JPWO2021229235A5 - - Google Patents

Description

SEQ ID NO:19; CDR3 CD8α (residues 118-123)
LSN SIM

The inventions described in the original claims of this application are listed below.
[Invention 1]
1. A method of treating, preventing or delaying the progression of cancer and/or tumors in a subject, comprising administering to said subject a therapeutic regimen comprising an effective amount of modified immunoresponsive cells that express or display a heterologous T cell receptor (TCR) that binds to a peptide antigen of GVYDGREHTV, MAGE A4 comprising SEQ ID NO:2, wherein said cancer and/or tumor is a gastroesophageal cancer and/or tumor.
[Invention 2]
2. The method of claim 1, wherein said peptide antigen of MAGE A4 comprises the sequence GVYDGREHTV, SEQ ID NO:2.
[Invention 3]
The method according to claim 1 or 2, wherein the heterologous TCR specifically and/or selectively binds to the peptide antigen.
[Invention 4]
4. The method according to any one of claims 1 to 3, wherein said peptide antigen is associated with gastroesophageal cancer and/or tumors and/or is presented by tumor and/or cancer cells or tissues.
[Invention 5]
5. The method according to any one of claims 1 to 4, wherein said cancer and/or tumor is a MAGE A4 expressing cancer and/or tumor and/or expresses MAGE A4 or a peptide antigen thereof, or a peptide antigen of MAGE A4 comprising GVYDGREHTV, SEQ ID NO:2.
[Invention 6]
6. The method according to any one of claims 1 to 5, wherein the peptide antigen is complexed to a peptide presenting molecule, optionally a major histocompatibility complex (MHC) or a human leukocyte antigen (HLA), optionally class I or class II.
[Invention 7]
7. The method according to invention 6, wherein said peptide presenting molecule is optionally HLA-A*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 selected from HLA-A*02:01 or HLA-A*02.
[Invention 8]
The method according to any one of claims 1 to 6, wherein the heterologous TCR specifically and/or selectively binds to the peptide antigen and/or the peptide presenting molecule, and/or a complex thereof.
[Invention 9]
6. The method according to any one of claims 1 to 5, wherein the peptide antigen is presented independently of a peptide-presenting molecule.
[Invention 10]
the heterologous TCR comprises a TCR alpha chain variable domain and a TCR beta chain variable domain;
(i) the alpha chain variable domain has the sequence
VSPFSN (αCDR1), SEQ ID NO:11, or amino acid residues 48-53 of SEQ ID NO:5, or a sequence having at least 50% sequence identity thereto;
LTFSEN (αCDR2), SEQ ID NO: 12, or amino acid residues 71-76 of SEQ ID NO: 5, or a sequence having at least 50% sequence identity thereto; and
CVVSGGTDSWGKLQF (αCDR3), SEQ ID NO:13, or amino acid residues 111-125 of SEQ ID NO:5, or a sequence having at least 50% sequence identity thereto.
and
(ii) the beta chain variable domain has the sequence
KGHDR (βCDR1), SEQ ID NO: 14, or amino acid residues 46-50 of SEQ ID NO: 7, or a sequence having at least 50% sequence identity thereto;
SFDVKD (βCDR2), SEQ ID NO: 15, or amino acid residues 68-73 of SEQ ID NO: 7, or a sequence having at least 50% sequence identity thereto; and
CATSGQGAYEEQFF (βCDR3), SEQ ID NO: 16, or amino acid residues 110-123 of SEQ ID NO: 7, or a sequence having at least 50% sequence identity thereto.
and
The method according to any one of claims 1 to 9.
[Invention 11]
The heterologous TCR is
(a) the alpha chain variable domain comprises an amino acid sequence having at least 80% identity to SEQ ID NO:9, and/or the beta chain variable domain comprises an amino acid sequence having 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 having at least 80% identity to SEQ ID NO:5, and/or the beta chain comprises an amino acid sequence having 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;
11. The method according to any one of claims 1 to 10, comprising a TCR.
[Invention 12]
12. The method of any one of claims 1 to 11, wherein said engineered immunoresponsive cell expressing or presenting a heterologous TCR further expresses or presents a heterologous co-receptor, optionally said co-receptor being a CD8 co-receptor.
[Invention 13]
13. The method according to claim 12, wherein said heterologous CD8 co-receptor is a heterodimer or a homodimer, a CD8αb heterodimer or a CD8αα homodimer.
[Invention 14]
the heterologous CD8 co-receptor
(a) an amino acid sequence VLLSNPTSG, a CDR1 having at least 80% sequence identity with SEQ ID NO:17, an amino acid sequence YLSQNKPK, a CDR2 having at least 80% sequence identity with SEQ ID NO:18, and an amino acid sequence LSNSIM, a CDR3 having at least 80% sequence identity with SEQ ID NO:19;
(b) the amino acid sequence VLLSNPTSG, CDR1 of SEQ ID NO: 17, the amino acid sequence YLSQNKPK, CDR2 of SEQ ID NO: 18, and the amino acid sequence LSNSIM, CDR3 of SEQ ID NO: 19;
(c) an amino acid sequence having at least 80% sequence identity to amino acid numbers 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 with amino acid numbers 22 to 235 of SEQ ID NO: 3, or amino acid numbers 22 to 135 of SEQ ID NO: 3
12. The method according to any one of claims 10 to 11, comprising any one of the steps:
[Invention 15]
15. The method of any one of claims 1 to 14, wherein said modified immunoresponsive cell expressing or presenting a heterologous TCR further expresses or presents a heterologous costimulatory ligand, optionally 4-1BBL or CD80.
[Invention 16]
16. The method of any one of claims 1 to 15, wherein the modified immunoresponsive cell is (a) a B cell, a T cell, or a natural killer (NK) cell; (b) a T cell, optionally a CD4 ⁺ T cell and/or a CD8 ⁺ T cell.
[Invention 17]
17. The method of any one of claims 1 to 16, wherein the modified immunoresponsive cells are a population of CD4+ T cells; or CD8+ T cells, or a mixed population of CD4+ and CD8+ T cells.
[Invention 18]
18. The method of any one of claims 1 to 17, wherein the modified immunoresponsive cells are administered continuously or intermittently.
[Invention 19]
19. The method of any one of claims 1 to 18, wherein the modified immunoresponsive cells are administered as multiple doses or as a single dose.
[Invention 20]
20. The method of claim 19, wherein said single or multiple doses are administered in one or multiple dosing cycles, and optionally said doses can be fixed doses or variable doses.
[Invention 21]
21. The method of any one of claims 1 to 20, wherein said modified immunoresponsive cells are administered at a dose of 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.
[Invention 22]
the modified immunoresponsive cell comprises:
(a) a single dose in each of one or more dosing cycles;
(b) one or more doses during each of one or more dosing cycles;
(c) a single dose on day 1 of each of one or more dosing cycles;
(d) one or more doses in each of one or more dosing cycles, with at least one dose on day 1 of each cycle;
(e) one or more doses in each of one or more dosing cycles, with at least one dose on day 1 of each cycle;
(f) Single dose
22. The method according to any one of claims 1 to 21, wherein the compound is administered as a medicament.
[Invention 23]
23. The method according to any one of claims 20 to 22, wherein said dosing cycle is for 2 to 6 months or during disease progression.
[Invention 24]
The dosing cycle comprises:
(a) disease progression following a prior administration of modified immunoresponsive cells, and 12 weeks or more after a prior administration of modified immunoresponsive cells;
In
(b) the tumor and/or cancer expresses MAGE-A4 and/or a peptide antigen thereof, and/or
(c) MAGE-A4 and/or its peptide antigens are detected in the subject's biological sample and/or are above the normal range;
24. The method according to any one of claims 20 to 23.
[Invention 25]
The dosing cycle comprises:
(a) a complete or partial response following the previous administration of modified immunoresponsive cells, or (b) stable disease for a period of more than or equal to 4 months following the previous administration of modified immunoresponsive cells, followed by disease progression; and (c) more than or equal to 12 weeks following the previous administration of modified immunoresponsive cells.
In
(d) the tumor and/or cancer expresses MAGE-A4 and/or a peptide antigen thereof, and/or
(e) MAGE-A4 and/or its peptide antigens are detected in the subject's biological sample and/or are above the normal range;
24. The method according to any one of claims 20 to 23.
[Invention 26]
26. The method of any one of claims 1 to 25, wherein said engineered immunoresponsive cells are administered intravenously or by intravenous infusion.
[Invention 27]
27. The method according to any one of claims 1 to 26, wherein prior to treatment, the subject has measurable disease according to Eastern Cooperative Oncology Group (ECOG) of 0-1, and/or Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, and/or histologically confirmed gastroesophageal cancer and/or tumors.
[Invention 28]
Prior to treatment, the subject:
(a) the HLA-A genotype is HLA-A*02:07b as the only HLA-A*02 allele;
(b) the HLA-A genotype is HLA-A* with any A*02 null allele as the only HLA-A*02 allele; or
(c) Symptomatic CNS metastases
28. The method according to any one of claims 1 to 27, wherein the subject is excluded from said treatment if he/she has any one or more of the following:
[Invention 29]
29. The method according to any one of claims 1 to 28, wherein said subject is intolerant to standard care treatment, optionally systemic platinum-based chemotherapy treatment.
[Invention 30]
30. The method according to any one of claims 1 to 29, wherein said gastroesophageal cancer and/or tumor has previously failed treatment with standard of care treatment, optionally with systemic platinum-based chemotherapy treatment.
[Invention 31]
31. The method according to any one of claims 1 to 30, wherein said gastroesophageal cancer and/or tumor has previously failed treatment with any of surgery (resection), radiation therapy, targeted therapy, immunotherapy, or chemotherapy in combination with surgery (resection), radiation therapy, radiation therapy, targeted therapy, checkpoint inhibitor, or immunotherapy.
[Invention 32]
The method according to any one of claims 1 to 31, wherein the subject has a primary cancer, a secondary cancer, a relapsing or refractory cancer, a recurrent cancer, a locally recurrent cancer, or a metastatic cancer, an unresectable or locally localized cancer with no surgical or radiotherapy options, or an inoperable cancer, or the gastroesophageal cancer and/or tumor is a primary cancer, a secondary cancer, a relapsing or refractory cancer, a recurrent cancer, a locally recurrent cancer, or a metastatic cancer, an unresectable or locally localized cancer with no surgical or radiotherapy options, or an inoperable cancer, and optionally the cancer is not suitable for transplantation or locoregional therapy.
[Invention 33]
33. The method according to any one of claims 1 to 32, wherein said gastroesophageal cancer and/or tumor is any of esophageal squamous cell carcinoma (ESCC), esophageal adenocarcinoma (EAC), esophagogastric junction cancer, carcinoma, adenocarcinoma, or tumor (EGJ), or stomach or gastric cancer, carcinoma, or tumor, optionally metastatic and/or progressive and/or locally progressive and/or recurrent ESCC, EAC, EGJ, or stomach or gastric cancer, carcinoma, or tumor.
[Invention 34]
34. The method of any one of claims 1 to 33, wherein the subject undergoes lymphodepleting chemotherapy prior to administration of the engineered immunoresponsive cells expressing or displaying a heterologous T cell receptor (TCR).
[Invention 35]
35. The method according to claim 34, wherein said lymphodepleting chemotherapy comprises the administration of cyclophosphamide and fludarabine, optionally at a dose of 500 mg/m2/d x 3d cyclophosphamide and 20 mg/m2 ^{/ d} x 3d fludarabine, or at a dose of 600 mg/ ^m2 /d x 3d cyclophosphamide and 30 mg/m2/d x 4d fludarabine.
[Invention 36]
36. The method of claim 34 or 35, wherein said lymphodepleting chemotherapy is administered 7 to 5 or 7 to 4 days prior to administration of said engineered immunoresponsive cells expressing or displaying a heterologous T-cell receptor (TCR).
[Invention 37]
37. The method according to any one of claims 1 to 36, wherein the subject has not had prior treatment for cancer and/or tumor.
[Invention 38]
37. The method of any one of claims 1 to 36, wherein the subject has undergone a prior cancer and/or tumor treatment and/or has not responded to a prior cancer and/or tumor treatment, optionally wherein the prior treatment is for gastroesophageal cancer and/or tumor.
[Invention 39]
39. The method of claim 38, wherein said prior treatment comprises systemic and/or local therapy, optionally any one or more of surgery, radiation therapy, cryotherapy, laser therapy, local therapy, and/or any one or more of systemic therapy, such as chemotherapy, hormonal therapy, targeted drugs, targeted chemotherapy, or immunotherapy.
[Invention 40]
40. The method of claim 39, wherein said prior treatment comprises a PD-L1 binding antagonist or a PD-1 binding antagonist, and optionally the PD-1 axis binding antagonist or the PD-L1 binding antagonist is an antibody.
[Invention 41]
40. The method of claim 39, wherein said prior treatment comprises 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.
[Invention 42]
40. The method of claim 39, wherein said prior treatment optionally comprises chemotherapy comprising a platinum compound selected from any of the following: lipoplatin, cisplatin, carboplatin, oxaliplatin, nedaplatin, triplatin tetranitrate, phenanthriplatin, satraplatin, picoplatin.
[Invention 43]
40. The method of claim 39, wherein said prior treatment comprises chemotherapy comprising a chemotherapeutic agent selected from any of methotrexate, capecitabine, taxanes, anthracyclines, paclitaxel, docetaxel, paclitaxel protein-bound particles, doxorubicin, epirubicin, 5-fluorouracil, cyclophosphamide, afatinib, vincristine, etoposide, or combinations thereof.
[Invention 44]
40. The method of claim 39, wherein said prior treatment comprises chemotherapy comprising a chemotherapeutic agent selected from any of the following: FEC: 5-fluorouracil, epirubicin, cyclophosphamide; FAC: 5-fluorouracil, doxorubicin, cyclophosphamide; AC: doxorubicin, cyclophosphamide; EC: epirubicin, cyclophosphamide.
[Invention 45]
45. The method according to any one of claims 39 to 44, wherein the subject has not received prior treatment in a relapse less than or equal to 12 months since the last treatment, or less than or equal to 6 months since the last treatment.
[Invention 46]
45. The method according to any one of claims 39 to 44, wherein the subject has not received any prior adjuvant therapy (e.g. surgery followed by radiation and/or chemotherapy) or locoregional therapy in a recurrence less than or equal to 12 months since the last treatment, or in a recurrence less than or equal to 6 months since the last treatment.
[Invention 47]
the treatment is compared to a placebo treatment, or compared to prior treatment, or compared to no treatment, or compared to a treatment including standard of care, optionally a systemic platinum-based chemotherapy treatment;
(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) Rate of stable disease or median stable disease
(j) median progression-free survival,
(k) median time to progression;
(l) median duration of response; or
(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,
(r) Median stable disease rate or median stable disease rate
47. The method according to any one of claims 1 to 46, which effectively extends or improves

Claims (1)

A method of treating, preventing or delaying the progression of cancer and/or tumors in a subject, comprising administering to the subject a therapeutic regimen comprising an effective amount of modified immunoresponsive cells that express or display a heterologous T cell receptor (TCR) that binds to a peptide antigen of MAGE A4, comprising GVYDGREHTV, SEQ ID NO:2, wherein the cancer and/or tumor is a gastroesophageal cancer and/or tumor.