGCTCAGGC CAAGTTCAGCCTGTCCCTGGAAAGCGCCATCCCCAACCAGACCGCCCTGTACTTTTGTGCCACAAGCG GCCAGGGCGCCTACGAGGAGCAGTTCTTTGGCCCTGGCACCCGGCTGACAGTGCTGGAAGATCTGAAG AACGTGTTCCCCCCAGAGGTGGCCGTGTTCGAGCCTTCTGAGGCCGAAATCAGCCACACCCAGAAAGC CACACTCGTGTGTCTGGCCACCGGCTTCTACCCCGACCACGTGGAACTGTCTTGGTGGGTCAACGGCA AAGAGGTGCACAGCGGCGTGTCCACCGATCCCCAGCCTCTGAAAGAACAGCCCGCCCTGAACGACAGC CGGTACTGCCTGAGCAGCAGACTGAGAGTGTCCGCCACCTTCTGGCAGAACCCCAGAAACCACTTCAG ATGCCAGGTGCAGTTTTACGGCCTGAGCGAGAACGACGAGTGGACCCAGGACAGAGCCAAGCCCGTGA CACAGATCGTGTCTGCCGAAGCTTGGGGGCGCGCCGATTGTGGCTTTACCAGCGAGAGCTACCAGCAG GGCGTGCTGAGCGCCACCATCCTGTACGAGATCCTGCTGGGAAAGGCCACACTGTACGCCGTGCTGGT GTCTGCCCTGGTGCTGATGGCCATGGTCAAGCGGAAGGACAGCCGGGGC (MAGE A4 TCR α chain variable region)136AA - CDRs bold underlined SEQ ID NO: 9; MKKHLTTFLVILWLYFYRGNGKNQVEQSPQSLIILEGKNCTLQCNYTVSPFSNLRWYKQDTGRGPVSL TILTFSENTKSNGRYTATLDADTKQSSLHITASQLSDSASYICVVSGGTDSWGKLQFGAGTQVVVTPD (MAGE A4 TCR β chain variable region)133AA - CDRs bold underlined SEQ ID NO: 10; MASLLFFCGAFYLLGTGSMDADVTQTPRNRITKTGKRIMLECSQTKGHDRMYWYRQDPGLGLRLIYYS FDVKDINKGEISDGYSVSRQAQAKFSLSLESAIPNQTALYFCATSGQGAYEEQFFGPGTRLTVLE CDR1 MAGE A4 TCR α chain, (residues 48-53) SEQ ID NO: 11; VSPFSN CDR2 MAGE A4 TCR α chain, (residues 71-76) SEQ ID NO: 12; LTFSEN CDR3 MAGE A4 TCR α chain, (residues 111-125) SEQ ID NO: 13; CVVSGGTDSWGKLQF CDR1 MAGE A4 TCR β chain, (residues 46-50) SEQ ID NO: 14; KGHDR CDR2 MAGE A4 TCR β chain, (residues 68-73) SEQ ID NO: 15; SFDVKD CDR3 MAGE A4 TCR β chain, (residues 110-123) SEQ ID NO: 16; CATSGQGAYEEQFF CDR1 CD8α (residues 45-53) SEQ ID NO: 17; VLLSNPTSG CDR2 CD8α (residues 72-79) SEQ ID NO: 18; YLSQNKPK CDR3 CD8α (residues 118-123) SEQ ID NO: 19; LSNSIM