Treatment methods for cancer or tumors

Abstract

The present invention relates to 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) having the property of binding to MAGE A4.

Description

[Technical Field]

[0001] The present invention relates to a method for treating, preventing or delaying the progression of cancer and / or tumors in a subject, particularly head and neck cancer or lung cancer, comprising administering to the subject a therapeutic regimen comprising a therapeutic regimen comprising a subject expressing or presenting a modified immune-responsive cell expressing or presenting a heterologous T cell receptor (TCR) having the property of binding to MAGE A4 or its antigenic peptide. [Background technology]

[0002] Treatment for Head and Neck Cancer: Head and neck cancer is a group of cancers affecting the oral cavity, nose, pharynx, larynx, sinuses, or salivary glands, the majority of which are squamous cell carcinomas. These cancers are the seventh most common cancer overall, the ninth leading cause of cancer death, and affect more than 5.5 million people worldwide. While these cancers are strongly associated with smoking and alcohol consumption, other known risk factors are viral in origin, including Epstein-Barr virus or human papillomavirus infection. Mutation profiles of HPV+ and HPV- head and neck cancers indicate that these are fundamentally different cancers.

[0003] Head and neck cancers generally affect people aged 55 to 65, and men are twice as likely to be affected as women. The average 5-year survival rate after diagnosis is 42-64%, and while the cure rate for early-stage oral cancer has improved, the majority of patients have more advanced cancer, which is not easy to treat. After successful first-line treatment, a significant percentage of patients experience progression, with 9-23% developing secondary primary tumors 20 years later, often due to the same carcinogenic exposure that caused the original tumor. Diagnosis is staging according to the TNM classification system, where T represents tumor size and location, N represents the presence or absence of lymph node metastasis, and M represents the presence or absence of distant metastasis. The combination of T, N, and M characteristics determines the "stage" of the cancer, from I to IVB. Surgical resection and radiotherapy (including 3D conformal radiotherapy, intensity-modulated radiotherapy, particle beam therapy, and short-range radiotherapy) or combination chemotherapy regimens are the standard treatment for most head and neck cancers with regional lymph node metastasis (stage III or IV), although surgery alone may be sufficient for early primary cancers without regional lymph node metastasis (stage I or II). Typical chemotherapy agents are paclitaxel and carboplatin, but docetaxel is also approved for advanced head and neck cancer, either alone or in combination with cisplatin and / or fluorouracil. Immune checkpoint inhibitors are also further treatment options; pembrolizumab is approved as a first-line treatment for metastatic or unresectable recurrent HNSCC, or nivolumab is approved for the treatment of recurrent or metastatic HNSCC that has progressed during or after platinum-based chemotherapy. Several targeted antibody therapy options for head and neck squamous cell carcinoma include cetuximab, bevacizumab, and erlotinib, as well as a combination of cetuximab with the conventional chemotherapy drug cisplatin. Cetuximab and cisplatin / 5-fluorouracil are recognized as first-line regimens.

[0004] If head and neck cancer affects the pharynx, or if pharyngeal cancer is located near the lower part of the pharynx, there is a high probability of it spreading to the lungs.

[0005] Lung Cancer Treatment: Lung cancer is the leading cause of cancer-related death in men in the United States, and the second leading cause of cancer-related death in women, after breast cancer, with a 5-year survival rate of around 20%. It is caused by environmental carcinogens resulting from smoking, exposure to chemicals or asbestos, and air pollution, which cause genetic damage and epigenetic changes to DNA, and may be combined with predisposing genetic factors. Approximately 8% of lung cancers are related to genetic factors. The disease is commonly treated with surgery (resection), chemotherapy, and radiation therapy. For early-stage non-small cell lung cancer (NSCLC), lobectomy is the surgical treatment of choice, while chemotherapy and / or radiation therapy are typically used for small cell lung cancer (SCLC).

[0006] In advanced NSCLC, chemotherapy is used as the first-line treatment, and sometimes as a second-line treatment. Typically, two drugs are used, one of which is often a platinum-based drug (cisplatin or carboplatin). Other commonly used drugs include gemcitabine, paclitaxel, nab-paclitaxel-docetaxel, pemetrexed, etoposide, or vinorelbine. The combination of vinorelbine and cisplatin is used in adjuvant therapy. In SCLC, cisplatin and etoposide are the most commonly used. Combinations with carboplatin, gemcitabine, paclitaxel, vinorelbine, topotecan, and irinotecan may also be used. Radiotherapy is often used in combination with chemotherapy and may be used for curative purposes in non-small cell lung cancer patients who are not candidates for surgery and in small cell lung cancer patients with a potential for cure. Targeted therapies are becoming increasingly important for both advanced lung cancers, e.g., SCLC and NSCLC, and include, for example, tyrosine kinase inhibitors and epidermal growth factor receptor (EGFR) inhibitors, e.g., erlotinib, gefitinib, afatinib (e.g., for EGFR mutations or EGFR M+ lung cancer), or denosumab monoclonal antibodies against the receptor activator of nuclear factor κ-B ligand.

[0007] Therefore, there is a need for a treatment method for treating tumors and / or cancers, such as head and neck cancer or lung cancer and / or tumors, which is cancer-specific and can treat intermediate or advanced cancers or single or multiple solid tumors, particularly when primary therapy or surgery is unsuccessful or there is a recurrence thereafter. Preferably, there is also a need to provide a treatment method that minimizes or reduces the risk of toxicity or side effects, such as systemic toxicity of chemotherapeutic agents (e.g., nausea, vomiting, anemia, and thrombocytopenia) or tissue damage caused by radiotherapy.

[0008] The present invention relates to the treatment of head and neck or lung cancer and / or tumors in a subject, and includes administering to the subject a therapeutic regimen comprising an effective amount of modified T cells that express or present a heterologous T cell receptor (TCR) having the property of binding to MAGE A4, particularly the property of specifically binding to GVYDGREHTV, SEQ ID NO: 2. In particular, the HLA-A2 restricted MAGE A4 peptide GVYDGREHTV, SEQ ID NO: 2, is a suitable target for a novel immunotherapeutic intervention, and this peptide is naturally processed and isolated from head and neck cancer and lung cancer cell lines.

Summary of the Invention

[0009] According to a first aspect of the present invention, there is provided a method of treating, preventing, or delaying the progression of head and neck or lung cancer and / or tumors in a subject, comprising administering to the subject a therapeutic regimen comprising an effective amount of modified immunoreactive cells that express or present a heterologous T cell receptor (TCR) or chimeric antigen receptor (CAR) that binds to MAGE A4 or an MAGE A4 antigenic peptide thereof.

[0010] According to the present invention, the TCR or CAR can bind to MAGE A4 or an antigenic peptide thereof, such as human MAGE A4 or MAGE A4 of SEQ ID NO: 1 or an antigenic peptide thereof. The TCR or CAR can bind to an antigenic peptide comprising SEQ ID NO: 2, GVYDGREHTV.

[0011] The present invention further provides modified immune-responsive cells that express or present a heterologous T cell receptor (TCR) or chimeric antigen receptor (CAR) that binds to MAGE A4 or its MAGE A4 antigenic peptide, for use in treating, preventing, or delaying the progression of cancer and / or tumors in a subject.

[0012] In several embodiments, the heterologous T cell receptor (TCR) is a TCR that binds to the MAGE A4 peptide antigen, which includes GVYDGREHTV, SEQ ID NO: 2.

[0013] In certain embodiments, use of the present invention involves administering a therapeutic regimen to a subject that comprises an effective amount of modified immune-responsive cells expressing or presenting a heterologous T cell receptor (TCR).

[0014] Immune-responsive cells According to the present invention, modified immune-responsive cells may be lymphoid cells including B, T, or natural killer (NK) cells. Modified immune-responsive cells may be lymphoid cells including T cells and natural killer T (NKT) cells, as well as embryonic stem cells and their precursors including pluripotent stem cells (e.g., from which lymphoid cells can differentiate). T cells are lymphocytes that mature in the thymus and are primarily responsible for cell-mediated immunity, and can also be involved in the adaptive immune system. According to the present invention, T cells may include, but are not limited to, helper T cells, cytotoxic T cells, memory T cells (including central memory T cells, stem cell-like memory T cells (or stem-like memory T cells)), and two types of effector memory T cells: e.g., TEM cells and TEMRA cells, regulatory T cells (also known as suppressor T cells), natural killer T cells, mucosa-associated invariant T cells, and gamma-delta T cells. Cytotoxic T cells (CTLs or killer T cells) are a subset of T lymphocytes capable of inducing the death of infected somatic or tumor cells. A subject's own T cells can be genetically engineered to target specific antigens by introducing xenolytic TCRs or CARs. Preferably, the modified immune-responsive cells are T cells, and optionally, CD4 + T cells or CD8 + These are T cells. Therefore, the modified immune-responsive cells may be T cells, optionally CD4+ T cells or CD8+ T cells, or the modified immune-responsive cells may be a population of modified T cells, optionally CD4+ T cells or CD8+ T cells; or a mixed population of CD4+ T cells and CD8+ T cells.

[0015] Heterogeneous TCR / CAR According to the present invention, modified immune-responsive cells can express xenotypic T cell receptors (TCRs) or xenotypic chimeric antigen receptors (CARs) (for example, cells are transduced or manipulated, for example by gene knock-in, to contain nucleic acid sequences encoding xenotypic TCRs or CARs). Upon antigen binding, modified immune-responsive cells can exhibit T cell effector function and / or cytolytic activity against antigen-carrying cells and / or undergo proliferation and / or cell division. In certain embodiments, modified immune-responsive cells containing xenotypic TCRs exhibit equivalent or better therapeutic efficacy compared to cells containing chimeric antigen receptors (CARs) targeting the same cancer and / or tumor antigens and / or peptides (antigenic peptides). Activated modified immune-responsive cells containing xenotypic TCRs or CARs can secrete antitumor cytokines, including, but not limited to, TNFα, IFNγ, and IL2.

[0016] According to the present invention, modified immune-responsive cells may include nucleic acids, constructs, or vectors encoding heterologous T cell receptors (TCRs) or heterologous chimeric antigen receptors (CARs), or heterologous nucleic acids, constructs, or vectors. Optionally, the TCR may be an affinity-enhanced TCR, for example, a specific peptide-enhanced affinity receptor (SPEAR) TCR.

[0017] The terms "exogenous" or "heterogeneous" refer to polypeptides or nucleic acids that are foreign to a particular biological system, such as a cell or host cell, and that do not naturally exist in that system but can be introduced into the system by artificial or recombinant means. Therefore, the expression of heterogeneous TCRs or CARs can thereby alter the immunogenicity specificity of immunogenic cells, such as T cells, so that they recognize or exhibit improved recognition of one or more tumor or cancer antigens and / or peptides present on the surface of cancer cells in an individual with cancer. Modification of immunogenic cells or T cells and their subsequent expansion can be carried out in vitro and / or ex vivo.

[0018] Cancer / tumor antigen or peptide antigen According to the present invention, the cancer and / or tumor antigen or its peptide antigen may be a carcinometris antigen, for example, one of MAGE, melanoma-associated antigen or a member of the MAGEA gene family, for example, MAGE A1, A2, A3, A4, A5, A6, A7, A8, A9, A10, A11 or A12, or its peptide antigen. Preferably, the tumor antigen is MAGE-A4, SEQ ID NO: 1, or its peptide antigen. Preferably, the cancer and / or tumor antigen peptide contains or has the amino acid sequence GVYDGREHTV, SEQ ID NO: 2.

[0019] Co-stimulatory ligand According to the present invention, modified immune-responsive cells may further contain at least one exogenous or recombinant (e.g., cells are transduced or manipulated, e.g., by gene knock-in, to contain nucleic acid sequences encoding costimulatory ligands), and optionally one, two, three, or four more costimulatory ligands. Modified immune-responsive cells can co-express a heterologous TCR or CAR with at least one exogenous or heterologous costimulatory ligand. The interaction between the heterologous TCR or CAR and at least one exogenous costimulatory ligand may result in non-antigen-specific signaling and / or cell activation. Examples of costimulatory ligands include, but are not limited to, members of the tumor necrosis factor (TNF) superfamily and immunoglobulin (Ig) superfamily ligands. TNF is a cytokine involved in systemic inflammation and stimulates acute phase responses. Members of the TNF superfamily include, but are not limited to, nerve growth factor (NGF), CD40L (CD40L) / CD154, CD137L / 4-1BBL, TNF-α, CD134L / OX40L / CD252, CD27L / CD70, Fas ligand (FasL), CD30L / CD153, tumor necrosis factor β (TNFP) / lymphotoxin-α (LTa), lymphotoxin-β (TTb), CD257 / B cell activator (BAFF) / Blys / THANK / Tall-1, glucocorticoid-inducible TNF receptor ligand (GITRL), and TNF-related apoptosis-inducible ligand (TRAIL), LIGHT (TNFSF14). The immunoglobulin (Ig) superfamily is a large group of cell surface proteins and soluble proteins involved in cell recognition, binding, or adhesion processes. These proteins share structural features with immunoglobulins and possess an immunoglobulin domain (folding). Examples of immunoglobulin superfamily ligands include, but are not limited to, CD80 and CD86, both ligands for CD28. In certain embodiments, at least one co-stimulatory ligand is selected from the group consisting of 4-1BBL, CD275, CD80, CD86, CD70, OX40L, CD48, TNFRSF14, and combinations thereof.At least one exogenous or recombinant costimulatory ligand may be 4-1BBL or CD80, preferably at least one exogenous or recombinant costimulatory ligand is 4-1BBL. The modified immune-responsive cells may contain two exogenous or recombinant costimulatory ligands, preferably the two exogenous or recombinant costimulatory ligands are 4-1BBL and CD80.

[0020] Modified immune-responsive cells may include at least one exogenous or recombinant construct (e.g., cells are transduced or manipulated, e.g., by gene knock-in, etc.) that overcomes the immunosuppressive tumor microenvironment. Such constructs may include, but are not limited to, cyclic AMP phosphodiesterase and dominant-negative transforming growth factor β (TGFβ) receptor II. Modified immune-responsive cells, modified T cells, or populations of modified T cells may be engineered to release cytokines that positively affect the cytolytic activity of the cells. Such cytokines may include, but are not limited to, interleukin-7, interleukin-15, and interleukin-21.

[0021] Specific binding TCR / CAR According to the present invention, modified immune-responsive cells, such as modified T cells, can be modified to bind or specifically bind to tumor cells and / or tissues and / or cancer cells and / or tissues of subjects, patients or cancer patients suffering from a diseased or cancerous condition, and optionally express heterologous TCRs or CARs that express or present cancer and / or tumor antigens or their peptide antigens as described herein. Subjects, patients or cancer patients can then be treated with modified immune-responsive cells or modified T cells or populations thereof according to the present invention. Cancer patients suitable for treatment according to the present invention using modified immune-responsive cells or modified T cells can be identified by a method comprising: obtaining a sample of tumor and / or cancer cells from an individual or subject having a tumor and / or cancer; and identifying that cancer cells bind to TCRs or CARs expressed by modified immune-responsive cells.

[0022] According to the present invention, heterologous TCRs or CARs bind to or specifically bind to cancer and / or tumor antigens or their peptide antigens. According to the present invention, heterologous TCRs or CARs bind to or specifically bind to cancer and / or tumor antigens or their peptide antigens that are associated with a cancerous condition and / or presented by a tumor or cancer cells or tissues.

[0023] According to the present invention, the cancerous condition may be cancer and / or tumor of the head and neck or lungs.

[0024] Specificity describes the strength of binding between a heterologous TCR or CAR and a specific target cancer and / or tumor antigen or its peptide antigen, and can be described by the dissociation constant, Kd, ​​i.e., the ratio of the bound state to the unbound state relative to the receptor ligand system. In addition, the fewer different cancer and / or tumor antigens or their peptide antigens that a heterologous TCR or CAR can bind to, the greater its binding specificity. According to the present invention, a heterologous TCR or CAR can bind to 10, 9, 8, 7, 6, 5, 4, 3, or fewer than 2 different cancer and / or tumor antigens or their peptide antigens.

[0025] According to the present invention, a heterologous TCR or CAR is, for example, MAGE A4 or its antigenic peptide, for example, human MAGE A4 or MAGE of Sequence ID No. 1. A4 or its antigenic peptide, or an antigenic peptide containing or consisting of SEQ ID NO: 2, GVYDGREHTV, is optionally measured using surface plasmon resonance at optionally 25°C and optionally at pH 6.5-6.9 or 7.0-7.5, with concentrations of 0.01 μM-100 μM, 0.01 μM-50 μM, 0.01 μM-20 μM, 0.05 μM-20 μM, or 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1 μM, 0.15 μM, 0.2 μM, 0.25 μM, 0.3 μM, 0.35 μM, 0.4 μM, 0.45 μM, 0.5 μM, 0.55 μM, 0.6 μM, 0.65 μM, 0 .7μM, 0.75μM, 0.8μM, 0.85μM, 0.9μM, 0.95μM, 1.0μM, 1.5μM, 2.0μM, 2.5μM, 3.0μM, 3.5μM , 4.0μM, 4.5μM, 5.0μM, 5.5μM, 6.0μM, 6.5μM, 7.0μM, 7.5μM, 8.0μM, 8.5μM, 9.0μM, 9.5μM, It can bind with dissociation constants of 10.0 μM; or 10 μM to 1000 μM, 10 μM to 500 μM, 50 μM to 500 μM, or 10, 20, 30, 40, 50, 60, 70, 80, 90, 100 μM, 150 μM, 200 μM, 250 μM, 300 μM, 350 μM, 400 μM, 450 μM, and 500 μM. Dissociation constant, K D or koff / k on The dissociation rate constant k off , and the coupling rate constant k on This can be determined by experimental measurement. The TCR dissociation constant can be measured using a soluble form of TCR, which includes a TCRα chain variable domain and a TCRβ chain variable domain. Therefore, heterologous TCRs or CARs for use according to the present invention can optionally bind to HLA presenting GVYDGREHTV, SEQ ID NO: 2, with dissociation constants of, for example, 0.01 μM to 100 μM, for example, 50 μM, 100 μM, 200 μM, 500 μM, preferably 0.05 μM to 20.0 μM, with a complex of peptide-presenting molecules, e.g., HLA, e.g., HLA-A*02 or HLA-A*0201, or alternatively, without presentation in a complex with a peptide-presenting molecule.

[0026] According to the present invention, modified immune-responsive cells, for example, modified T cells, may optionally contain heterologous TCRs or CARs that can bind, specifically bind, and / or bind with high affinity to cancer and / or tumor antigens or their peptide antigens, which are associated with a cancerous condition and / or presented by tumors of cancer cells or tissues; optionally, cancer and / or tumor antigens or their peptide antigens may be recognized by heterologous TCRs or CARs without presentation in a peptide-presenting molecule, for example, HLA, for example, HLA-A*02 or HLA-A*0201 (i.e., MAGE-A4 or its peptide antigen, or the MAGE A4 peptide antigen including GVYDGREHTV, SEQ ID NO: 2, may be presented independently of the peptide-presenting molecule). For example, cancer and / or tumor antigens or their peptide antigens are MAGE A4, or its antigenic peptide, such as human MAGE A4 or MAGE A4 or its antigenic peptide of SEQ ID NO: 1, or antigenic peptides containing or consisting of SEQ ID NO: 2, GVYDGREHTV.

[0027] According to the present invention, heterologous T cell receptors (TCRs) or CARs, and modified immune-responsive cells containing heterologous T cell receptors (TCRs) or CARs, may have binding properties to cancer and / or tumor antigens or their peptide antigens on the surface of endogenously expressed tumor cells, optionally independent of the presentation of cell surface antigens as a complex with peptide-presenting or antigen-presenting molecules, such as major histocompatibility complex (MHC) or human leukocyte antigen (HLA) or major histocompatibility complex class-associated protein (MR) 1. For example, the cancer and / or tumor antigen or its peptide antigen is an antigenic peptide containing or comprising MAGE A4 or its antigenic peptide, such as human MAGE A4 or MAGE A4 of SEQ ID NO: 1 or SEQ ID NO: 2, GVYDGREHTV.

[0028] According to the present invention, TCR or CAR binding may optionally be specific to one cancer and / or tumor antigen, such as human MAGE A4 or MAGE A4 of SEQ ID NO: 1 or its antigenic peptide, or an antigenic peptide containing or comprising SEQ ID NO: 2, GVYDGREHTV, compared to closely related cancer and / or tumor antigen or peptide antigen sequences. Closely related cancer and / or tumor antigen or peptide antigen sequences may have similar or identical lengths and / or similar or identical numbers of amino acid residues. Closely related peptide antigen sequences may share 50, 60, 70, or 80-90% identity, preferably 80-90% identity, and / or differ by 1, 2, 3, or 4 amino acid residues. Closely related peptide sequences may be derived from polypeptide sequences containing or comprising the sequence GVYDGREHTV, SEQ ID NO: 2.

[0029] Binding affinity can be determined by equilibrium methods (e.g., enzyme-linked immunosorbent assay (ELISA) or radioimmunoassay (RIA)) or kinetics (e.g., BIACORE® analysis). Binding strength is, for example, the sum of the strengths of the binding affinity between two molecules at multiple sites, taking into account the valence of the interaction. According to the present invention, immune-responsive cells can exhibit improved affinity and / or binding strength to cancer and / or tumor antigens or their peptide antigens, or cancer and / or tumor antigens or their peptide antigens presented by tumors in cancer cells or tissues and recognized by the heterologous TCR or CAR, compared to immune-responsive cells lacking a heterologous TCR or CAR or having a different heterologous TCR or CAR.

[0030] Selective binding TCR / CAR According to the present invention, heterologous TCRs or CARs can optionally selectively bind to cancer and / or tumor antigens or their peptide antigens that are associated with a cancerous condition and / or presented by tumor cells or tissues; optionally, the cancer and / or tumor antigens or their peptide antigens are preferably expressed by tumor cells or cancer cells or tissues, optionally, peptide-presenting molecules, such as major histocompatibility complexes (MHC) or HLA, optionally class I or II is recognized in a complex with, for example, HLA-A2, or selected from HLA-A*02, HLA-A*02:01, HLA-A*02:02, HLA-A*02:03, HLA-A*02:04, HLA-A*02:06, HLA-A*02:642, or HLA-A*02:07, preferably with HLA-A*02:01 or HLA-A*02; alternatively, recognized by a heterologous TCR or CAR without presentation in a peptide-presenting molecule or complex with HLA. Preferably, the malignant condition is cancer and / or tumor of the head and neck or lung.

[0031] Selective binding means that a heterologous TCR or CAR binds with a high affinity to a certain cancer and / or tumor antigen or its peptide antigen as compared to another antigen. Selective binding is represented by the equilibrium constant for the substitution of one ligand antigen by another ligand antigen in a complex with a heterologous TCR or CAR.

[0032] According to the present invention, the cancerous condition can be a cancer and / or tumor of the head and neck or the lung.

[0033] Specific / selective binding TCR / CAR According to the present invention, heterologous TCR or CAR binding is selective and / or specific for a cancer and / or tumor antigen or its peptide antigen that can be MAGE-A4 or its peptide antigen. Preferably, the tumor antigen is MAGE-A4 or its peptide antigen. Preferably, the cancer and / or tumor antigen peptide contains or has the amino acid sequence GVYDGREHTV, SEQ ID NO: 2. According to the present invention, a heterologous TCR or CAR can bind and / or specifically bind and / or selectively bind to a peptide presenting molecule, such as HLA, that presents or displays a cancer and / or tumor antigen or its peptide antigen, i.e., a peptide fragment (pHLA) of a cancer and / or tumor antigen, where HLA corresponds to MHC class I (A, B, and C) all of which are HLA class 1 or its specific alleles, or HLA corresponds to MHC class II (DP, DM, DO, DQ, and DR) or its specific alleles, preferably, HLA is class 1, preferably, the allele is HLA-A2 or HLA-A * 02 or HLA-A2+ or HLA-A * 02 positive HLA, preferably HLA- * 0201. Alternatively, a heterologous TCR or CAR can bind and / or specifically bind and / or selectively bind to a cancer and / or tumor antigen or its peptide antigen that is not presented or displayed by HLA.

[0034] Preferably, the heterologous TCR or CAR is not spontaneously expressed by immune-responsive cells (i.e., the TCR or CAR is exogenous or heterologous). The heterologous TCR may include an αβTCR heterodimer. The heterologous TCR or CAR may be recombinant, synthetic, or artificial TCR or CAR, i.e., a CAR or TCR that does not exist in nature. For example, the heterologous TCR may be genetically engineered to increase its affinity or binding affinity to specific cancer and / or tumor antigens or their peptide antigens (i.e., affinity-enhanced TCR or specific peptide-enhanced affinity receptor (SPEAR) TCR). The affinity-enhanced TCR or (SPEAR) TCR may include one or more mutations in a naturally occurring TCR, for example, one or more mutations in the hypervariable complementarity-determining regions (CDRs) of the variable regions of the TCR α and β chains. These mutations, optionally expressed by tumors and / or cancer cells and / or tissues, can increase the affinity of TCRs to MHCs that present peptide fragments of cancer and / or tumor antigens or their peptide antigens, or to MHCs that present peptide fragments of cancer and / or tumor antigens. A preferred method for generating affinity-enhanced or mature TCRs is screening libraries of TCR mutants using phage or yeast displays, which is well known in the art (see, for example, Robbins et al J Immunol (2008) 180(9):6116; San Miguel et al (2015) Cancer Cell 28 (3) 281-283; Schmitt et al (2013) Blood 122 348-256; Jiang et al (2015) Cancer Discovery 5 901). Preferred affinity-enhanced TCRs can bind to tumor or cancer cells expressing cancer and / or tumor antigens of the MAGE family, such as MAGE A4 or its peptide antigen, such as the sequence GVYDGREHTV, SEQ ID NO: 2, or a peptide comprising the same sequence.

[0035] According to the present invention, a heterologous TCR may be a MAGE-A4 TCR that may include the α-chain reference amino acid sequence of SEQ ID NO: 5 or a variant thereof and the β-chain reference amino acid sequence of SEQ ID NO: 7 or a variant thereof. The variant may have an amino acid sequence having at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity with respect to the reference amino acid sequence (for example, with respect to either the α-chain reference sequence and / or the β-chain reference sequence). The TCR may be encoded by the α-chain reference nucleotide sequence of SEQ ID NO: 6 or a variant thereof and the β-chain reference nucleotide sequence of SEQ ID NO: 8 or a variant thereof. The mutant may have a nucleotide sequence with at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity with respect to the reference nucleotide sequence (for example, with respect to either the α-chain reference sequence and / or the β-chain reference sequence).

[0036] According to the present invention, the TCR may include a TCRα chain variable domain and a TCRβ chain variable domain. (i) The α-chain variable domain is sequence VSPFSN(αCDR1), amino acids 48-53 of SEQ ID NO: 11 or 5, LTFSEN(αCDR2), amino acids 71-76 of SEQ ID NO: 12 or SEQ ID NO: 5, and CVVSGGTDSWGKLQF(αCDR3), amino acids 111-125 of SEQ ID NO: 13 or SEQ ID NO: 5 Includes a CDR having and / or (ii) The β-chain variable domain is sequence KGHDR(βCDR1), amino acids 46-50 of SEQ ID NO: 14 or SEQ ID NO: 7, SFDVKD(βCDR2), amino acids 68-73 of SEQ ID NO: 15 or SEQ ID NO: 7, and CATSGQGAYEEQFF(βCDR3), amino acids 110-123 of SEQ ID NO: 16 or SEQ ID NO: 7 Includes a CDR having; or Each of these sequences contains at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity, each optionally containing sequences with 100% sequence identity.

[0037] Therefore, a TCR may include one in which the α-chain variable domain contains an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the sequence of amino acid residues 1-136 of SEQ ID NO: 9 or SEQ ID NO: 6, and / or the β-chain variable domain contains an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the sequence of amino acid residues 1-133 of SEQ ID NO: 10 or SEQ ID NO: 7.

[0038] The term “precursor TCR” is used herein to mean a TCR comprising the MAGE-A4 TCRα chain and MAGE-A4 TCRβ chain of Sequence ID No. 5 and 7, respectively. It is desirable to provide a TCR that is mutated or modified relative to the precursor TCR, having equal, equivalent, or higher affinity and / or off-rate to the peptide-HLA complex of the precursor TCR. According to the present invention, a heterologous TCR may have two or more mutations present in the α-chain variable domain and / or β-chain variable domain relative to the precursor TCR, and may be referred to as a “genetically modified TCR” or “mutant TCR”. These mutations can improve the binding affinity and / or specificity and / or selectivity and / or binding affinity to MAGE-A4 or its peptide antigen. In certain embodiments, the α-chain variable domain may contain one, two, three, four, five, six, seven, or eight mutations, e.g., four or eight mutations, and / or the β-chain variable domain may contain one, two, three, four, or five mutations, e.g., five mutations. In some embodiments, the α-chain variable domain of the TCR of the present invention may contain an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid residue sequence of SEQ ID NO: 9. In some embodiments, the β-chain variable domain of the TCR of the present invention may contain an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid residue sequence of SEQ ID NO: 10.

[0039] According to the present invention, the heterologous TCR has an α-chain variable domain in which the amino acid sequence of amino acid residues 1-136 of SEQ ID NO: 9 or SEQ ID NO: 5, or in which amino acid residues 1-47, 54-70, 77-110 and 126-136 are at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% of the sequence of amino acid residues 1-47, 54-70, 77-110, and 126-136 of SEQ ID NO: 9. It may contain a TCR having the same identity as and / or amino acid residues 48-53, 71-76, and 111-125, respectively, in which CDR1, CDR2, and CDR3 have at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity with the sequences of CDR1, CDR2, and CDR3 in sequence number 9.

[0040] According to the present invention, the TCR, in the α-chain variable domain, (i) The amino acid residues 1-47 may (a) have at least 70%, 75%, 80%, 85%, 90%, or 95% identity with the sequence of amino acid residues 1-47 of SEQ ID NO: 9, or (b) have one, two, or three amino acid residues inserted into or deleted from residues 1-47 of SEQ ID NO: 9. (ii) Amino acid residues 48-53 are amino acids 48-53 of VSPFSN, CDR1, SEQ ID NO: 11 or SEQ ID NO: 9, (iii) The amino acid residues 54-70 may (a) have at least 70%, 75%, 80%, 85%, 90%, or 95% identity with the sequence of amino acid residues 54-70 of SEQ ID NO: 9, or (b) have one, two, or three amino acid residues that are inserted into or deleted from the sequence of amino acid residues 54-70 of SEQ ID NO: 9. (iv) Amino acid residues 71-76 may be amino acids 71-76 of LTFSEN, CDR2, SEQ ID NO: 12, or SEQ ID NO: 9, (v) The amino acid residues 77-110 may have at least 70%, 75%, 80%, 85%, 90%, or 95% identity with the sequence of amino acid residues 77-110 of SEQ ID NO: 9, or may have one, two, or three insertions, deletions, or substitutions with respect to the sequence of amino acid residues 77-110 of SEQ ID NO: 9. (vi) Amino acids 111-125 may be CVVSGGTDSWGKLQF, CDR3, SEQ ID NO: 13 or SEQ ID NO: 9, (vii) The amino acid residues 126-136 may have at least 70%, 75%, 80%, 85%, 90%, or 95% identity with the sequence of amino acid residues 126-136 of SEQ ID NO: 9, or may have one, two, or three insertions, deletions, or substitutions with respect to the sequence of amino acid residues 126-136 of SEQ ID NO: 9. The sequence may contain TCRs.

[0041] According to the present invention, a TCR may include a β-chain variable domain that contains an amino acid sequence in which amino acid residues 1-45, 51-67, 74-109, and 124-133 of the β-chain variable domain have at least 70%, 75%, 80%, 85%, 90%, or 95% identity with amino acid residues 1-45, 51-67, 74-109, and 124-133 of the β-chain variable domain, and amino acid sequences in which amino acid residues 46-50, 68-73, and 110-123 have at least 70%, 75%, 80%, 85%, 90%, or 95% identity with amino acid residues 46-50, 68-73, and 110-123 of the β-chain variable domain, and amino acid sequences in which amino acid residues 46-50, 68-73, and 110-123 have at least 70%, 75%, 80%, 85%, 90%, or 95% identity with the sequences of CDR1, CDR2, and CDR3, respectively.

[0042] According to the present invention, the TCR, in the β-chain variable domain, (i) The amino acid residues 1-45 may (a) have at least 70%, 75%, 80%, 85%, 90%, or 95% identity with the sequence of amino acid residues 1-45 of SEQ ID NO: 10, or (b) have one, two, or three amino acid residues that are inserted into or deleted from residues 1-45 of SEQ ID NO: 10. (ii) Amino acid residues 46-50 are amino acids 46-50 of KGHDR, CDR1, SEQ ID NO: 14, or SEQ ID NO: 10, (iii) The amino acid residues 51-67 may (a) have at least 70%, 75%, 80%, 85%, 90%, or 95% identity with the sequence of amino acid residues 51-67 of SEQ ID NO: 10, or (b) have one, two, or three amino acid residues that are inserted into or deleted from the sequence of amino acid residues 51-67 of SEQ ID NO: 10. (iv) Amino acid residues 68-73 may be amino acids 68-73 of SFDVKD, CDR2, SEQ ID NO: 15 or SEQ ID NO: 10, (v) The amino acid residues 74-109 may have at least 70%, 75%, 80%, 85%, 90%, or 95% identity with the sequence of amino acid residues 74-109 of SEQ ID NO: 10, or may have one, two, or three insertions, deletions, or substitutions with respect to the sequence of amino acid residues 74-109 of SEQ ID NO: 10. (vi) Amino acids 110-123 may be CATSGQGAYEEQFF, CDR3, SEQ ID NO: 16 or SEQ ID NO: 10, (vii) The amino acid residues 124-133 may have at least 70%, 75%, 80%, 85%, 90%, or 95% identity with the sequence of amino acid residues 124-133 of SEQ ID NO: 10, or may have one, two, or three insertions, deletions, or substitutions with respect to the sequence of amino acid residues 124-133 of SEQ ID NO: 10. The sequence may contain TCRs.

[0043] According to the present invention, the TCR may include a TCR comprising the α-chain variable domain of SEQ ID NO: 9 and / or the β-chain variable domain of SEQ ID NO: 10. According to the present invention, the TCR may include a TCR comprising the α-chain of SEQ ID NO: 5 and / or the β-chain of SEQ ID NO: 7.

[0044] The sequence identity of amino acids and nucleotides is generally defined by referring to the GAP algorithm (GCG Wisconsin Package®, Accelrys, San Diego, CA). GAP uses the Needleman & Wunsch algorithm (J. Mol. Biol. (48): 444-453 (1970)) to align two complete sequences to maximize the number of matches and minimize the number of gaps. Generally, default parameters are used, with a gap creation penalty of 12 and a gap elongation penalty of 4. While the use of GAP is preferred, other algorithms, such as BLAST, psiBLAST, or TBLASTN (which uses the method described in Altschul et al. (1990) J. Mol. Biol. 215: 405-410), FASTA (which uses the method described in Pearson and Lipman (1988) PNAS USA 85: 2444-2448), or the Smith-Waterman algorithm (Smith and Waterman (1981) J. Mol Biol. 147: 195-197), can also be used, generally employing their default parameters.

[0045] A specific amino acid sequence variant may differ from the reference sequence by the insertion, addition, substitution, or deletion of one, two, three, four, five to ten, ten to twenty, or twenty to thirty amino acids. In some embodiments, the variant sequence may include a reference sequence in which one, two, three, four, five, six, seven, eight, nine, ten, or more residues are inserted, deleted, or substituted. For example, up to 15, up to 20, up to 30, or up to 40 residues may be inserted, deleted, or substituted.

[0046] In some preferred embodiments, the mutant may differ from the reference sequence by one, two, three, four, five, six, seven, eight, nine, ten or more conservative substitutions. Conservative substitutions involve replacing one amino acid with another amino acid having similar properties. For example, an aliphatic residue can be replaced with another aliphatic residue, a nonpolar residue with another nonpolar residue, an acidic residue with another acidic residue, a basic residue with another basic residue, a polar residue with another polar residue, or an aromatic residue with another aromatic residue. Conservative substitutions may occur, for example, between amino acids in the following groups: Alanine and glycine; Glutamic acid, aspartic acid, glutamine, and asparagine Arginine and lysine; Asparagine, glutamine, glutamic acid, and aspartic acid Isoleucine, leucine, and valine; Phenylalanine, tyrosine, and tryptophan Serine, threonine, and cysteine.

[0047] CD8α coreceptor According to the present invention, modified immune-responsive cells expressing or presenting a heterologous TCR or CAR may further express or present a heterologous coreceptor (for example, cells may be transduced or manipulated, for example by gene knock-in, to contain a nucleic acid sequence encoding the coreceptor). The heterologous coreceptor may be a CD8 coreceptor. The CD8 coreceptor may contain a dimer or pair of CD8 chains including CD8-α and CD8-β chains or CD8-α and CD8-α chains. Preferably, the CD8 coreceptor is a CD8αα coreceptor containing CD8-α and CD8-α chains. The CD8α coreceptor may contain an amino acid sequence with at least 80% identity to SEQ ID NO: 3, SEQ ID NO: 3 or a variant thereof. The CD8α coreceptor may be a homodimer.

[0048] The CD8 coreceptor binds to class 1 MHC and enhances TCR signaling. According to the present invention, the CD8 coreceptor may have the reference amino acid sequence of SEQ ID NO: 3, or may be a variant thereof. The variant may have an amino acid sequence having at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity with the reference amino acid sequence of SEQ ID NO: 3. The CD8 coreceptor may be encoded by the reference nucleotide sequence of SEQ ID NO: 4, or may be a variant thereof. The mutant may have a nucleotide sequence that has at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity with respect to the reference nucleotide sequence, SEQ ID NO: 4.

[0049] According to the present invention, heterologous CD8 coreceptors have a sequence in the Ig-like V-type domain; (i) Amino acids 45-53 of VLLSNPTSG, CDR1, SEQ ID NO: 17, or SEQ ID NO: 3, (ii) YLSQNKPK, CDR2, amino acids 72-79 of SEQ ID NO: 18 or SEQ ID NO: 3, (iii) LSNSIM, CDR3, amino acids 80-117 of SEQ ID NO: 19 or SEQ ID NO: 3, Or sequences having at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity. It may include CD8 coreceptors, including CDRs that have the following properties.

[0050] According to the present invention, a heterologous CD8 coreceptor may include a CD8 coreceptor that contains an amino acid sequence in which residues 22-135 of the amino acid sequence of SEQ ID NO: 3, or its amino acid residues 22-44, 54-71, 80-117, and 124-135 have at least 70%, 75%, 80%, 85%, 90%, or 95% identity with the sequences of CDR1, CDR2, and CDR3, respectively, and amino acid residues 45-53, 72-79, and 118-123 have at least 70%, 75%, 80%, 85%, 90%, or 95% identity with the sequences of amino acid residues 45-53, 72-79, and 118-123, respectively, or is contained in an Ig-like V-type domain.

[0051] According to the present invention, the CD8 coreceptor is (i) The amino acid residues 22-44 may (a) have at least 70%, 75%, 80%, 85%, 90%, or 95% identity with the sequence of amino acid residues 22-44 of SEQ ID NO: 3, or (b) have one, two, or three amino acid residues inserted into or deleted from residues 22-44 of SEQ ID NO: 3. (ii) Amino acid residues 45-53 are amino acids 45-53 of VLLSNPTSG, SEQ ID NO: 17, CDR1, or SEQ ID NO: 3, (iii) The amino acid residues 54-71 may (a) have at least 70%, 75%, 80%, 85%, 90%, or 95% identity with the sequence of amino acid residues 54-71 of SEQ ID NO: 3, or (b) have one, two, or three amino acid residues that are inserted into or deleted from the sequence of amino acid residues 54-71 of SEQ ID NO: 3. (iv) Amino acid residues 72-79 may be amino acids 72-79 of YLSQNKPK, CDR2, SEQ ID NO: 18 or SEQ ID NO: 3, (v) The amino acid residues 80-117 may have at least 70%, 75%, 80%, 85%, 90%, or 95% identity with the sequence of amino acid residues 80-117 of SEQ ID NO: 3, or may have one, two, or three insertions, deletions, or substitutions with respect to the sequence of amino acid residues 80-117 of SEQ ID NO: 3. (vi) Amino acids 118-123 may be amino acids 80-117 of LSNSIM, CDR3, SEQ ID NO: 19 or SEQ ID NO: 3, (vii) The amino acid residues 124-135 may have at least 70%, 75%, 80%, 85%, 90%, or 95% identity with the sequence of amino acid residues 124-135 of SEQ ID NO: 3, or may have one, two, or three insertions, deletions, or substitutions with respect to the sequence of amino acid residues 124-135 of SEQ ID NO: 3. The CD8 coreceptor may contain the above sequence, or the above sequence in the Ig-like V domain.

[0052] Modified immune-responsive cells expressing heterologous CD8 coreceptors may exhibit improved affinity and / or binding and / or improved T cell activation, as can be determined by assays disclosed herein, in response to or in response to stimulation by antigenic peptides, tumor or cancer antigens, when optionally presented on HLA, compared with modified immune-responsive cells that do not express heterologous CD8 coreceptors. Heterologous CD8 on modified immune-responsive cells may interact with or specifically bind to MHC, which may be class I or class II, preferably class I major histocompatibility complex (MHC), HLA-I molecule, or accompanied by MHC class I HLA-A / B2M dimers, and preferably CD8-α interacts with the α3 portion (residues 223-229) of class I MHC, preferably via the IgV-like domain of CD8. Therefore, heterologous CD8 improves the TCR binding of immune-responsive cells to HLA pMHCI or pHLA, or to HLA and / or antigenic peptides presented by them, on the surface of antigen-presenting cells, dendritic cells, and / or tumor or cancer cells, or tumor or cancer tissue, compared to immune-responsive cells lacking heterologous CD8. Therefore, heterologous CD8 improves the off-rate (k) of cell (TCR) / peptide-major histocompatibility complex class I (pMHCI) interactions of immune-responsive cells on the surface of antigen-presenting cells, dendritic cells, and / or tumor or cancer cells, or tumor or cancer tissue, compared to cells lacking heterologous CD8. off ), and therefore its half-life can be improved or increased, thereby also providing improved ligation affinity and / or binding affinity. Heterogeneous CD8 can improve the organization of TCRs on the surface of immune-responsive cells, thereby enabling coordination in pHLA binding and providing improved therapeutic binding affinity. Thus, heterogeneous CD8 coreceptor-modified immune-responsive cells can bind to or interact with LCK (lymphocyte-specific protein tyrosine kinase) in a zinc-dependent manner, thereby resulting in the activation of transcription factors such as NFAT, NF-κB, and AP-1.

[0053] According to the present invention, modified immune-responsive cells may, when optionally presented by cancer cells or tumor tissue, have improved or increased CD40L expression, cytokine production, cytotoxic activity, induction of dendritic cell maturation, or induction of dendritic cell cytokine production in response to cancer and / or tumor antigens or their peptide antigens, compared to immune-responsive cells lacking heterologous CD8 coreceptors.

[0054] treatment method head and neck cancer According to the present invention, cancer can be a cancer, carcinoma, or tumor of the head and neck, which may be primary, secondary, recurrent, metastatic, or progressive. Preferably, head and neck cancer can be selected from any one of head and neck cancer, head and neck squamous cell carcinoma (HNSCC), oral cancer, oropharyngeal cancer, hypopharyngeal cancer, pharyngeal cancer, laryngeal cancer, tonsil cancer, tongue cancer, soft palate cancer, or pharyngeal cancer. Thus, cancer can be an oral cancer or carcinoma, including squamous cell carcinoma of the inside of the lips, lips, tongue, floor of the mouth, gingiva, or hard palate, or a cancer or carcinoma of the oral cavity.

[0055] Therefore, cancer can be sinus cancer or carcinoma or squamous cell carcinoma of the nose, including the sinuses, and nasal cavity cancer affecting the nasal cavity, as well as sinus cancer or nasopharyngeal cancer, including cancer occurring in the nasopharynx, nasal cavity and Eustachian tube and upper pharynx, and cancer can also be lymphoepithelioma.

[0056] Therefore, cancer can be pharyngeal cancer, such as oropharyngeal cancer, oropharyngeal squamous cell carcinoma, HPV-positive oropharyngeal cancer, or HPV-positive oropharyngeal squamous cell carcinoma, and optionally, squamous cell carcinoma is of the oropharynx or pharynx, including the soft palate, base of the tongue and tonsils.

[0057] Therefore, the cancer may be hypopharyngeal cancer, including cancer of the piriform sinus, posterior pharyngeal wall, or postcricocele, or its metastasis to the perilaryngeal lymphatic network.

[0058] Therefore, cancer can be laryngeal cancer, including laryngeal cancer, glottic cancer, supraglottic cancer, or subglottic cancer.

[0059] Therefore, cancer can be tracheal cancer, salivary gland teratoma cancer or squamous cell carcinoma, adenocarcinoma of the upper respiratory tract and gastrointestinal tract, adenoid cystic carcinoma, and mucoepidermoid carcinoma or melanoma or lymphoma.

[0060] Therefore, the cancer may be metastatic head and neck cancer that has spread to the adrenal glands, skin, liver, pleura, bones, lungs, or mediastinal lymph nodes.

[0061] Therefore, head and neck cancers, carcinomas, or tumors may express MAGE protein, its peptide, antigen, or peptide antigen, optionally the MAGE-A4 protein, its peptide, antigen, or peptide antigen described herein. According to the present invention, the cancer may optionally be recurrent or metastatic HNSCC having disease progression after chemotherapy including a platinum-based agent, and optionally expressing the MAGE-A4 protein, its peptide, antigen, or peptide antigen described herein (e.g., MAGE A4 peptide antigen including GVYDGREHTV, SEQ ID NO: 2).

[0062] lung cancer According to the present invention, the cancer may be primary, secondary, recurrent, metastatic, or progressive lung cancer, carcinoma, or tumor. Preferably, the lung cancer, carcinoma, or tumor is selected from any of the following: large cell carcinoma or large cell carcinoma of the lung, small cell lung cancer or small cell lung carcinoma (SCLC) of the lung, primary and secondary bronchial SCLC, non-small cell lung cancer or non-small cell lung carcinoma (NSCLC), metastatic or progressive NSCLC, squamous cell NSCLC, adenosquamous cell NSCLC, adenocarcinoma NSCLC, large cell NSCLC, adenocarcinoma, bronchioloalveolar carcinoma, pulmonary intestinal adenocarcinoma, squamous cell carcinoma, adenosquamous cell carcinoma, carcinoid tumor, bronchial adenocarcinoma, or sarcomatoid carcinoma.

[0063] Therefore, the cancer may be metastatic lung cancer that has spread to the brain, bones, liver, or adrenal glands. Therefore, the lung cancer may be lung cancer that has invaded the diaphragm, mediastinum, heart, superior vena cava, inferior vena cava, pulmonary artery, pulmonary vein, aorta, trachea, tracheal bifurcation, recurrent laryngeal nerve, esophagus, spine, or vertebral bodies.

[0064] Therefore, lung cancer, carcinoma, or tumor expresses MAGE protein, its peptide, antigen, or peptide antigen, optionally MAGE-A4 protein, its peptide, antigen, or peptide antigen. According to the present invention, cancer may optionally have disease progression after chemotherapy including a platinum-based agent, and optionally express MAGE-A4 protein, its peptide, antigen, or peptide antigen as described herein (e.g., MAGE A4 peptide antigen including GVYDGREHTV, SEQ ID NO: 2).

[0065] standard treatment The standard treatment for lung cancer or tumor may be platinum-based systemic chemotherapy, which can be selected from chemotherapy with cisplatin or carboplatin. Alternatively, the standard treatment for lung cancer or tumor may be selected from one of the following: ifosfamide, mitomycin C, vindesine, vinblastine, etoposide, gemcitabine, paclitaxel, docetaxel, vinorelbine, pemetrexed, erlotinib, gefitinib, or bevacizumab.

[0066] Standard treatment for head and neck cancer or tumors may be platinum-based systemic chemotherapy selected from cisplatin or carboplatin chemotherapy, or platinum-based combination chemotherapy selected from cisplatin or carboplatin combinations with one of the following: cetuximab, fluorouracil, or taxane, such as paclitaxel (Taxol) or docetaxel. Alternatively, standard treatment for head and neck cancer or tumors may be selected from combinations of one of the following PD-1 antibodies, such as pembrolizumab or nivolumab, cetuximab, or cetuximab, with one of the following: fluorouracil, methotrexate, cisplatin, carboplatin, or taxane, such as paclitaxel (Taxol) or docetaxel.

[0067] Accordingly, the present invention and the methods, treatments, and uses thereof provide a reduction in MAGE-A4 expression or concentration in the subject compared to placebo administration, or compared to no treatment, or compared to prior treatment, or compared to treatment including standard treatment.

[0068] Disease biomarkers The present invention, as well as the methods, treatments, and uses and / or kits of the present invention, provide treatment, prevention, or delay of progression of cancer and / or tumors of the head and neck or lung in a subject, as determined by changes in the expression or concentration of disease biomarkers in the subject compared to the expression or concentration of disease biomarkers before treatment, compared to placebo administration or no treatment, or compared to treatment including standard treatment.

[0069] Changes in disease biomarker levels from baseline (pre-treatment) correlate with treatment response and correspond to the therapeutic effect and response of cancer and / or tumor treatment.

[0070] Disease biomarkers for head and neck cancer or tumors include: expression or mRNA expression of CXC chemokine receptor 2 (CXCR2), expression or mRNA expression of CC chemokine receptor 4 (CCR4), expression or mRNA expression of CC chemokine receptor 7 (CCR7), expression or concentration of human papillomavirus (HPV) viral proteins, e.g., expression of HPV16 or 18 oncoplastic proteins, e.g., E6 or E7 oncoplastic proteins, detection of loss of heterozygosity in tumor cell-derived DNA, presence or absence of hypermethylation of cytosine-phosphate-guanine (CpG) rich promoter regions. The following may be selected from one or more of the following: the expression of metalloproteinases, e.g., MMP-1 or gelatinase MMP-2 or MMP-9 or stromelycin, MMP-3 and MMP-10, the level or expression of interleukins IL-6 and IL-8, the expression of MAGE-A1, 2, 3, 4, 5, and 6, the concentration or expression level of cytokeratin (e.g., CK6, 16, or 17) or actin or myosin, the overexpression of eukaryotic translation factor 4E (eIF4E), e.g., the level of mutation in DNA repair genes of the nucleotide excision repair (NER) group.

[0071] Disease biomarkers for lung cancer or tumors may be selected from one or more of the following: presence or level of anaplastic lymphoma kinase (ALK) translocation, presence or level of epidermal growth factor receptor (EGFR) mutation, presence or level of Kirsten rat sarcoma virus oncogene homolog (KRAS) mutation, expression of human epidermal growth factor receptor-2 (HER2 / neu), presence or level of B-Raf oncogene serine / threonine kinase (BRAF) mutation, presence or level of C-KIT oncogene mutation, expression of MAGE-A1, 2, 3, 4, 5, 6, presence or level of Janus kinase 2 (JAK2) mutation, expression levels of Programmed Cell Death 1 (PD-1) and Programmed Cell Death-Ligand 1 / 2 (PD-L1, PD-L2), expression levels of fibroblast growth factor receptor (FGFR), and expression levels of hepatocyte growth factor (HGF). Further disease biomarkers for lung cancer may include EML4-ALK tyrosine kinase fusion, epigenetic changes such as altered DNA methylation, histone tail modifications, or microRNA regulation leading to tumor suppressor inactivation, as well as mutations and amplifications of c-MET, NKX2-1, LKB1, PIK3CA, and BRAF.

[0072] Other possible disease biomarkers include circulating tumor cells (CTCs), cell-free DNA, microRNA, cell-free RNA, and cell-derived vesicles, such as exosomes that can circulate in biological samples as described herein. CTCs are disseminated tumor cells that circulate in the bloodstream, and their presence is clinically associated with cancer or progressive or metastatic disease.

[0073] According to the present invention, disease biomarkers can be measured in a biological sample of a subject, for example, as described herein.

[0074] biological samples A biological sample may be any subject or patient fluid that may contain disease biomarkers or cells or genetic material from cancer or tumors (e.g., cancers and / or tumors of the head and neck or lungs), such as blood, serum, plasma, urine, tissue, cells, cell cultures, saliva, sputum, cerebrospinal fluid, lavage fluid or liquid from the lungs, nose, bronchi, bronchoalveolars, esophagus, stomach or gastrointestinal tract, circulating tumor cells (CTCs), cell-free DNA, microRNA, cell-free RNA and cell-derived vesicles, such as exosomes, or peripheral blood samples from a patient or subject with cancer. CTCs are disseminated tumor cells circulating in the bloodstream, either as single cells or, less frequently, as cell clusters, originating from either a primary tumor or metastases. The presence of CTCs, like other disease biomarkers, is clinically associated with tumors and / or cancer, progressive or metastatic disease. For example, in both head and neck cancer and lung cancer, disease biomarkers or biomarkers or antibodies against MAGE-A4 may be detected in biological samples, such as body fluids, such as serum or saliva / sputum, as biomarkers for cancer and / or tumor and / or tissue expressing MAGE-A4.

[0075] Therapeutic effect Analysis of serum cytokines and soluble factors, and T cell infiltration of tumors The present invention, as well as the methods, treatments, and uses thereof, provide an increase in serum cytokine and / or interferon levels or concentrations in a subject compared to pre-treatment serum cytokine and / or interferon levels or concentrations, or compared to treatments including placebo, no treatment, or standard treatment.

[0076] Accordingly, the present invention and its methods, treatments and uses result in improved or enhanced cancer and / or tumor immunogenicity, as measured, for example, by its ability to induce an immune response in response to cancer and / or tumors or cancer and / or tumor antigens, for example, by increased secretion of cytokines and / or interferons, increased T cell proliferation, increased antigen responsiveness, target cell death, T cell activation, CD28 signaling, tumor T cell infiltration, and the ability to recognize and bind antigens presented by dendritic cells, compared to such levels before treatment or intervention, or compared to placebo, or compared to no treatment, or compared to treatment including standard treatment, for example, at least 10%, alternatively 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 120%, 150%, 200%, or more enhancement.

[0077] The effectiveness of cancer immunotherapy depends on tumor infiltration by activated tumor-specific T cells. The activity of these T cells is then influenced by the presence of an immunosuppressive environment (e.g., regulatory T cells) within the tumor. Therefore, direct evaluation of the "immune landscape" within the tumor is of great value in monitoring the effectiveness of T cell immunotherapy, which can be quantified by tumor biopsy to assess the immune status of the tumor before and after T cell injection. Accordingly, the present invention provides improved T cell infiltration and / or reduction of T cell suppressors in tumors, as determined by, for example, a decrease in the levels of T-reg, myeloid-derived suppressor cells (MDSCs), PD-L1 protein expression, serum cytokine levels selected from CCL3, IL8, IL1β, CXCL10, or sIL2Rα, or suppressor receptor levels selected from PD-1, CTLA-4, TIM-3, LAG-3, BTLA, or TIGIT, compared to prior treatment or no treatment, or compared to treatment including standard treatment. Alternatively, compared to prior treatment or no treatment, or to treatment including standard treatment as described above in this specification, interferon-γ, interleukin-6, interleukin-10, cytokine production, e.g., IL-2, TNF-α, IFN-γ and granzyme B, or innate immune cells, e.g., NK cells, adaptive immune cells (CD4) + and CD8 + This may be determined by an increase in the level of ), or, for example, by an improvement in T cell proliferation as determined by the Ki67 expression level.

[0078] Tumor size and tumor volume The present invention, as well as the methods, treatments, and uses thereof, provide an improved or enhanced level of tumor number or tumor volume, which reduces tumor growth or tumor growth rate or maintains tumor size after discontinuation of treatment, compared to pre-treatment, placebo, or treatment including no treatment or standard treatment, preferably by at least 10%, alternatively 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 120%, 150%, or 200% or more, as determined by measurement of tumor size or tumor number, compared to pre-treatment, placebo, or treatment including no treatment or standard treatment. Preferably, the improved or enhanced level or response may be a sustained improved or enhanced level or response and / or may have a duration of at least the same as the treatment duration, or at least 1.5, 2.0, 2.5, or 3.0 times the length of the treatment duration. Such improvements or enhanced levels or responses may be determined from RECIST1.1 measurements [EA Eisenhauer., et.al., EUROPEAN JOURNAL OF CANCER 45 (2009) 228-247], or from tumor biopsy or fluid biopsy (plasma from peripheral blood) to determine tumor-associated circulating free DNA (cfDNA) or exosomes (sources of stable mRNA). Exosomes (produced by all cells, including tumor cells and immune cells) and cfDNA (produced by dying tumor cells) may be used to monitor both tumor burden and immune response. Analysis of exosomes and cfDNA may allow for (a) estimation of overall tumor burden and genetic profiling (including MAGE-A4 mRNA expression or mutation profiling) from exosomes and cfDNA, and (b) systematic evaluation of immune response (gene expression by cytotoxic and regulatory immune cells) from exosomes.

[0079] According to the foregoing, standard treatment may be as described above herein for each type of cancer or tumor of the head and neck or lung.

[0080] MAGE-A4 TCR+ cell persistence The present invention, as well as its methods, treatments, and uses, provide improved therapeutic efficacy and improved treatment, prevention, or progression delay in subjects of head and neck cancers and / or tumors or lung cancers and / or tumors, compared to treatments including pretreatment, placebo, no treatment, or standard treatment, when determined, for example, by measuring the persistence of injected manipulated and modified immune-responsive cells expressing or presenting heterologous T cell receptors (TCRs) as described herein. The persistence of injected manipulated and modified immune-responsive cells correlates with therapeutic efficacy and is also a measure of long-term safety. Cell persistence can be determined by qPCR or flow cytometry (FCM). For example, quantification of MAGE-A4 or MAGE-A4+CD8 TCR+ cells by PCR of transgenes from DNA extracted from frozen subject PBMCs can be used as a measure, as can quantification of MAGE-A4 or MAGE-A4+CD8 TCR-expressing cells by FCM from frozen subject PBMCs. The phenotype and activity of T cells can be determined, for example, by the following series of assays: • Phenotypic analysis to determine T cell lineages in cell preparations and subject blood before and after injection. • Quantification of the senescence and activation status of T cells from subject PBMCs. • Quantification of soluble factors reflecting the in vivo function of injected T cells, e.g., MAGE-A4 or MAGE-A4+CD8 TCR+ T cells. • Ex-vivo activity of transdextrins of the subject at various time points to evaluate the potential functionality of those cells before and / or during treatment.

[0081] T cell function The present invention, as well as the methods, treatments, and uses thereof, provide enhancement of T cell function compared to prior treatment, placebo administration, or no treatment, or compared to treatment including standard treatment. Preferably, T cell function is enhanced by at least 10%, alternatively 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 120%, 150%, or 200% or more, as judged by, for example, increased secretion of γ interferon from CD8+ T cells, increased T cell proliferation, increased internal signaling, increased antigen responsiveness, increased secretion of cytokines and / or interferon, increased target cell death, increased T cell activation, increased CD28 signaling, increased ability of T cells to infiltrate tumors, and increased ability to recognize and bind antigens presented to dendritic cells.

[0082] According to the present invention and its methods and uses, tumor immunity or evasion of immune recognition by tumors may be attenuated, resulting in improved tumor recognition and attack by the immune system, thereby treating tumor immunity as measured, for example, by tumor binding, tumor shrinkage, and tumor clearance. Accordingly, the present invention provides a treatment for tumor immunity and / or a treatment for tumor immunity that is enhanced by at least 10%, alternatively 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 120%, 150%, or 200% or more, as measured, for example, by tumor binding, tumor shrinkage, or tumor clearance, compared to prior treatment, placebo administration, or no treatment, or compared to treatment including standard treatment.

[0083] In the context of T cell activity, the term “dysfunction” refers to a state of reduced immune responsiveness to antigen stimulation, including T cell depletion and / or anergy, where T cells can recognize and bind to antigens, e.g., cancer and / or tumor antigens or their peptide antigens, but exhibit reduced effectiveness in the progression of the immune response or in fighting cancer progression and / or tumor growth. Dysfunctioning T cells exhibit impaired ability to translate antigen recognition into downstream T cell effector functions, e.g., proliferation, cytokine and interferon production or target cell death, and / or appear unresponsive or unresponsive to antigen recognition, as is characteristic of T cell dysfunction. “T cell dysfunction” may be associated with or detectable as increased inappropriate T cell signaling via PD-1; reduced ability of T cells to proliferate and / or produce cytokines and / or cytolytic activity; T cell anergy; or tumor immunity.

[0084] T-cell depletion includes a state of T-cell dysfunction due to persistent TCR signaling as part of the response to cancer, which hinders the optimal response to tumors. Depletion can manifest through either cell-specific negative regulatory (co-stimulatory) pathways (e.g., PD-1, PD-1 axis, B7-H3, B7-H4) or extracellular negative regulatory pathways (immunomodulatory cytokines). T-cell depletion is characterized by reduced effector function, persistent expression of inhibitory receptors, and altered transcriptional activity that differs from functional effector T cells or memory T cells. T-cell anergy arises from incomplete signaling via T-cell receptors, often resulting in a state of unresponsiveness to antigen stimulation, even under co-stimulatory conditions, and consequently, such T cells do not undergo clonal expansion and / or acquire effector function.

[0085] Treatment and administration According to the present invention, modified immune-responsive cells can be administered sequentially or intermittently, either as a single dose or multiple doses, as desired.

[0086] Therefore, modified immune-responsive cells can be administered as a single dose or as two or more doses (multiple doses). Modified immune-responsive cells can be administered in any one of the following doses: approximately 500 million to approximately 1 billion cells, approximately 2 billion cells, approximately 3 billion cells, approximately 4 billion cells, approximately 5 billion cells, approximately 6 billion cells, approximately 7 billion cells, approximately 8 billion cells, approximately 9 billion cells, approximately 10 billion cells, approximately 11 billion cells, approximately 12 billion cells, approximately 13 billion cells, approximately 14 billion cells, approximately 15 billion cells, approximately 16 billion cells, approximately 17 billion cells, approximately 18 billion cells, approximately 19 billion cells, approximately 20 billion cells, or approximately 21 billion cells. Modified immune-responsive cells can be administered in doses of approximately 100 million to 200 million cells, 300 million to 400 million cells, 500 million to 600 million cells, 700 million to 800 million cells, or 900 million to 1 billion cells, or optionally, 500 million to 1 billion cells, 2 billion to 5 billion cells, or 6 billion to 10 billion cells.

[0087] According to the present invention, modified immune-responsive cells can be administered intravenously, intramuscularly, subcutaneously, topically, orally, percutaneously, intraperitoneally, intraorbitally, by transplantation, by inhalation, intrathecally, intraventricularly, or intranasally, or by intravenous infusion. Preferably, modified immune-responsive cells can be administered intravenously or by intravenous infusion.

[0088] According to the present invention, modified immune-responsive cells are (a) A single dose in each of one or more medication cycles, (b) One or more doses in each of one or more medication cycles, (c) A single dose on the first day of each of one or more medication cycles, (d) One or more doses in each of one or more medication cycles, including the dose for day one of each of one or more medication cycles, (e) One or more doses in each of one or more medication cycles, in which at least one dose is administered on the first day of each cycle. (f) Single dose It can be administered as such.

[0089] According to the present invention, modified immune-responsive cells can be administered in a dosing cycle that may be 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, or 28 weeks, or 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months (for example, since the previous dose). Therefore, the dosing cycle may be 10-12 weeks, 11-13 weeks, 14-17 weeks, 14-17 weeks, 18-21 weeks, 22-24 weeks, 24-27 weeks, 28-30 weeks, 3 months, 4 months, 5 months, or 6 months (for example, since the previous dose).

[0090] According to the present invention, modified immune-responsive cells are (a) Disease progression following previous administration of modified immune-responsive cells, and / or (b) Treatment may be continued, initiated, or resumed at least 12 weeks after the previous administration of modified immune-responsive cells. (c) Tumors and / or cancers express MAGE-A4 and / or its peptide antigens, and / or (d) MAGE-A4 and / or its peptide antigen are detected in the subject's biological sample and / or exceed the normal range. It can be administered in a medication cycle.

[0091] According to the present invention, modified immune-responsive cells are (a) a confirmed response, complete response, or partial response following prior administration of modified immune-responsive cells, or (b) disease stability for a period of 2, 3, or 4 months or longer following prior administration of modified immune-responsive cells, followed by disease progression, and / or (c) Treatment may be continued, initiated, or resumed at least 12 weeks after the previous administration of modified immune-responsive cells. (c) Tumors and / or cancers express MAGE-A4 and / or its peptide antigen, and / or (d) MAGE-A4 and / or its peptide antigen are detected in the subject's biological sample and / or exceed the normal range. It can be administered in a medication cycle.

[0092] Tumors and / or cancers may express MAGE-A4 and / or its peptide antigens in tumor and / or cancer cells at an immunohistochemical intensity level of 1+ or higher, and / or at an antigen expression frequency of 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% or higher, preferably 30 or 32% or higher. The MAGE-A4 and / or its peptide antigen levels in the subject's biological sample exceeding the normal range may be 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450 or 500 ng / mL or higher, preferably 50 or 100 ng / mL or higher.

[0093] According to the present invention, the dose can be fixed or variable. For example, when multiple doses are administered, i.e., when multiple doses are administered, the dose can be fixed or variable, and for example, when multiple doses are administered, the dose can be gradually increased or increased in each drug administration cycle, i.e., the dose level can be gradually increased, for example, from 100 million cells to 500 million cells, 1 billion cells, 5 billion cells, and 10 billion cells.

[0094] According to the present invention, the modified immune-responsive cells are preferably administered as a single dose of about 5 billion to about 10 billion cells.

[0095] According to the present invention, modified immune-responsive cells can be administered over a specified period, meaning that the administration cycle of modified immune-responsive cells can be administered over a specified period. The specified period may be any of 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, or 48 months, and is preferably 24 months.

[0096] According to the present invention, this method is (a) Administer modified immune-responsive cells in a single dose, (b) If disease progression is determined by determining the disease state at a certain period after administration of modified immune-responsive cells and comparing it to the state before administration of modified immune-responsive cells, (c) Modified immune-responsive cells are administered as a single dose, and optionally, the tumor and / or cancer express MAGE-A4 and / or its peptide antigen, and / or MAGE-A4 and / or its peptide antigen is detected in the subject's biological sample and / or exceeds the normal range. Preferably, this period is one or more weeks, preferably 12 weeks or more, of which 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, or 48 weeks. This may include steps.

[0097] According to the present invention, this method is (a) Administer modified immune-responsive cells as a single dose, (b) If the disease state is determined in the first and second periods after administration of the modified immune-responsive cells and compared to the state before administration of the modified immune-responsive cells, and disease stabilization is determined after the first period and disease progression is determined after the second period, (c) Modified immune-responsive cells are administered as a single dose, and optionally, the tumor and / or cancer express MAGE-A4 and / or its peptide antigen, and / or MAGE-A4 and / or its peptide antigen is detected in the subject's biological sample and / or is above the normal range. Preferably, the first period is one, two, three, four, five, six, seven, or eight months or longer, and preferably four months or longer. Preferably, the second period is one or more of the following months after the first period: 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, or 48 months, preferably four months or more. This may include steps.

[0098] According to the present invention, "complete response" (CR) is determined when all target lesions or tumors are evaluated or measured as having disappeared. "Partial response" (PR) is determined when, for example, a measurement of at least 30% reduction in the total size of the target lesions or tumors (SLD) is observed, relative to a control or pre-treatment comparison. "Disease progression" (PD) is determined when, for example, a measurement of at least 20% increase in the total size of the target lesions or tumors (SLD) is observed, relative to a control or pre-treatment comparison, after the start of treatment or the presence of one or more new lesions. "Stable disease" (SD) is determined when, using the smallest SLD since the start of treatment as a reference, there is no sufficient reduction or decrease in the total size of the target lesions or tumors (SLD) to qualify for PR, and there is no sufficient increase to qualify for PD.

[0099] According to the present invention, the subject before treatment has the expression of MAGE-A4 and / or its peptide antigen in tumors and / or cancer cells determined by immunohistochemistry, with an immunohistochemical intensity of 1+ or higher, and / or 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, It can contain antigens at an expression frequency of 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 or 50% or more, preferably 30 or 32% or more, and the expression of non-cancerous MAGE-A4 and / or its peptide antigen is at any intensity determined by immunohistochemistry to be 1, 2, 3, 5, 6, 7, 8, 9, 10% or less, preferably 1% or 5% or less, in cells of non-cancerous or non-tumor tissue.

[0100] According to the present invention, the pre-treatment subject may contain MAGE-A4 and / or its peptide antigen at a biological sample level of 10, 25, 50, 100, 200, 300 or 400 ng / mL or more, preferably 50 ng / mL or more, and the expression of MAGE-A4 is at any intensity determined by immunohistochemistry, at 1, 2, 3, 5, 7, 9% or less or less or less than 10%, preferably 1% or 5% or less, in cells of non-cancerous or non-tumorous tissue.

[0101] According to the present invention, pre-treatment subjects may include those with an Eastern Cooperative Oncology Group (ECOG) score of 0 to 1 and / or a measurable disease (cancer of the head and neck or lung) according to the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and / or histologically confirmed cancer / tumor of the head and neck or lung.

[0102] According to the present invention, a subject is determined to be HLA-A*02 positive before treatment, and / or the subject's cancer or tumor exhibits expression of MAGE-A4 and / or its peptide antigen, for example, preferably MAGE-A4 RNA or protein expression as described herein.

[0103] According to the present invention, before treatment, the subject, (a) The HLA-A genotype is HLA-A*02:05 positive, (b) The HLA-A genotype is HLA-A*02:07 with only one HLA-A*02 allele (for example, subjects with HLA alleles A*02:04 and A*02:07 are eligible), (c) The HLA-A genotype is HLA-A* of any A*02 null allele as the sole HLA-A*02 allele, or (d) Having symptomatic CNS metastases, If a subject has one or more of the following conditions, they are deemed ineligible for treatment.

[0104] According to the present invention, a subject may be positive for HLA-A*02 selected from, for example, HLA-A*02:01, HLA-A*02:02, HLA-A*02:03, HLA-A*02:04, HLA-A*02:06, HLA-A*02:642, or HLA-A*02:07, preferably HLA-A*02:01 or HLA-A*02:642, and / or head and neck or lung cancer and / or tumors may express MAGE-A4, MAGE-A4 peptide antigen, GVYDGREHTV, SEQ ID NO: 2, and MAGE-A4 peptide antigen.

[0105] According to the present invention, the subject may be intolerant to standard treatments, preferably as described herein, and additionally or alternatively, the subject and / or cancer and / or tumor may have previously been unsuccessful in treatment with standard treatments, or previously unsuccessful in treatment with any of the following: surgery (resection), radiotherapy, targeted therapy, immunotherapy or chemotherapy or chemotherapy in combination with surgery (resection), radiotherapy, radiotherapy targeted therapy or immunotherapy; or previously unsuccessful in treatment with local therapies optionally selected from chemical and / or hyperthermic percutaneous ablation and intra-arterial chemoembolization.

[0106] According to the present invention, cancer and / or tumors of the head and neck or lungs may be primary cancer, secondary cancer, recurrent or refractory cancer, recurrent or locally recurrent cancer, advanced cancer, locally advanced cancer, or metastatic cancer, unresectable cancer, locally limited cancer or inoperable cancer for which there are no surgical or radiotherapy options, cancer that is not suitable for transplantation or localized treatment, or any combination thereof. A subject may have recurrent or refractory cancer, recurrent or locally recurrent cancer, metastatic cancer, locally limited cancer, or inoperable cancer, or any combination thereof.

[0107] Preferably, the cancer and / or tumor of the head and neck is inoperable and / or metastatic and / or advanced and / or locally advanced head and neck cancer or squamous cell head and neck cancer or head and neck squamous cell carcinoma (HNSCC), and preferably, inoperable, metastatic, advanced, or locally advanced HNSCC.

[0108] Preferably, the lung cancer and / or tumor is an inoperable and / or metastatic and / or advanced and / or locally advanced and / or recurrent lung cancer, which may be NSCLC or squamous NSCLC, adenosquamous NSCLC, or large cell carcinoma. Adenosquamous cell carcinoma of the lung (ASC) is a subtype of non-small cell lung cancer (NSCLC) and includes components of lung adenocarcinoma (ADC) and lung squamous cell carcinoma (SCC). Lung squamous cell carcinoma, or lung squamous cell carcinoma, is a type of non-small cell lung cancer (NSCLC).

[0109] Further, the present invention provides a method or use of treatment for cases where the subject has not previously received treatment for cancer and / or tumors of the head and neck or lung, or where the subject has previously received treatment for cancer and / or tumors of the head and neck or lung and / or where the prior treatment was ineffective.

[0110] According to the present invention, prior treatment may include one or more systemic therapies and / or local therapies, such as surgery, radiotherapy, cryotherapy, laser therapy, local therapy, chemotherapy, hormone therapy, targeted drugs, or immunotherapy. Therefore, prior treatment may include one or more local therapies, such as surgery, radiotherapy, cryotherapy, laser therapy, or local therapy, and / or one or more systemic therapies, such as chemotherapy, hormone therapy, targeted drugs, or immunotherapy. According to the present invention, prior treatment may include one of systemic therapy for the initial diagnosis of a localized disease, systemic therapy after the diagnosis of a recurrent or metastatic disease, systemic therapy after a minor metastatic disease, or systemic therapy after a locally recurrent disease.

[0111] Therefore, if the treatment is for lung cancer and / or tumors, prior treatment may include treatment with EGFR inhibitors or ALK tyrosine kinase inhibitors, and / or the cancer or tumor has been demonstrated to have EGFR mutations or ALK gene rearrangements, and prior treatment with EGFR inhibitors or ALK tyrosine kinase inhibitors may have been unsuccessful, for example, due to progressive disease or unacceptable toxicity or intolerance. Alternatively, the cancer or tumor may have been demonstrated to have ROS-1 positive expression prior to ALK inhibitor treatment, e.g., crizotinib treatment, and may have been unsuccessful, for example, due to progressive disease or unacceptable toxicity or intolerance. Therefore, if the treatment is for lung cancer and / or tumors, prior treatment may include any of the following: platinum-based chemotherapy, e.g., cisplatin or carboplatin; or gemcitabine, paclitaxel, nab-paclitaxel-docetaxel, pemetrexed, topotecan, irinotecan, etoposide, vinorelbine, or a combination of these with platinum-based chemotherapy, e.g., cisplatin or carboplatin; or tyrosine kinase inhibitors or epidermal growth factor receptor (EGFR) inhibitors, e.g., crizotinib, erlotinib, gefitinib and afatinib; or immune checkpoint inhibitors, e.g., pembrolizumab or nivolumab; or monoclonal antibodies against nuclear factor κB ligands, e.g., denosumab; optionally, if prior treatment was unsuccessful, e.g., due to progressive disease or unacceptable toxicity or intolerance.

[0112] Therefore, when the treatment is for cancer and / or tumors of the head and neck, prior treatment may include, for example, adjuvant therapy for the treatment of a primary tumor in a locally advanced or metastatic condition, which has been unsuccessful due to progressive disease or unacceptable toxicity or intolerance, as described herein. Therefore, when the treatment is for cancer and / or tumors of the head and neck or lung, prior treatment may include, for example, systemic chemotherapy including a platinum-based agent, which may be selected from cisplatin or carboplatin chemotherapy, for the treatment of a primary tumor in a locally advanced or metastatic condition, which has been unsuccessful due to progressive disease or unacceptable toxicity or intolerance. Therefore, if the treatment is for head and neck cancer and / or tumors, prior treatment may include platinum-based chemotherapy, e.g., cisplatin or carboplatin; a combination of paclitaxel and carboplatin; docetaxel or a combination of docetaxel and cisplatin and / or fluorouracil; immune checkpoint inhibitors, e.g., pembrolizumab or nivolumab, optionally in combination with or after platinum-based chemotherapy; targeted therapy or targeted antibody therapy, e.g., cetuximab, bevacizumab, erlotinib, or a combination of cetuximab and conventional chemotherapy such as cisplatin, or platinum and 5-fluorouracil; optionally, if prior treatment was unsuccessful, e.g., due to progressive disease or unacceptable toxicity or intolerance.

[0113] According to the present invention, the prior treatment may include a PD-1 axis-binding antagonist, a PD-L1-binding antagonist, or a PD-1-binding antagonist. Therefore, the prior treatment is (a) Anti-PD-L1 antibodies that inhibit the binding of PD-L1 to PD-1 and / or the binding of PD-L1 to B7-1, (b) Anti-PD-L1 antibodies that inhibit PD-L1 on the surface of cancer cells from transmitting signals into intracellular pathways. (c) Anti-PD-1 antibodies that inhibit the binding of PD-L1 to PD-1 and / or the binding of PD-L2 to PD-1. (d) Anti-PD-1 antibodies that inhibit PD-1 on the surface of T cells from transmitting signals into intracellular pathways. (e) A PD-L1-binding antagonist selected from the following: (i) durvalumab, imfinzi or MEDI4736, (ii) Atezolizumab, Tecentriq or MPDL3280A, (iii) Avelumab, Babencio or MSB0010718C (iv) MDX-1105, BMS-936559, (f) The PD-1 binding antagonist is selected from the following: (i) Pembrolizumab, Keytruda, Lambrolizumab, or MK-3475, (ii) Semiprimab, ributayo, or REGN-2810, (iii) BMS / ONO, nivolumab, Opdivo, ONO-4538, BMS-936558 or MDX1106, It may include.

[0114] According to the present invention, prior treatment may include an epidermal growth factor receptor antagonist, optionally cetuximab. According to the present invention, if prior treatment includes chemotherapy, it may include one or more platinum compounds, optionally selected from lipoplatin, cisplatin, carboplatin, oxaliplatin, nedaplatin, triplatin tetranitrate, phenantriplatin, satraplatin, and picoplatin. Additionally or alternatively, if prior treatment includes chemotherapy, it may include one or more chemotherapeutic agents selected from methotrexate, capecitabine, taxanes, anthracyclines, paclitaxel, docetaxel, paclitaxel protein-binding particles, doxorubicin, epirubicin, 5-fluorouracil, cyclophosphamide, afatinib, vincristine, etoposide, or combinations thereof. Additionally or alternatively, if prior treatment includes chemotherapy, this may include one or more chemotherapeutic agents selected from FEC: 5-fluorouracil, epirubicin, cyclophosphamide; FAC: 5-fluorouracil, doxorubicin, cyclophosphamide; AC: doxorubicin, cyclophosphamide; EC: epirubicin, cyclophosphamide. According to the present invention, prior treatment may include one or more of the following: sorafenib, regorafenib, cabozantinib, sunitinib, brivanib, everolimus, tivantinib, linifanib, which are PD-1 or PD-L1 antagonists or inhibitors, or local therapies optionally selected from chemical and / or hyperthermic percutaneous ablation and intra-arterial chemoembolization.

[0115] According to the present invention, a subject may not have received any prior treatment in the event of a relapse within 12 months of the last treatment or within 6 months of the last treatment. According to the present invention, a subject may not have received any prior adjuvant therapy (postoperative radiation and / or chemotherapy) in the event of a relapse within 12 months of the last treatment or within 6 months of the last treatment.

[0116] According to the present invention, the treatment extends or improves, or effectively extends or effectively improves, the following compared to a control, for example, compared to placebo administration, or compared to before treatment, or compared to no treatment, or compared to treatment including standard treatment as described herein: (a) Progression-free survival, (b) progression-free period, (c) Duration of response, (d) overall survival; (e) Objective response or objective response rate, (f) Total response or total response rate, (g) Partial response or partial response rate, (h) Complete response or complete response rate; (i) Disease stability rate or median disease stability (j) median progression-free survival, (k) median progression-free interval, (l) median duration of response, or (m) Median overall survival rate; (n) Median objective response or median objective response rate, (о) 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 disease stability rate or median disease stability.

[0117] According to the present invention, a treatment extends or improves, or effectively extends or effectively improves, one or more of the following, compared to a control, for example, compared to placebo administration, or compared to before treatment, or compared to no treatment, or compared to a treatment including standard treatment as described herein: (a) Best Overall Response (BOR), (b) Time to Response (TTR), (c) Duration of Response (DoR), (d) Duration of Disease Stability (DoSD), (e) Progression-Free Survival (PFS), or (f) Overall Survival (OS);

[0118] Best Overall Response (BOR) may be defined as the best response recorded from the day of T cell infusion to disease progression. Time to Confirmation (TTR) may be defined as the period from T cell infusion to the first day of confirmed response. Duration of Response (DoR) may be defined as the period from the first day of confirmed response to the day of disease progression (PD), disease progression (or death). Duration of Disease Stability (DoSD) may be defined as the period from the day of T cell infusion to the day of disease progression (PD), disease progression (or death). Progression-Free Survival (PFS) may be defined as the interval from the day of T cell infusion to the earliest day of disease progression according to RECIST v1.1, or death from any cause. Overall Survival (OS) may be defined as the period from T cell infusion to death from any cause.

[0119] "Progression-free survival" (PFS) refers to the time from treatment (or randomization) to the first disease progression or death. "Time to progression" (TTP) is equivalent to PFS, except that it does not count patients who die from causes other than the cancer or tumor being treated. "Duration of response" (DoR) is the length of time that cancer, tumor, or lesion continues to respond to treatment without growth or dissemination. According to the present invention, DoR, TTP, and PFS can be evaluated by the Criteria for Response to Solid Tumors (RECIST), by CA-125 levels (cancer antigen 125) as a determinant of progression, or optionally by referring to disease biomarkers or MAGE-A4 expression, i.e., MAGE-A4 protein, peptide, or mRNA in the subject's biological sample, cancer, and / or tumor tissue or cells. The duration of response, response rate, readings, measurements, or time points can be measured from the day treatment was initiated, for example, from the day the modified immune-responsive cells were administered to the subject, or from the day standard treatment or placebo was administered.

[0120] According to the present invention, PFS and / or TTP and / or DoR, or the median thereof, can be extended or improved by at least 1, 2, 3, or 4 weeks, 1 month, 2 months, 2.3 months, 2.5 months, 2.9 months, 3 months, 3.5 months, 3.8 months, 4 months, 4.5 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 16 months, 18 months, 20 months, 22 months, 2 years, 3 years, 4 years, 5 years, 6 years, 7 years, 8 years, 9 years, or 10 years, compared to placebo administration, or compared to prior treatment, or compared to no treatment, or compared to treatment including standard treatment as described herein (control).

[0121] In one embodiment, PFS and / or TTP and / or DoR, or the median thereof, are extended by approximately 2.9 to 3.8 months compared to the control. In another embodiment, PFS and / or TTP and / or DoR, or the median thereof, are extended by at least approximately 3.8 months compared to the control. In yet another embodiment, PFS and / or TTP and / or DoR, or the median thereof, are extended by approximately 2.3 months, and in one embodiment, PFS and / or TTP and / or DoR, or the median thereof, are extended by approximately 6 months compared to placebo, or compared to prior treatment, or compared to no treatment, or compared to treatment including standard treatment as described herein (control).

[0122] "Overall survival" refers to the number of subjects who remain alive over a specified period. According to the present invention, overall survival, or the median thereof, is improved or extended by any or more of approximately 1 month, 2 months, 2.3 months, 2.5 months, 2.9 months, 3 months, 3.5 months, 3.8 months, 4 months, 4.5 months, 5 months, approximately 6 months, approximately 7 months, approximately 8 months, approximately 9 months, approximately 10 months, approximately 11 months, approximately 12 months, approximately 1.5 years, approximately 2 years, approximately 3 years, approximately 4 years, approximately 5 years, approximately 6 years, approximately 7 years, approximately 8 years, approximately 9 years, or approximately 10 years from the start of the method or treatment according to the present invention or initial diagnosis, and optionally, the event used for survival analysis may be death from any cause. "Survival" means that the subject remains alive, and includes progression-free survival (PFS) and overall survival (OS). "Overall survival" is the length of time a subject diagnosed with a disease, tumor, and / or cancer remains alive from the date of diagnosis or the start of treatment for that disease. Survival rates can be estimated by the Kaplan-Meier method, and the difference in survival rates is calculated using a stratified log-rank test; "extending survival" or "enhancing the likelihood of survival" means increasing the PFS and / or OS of a treated subject compared to placebo, or compared to prior treatment, or compared to no treatment, or compared to treatment including, for example, standard treatment as described herein. According to the present invention, overall survival or survival can be extended or improved by at least about 1 month, 2 months, 2.3 months, 2.5 months, 2.9 months, 3 months, 3.5 months, 3.8 months, 4 months, 4.5 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 16 months, 18 months, 20 months, 22 months, 2 years, 3 years, 4 years, 5 years, 6 years, 7 years, 8 years, 9 years, or 10 years, compared to placebo administration, compared to prior treatment, compared to no treatment, or compared to treatment including standard treatment (control).

[0123] Objective response rate (ObRR) is the percentage of subjects who have a predetermined amount of tumor size reduction over a minimum period, optionally determined by the sum of the target lesions or tumor longest diameters (SLDs). Overall response rate (ORR) is defined as the percentage of subjects who have a partial or complete response to therapy; stable disease is not included. ORR is generally defined as the sum of complete responses (CRs) and partial responses (PRs) over a specified period. According to the present invention, ObRR and / or ORR and / or PR and / or CR and / or SD can be extended or improved by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, and 95% compared to placebo administration, or compared to prior treatment, or compared to no treatment, or compared to treatment including standard treatment as described herein.

[0124] According to the present invention, the method may further include determining the expression level of a biomarker in a sample from a subject, a biological sample, where the biomarker level is compared to a reference level to determine the likelihood of the subject responding to treatment or to the level of the subject's response to treatment, and the sample is obtained before, during, or after treatment. The reference level may be the level of the subject before treatment, or it may be a level associated with the presence or absence of cancer. The biomarker may be a T-effector-related gene, e.g., CD8A, perforin (PRF1), granzyme A (GZMA), granzyme B (GZMB), interferon-γ (IFN-v), CXCL9, or CXCL10. The biomarker may also be an activated stromal-related gene, e.g., transforming growth factor-β (TGF-β), fibroblast-activating protein (FAP), podoplanin (PDPN), collagen gene, or biglycan (BGN). The biomarker may be a MyelokJ-derived suppressor cell-associated gene, such as CD68, CD163, FOXP3, or androgen-regulated gene 1. Alternatively, the biomarker may be PD-L1, CD8, or an androgen receptor (AR) gene. Alternatively, the biomarker may be a disease biomarker as described herein above.

[0125] According to the present invention, the subject undergoes lymphocyte apheresis chemotherapy prior to the administration of modified immune-responsive cells expressing or presenting heterologous T cell receptors (TCRs). Lymphocyte apheresis chemotherapy may include the administration of cyclophosphamide and / or fludarabine. Preferably, cyclophosphamide is administered in doses of about 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800 or 850 mg / m². 2 / d[d=day], preferably about 500 or 600 mg / m² 2The drug is administered in doses of / d, preferably over 1 day, 2 days (x2 days), 3 days (x3 days), 4 days (x4 days), or 5 days (x5 days). Preferably, fludarabine is 5, 10, 15, 20, 25, 30, 35, 40, 450, 50, 55, 60, 65, 70, 75, 80, or 85 mg / m². 2 The drug is administered in doses of approximately / d, preferably over 1 day, 2 days (x2 days), 3 days (x3 days), 4 days (x4 days), or 5 days (x5 days). Preferably, the lymphocyte apheresis chemotherapy is administered with cyclophosphamide and fludarabine, optionally at 500 mg / m². 2 Cyclophosphamide and 20 mg / m² daily for 3 days. 2 Fludarabine doses of 600 mg / m² or 600 mg / m² per day for 3 days. 2 Cyclophosphamide and 30 mg / m³ daily for 3 days. 2 This includes administration at a dose of / d x 4 days.

[0126] According to the present invention, lymphocyte apheresis chemotherapy can be administered 3, 4, 5, 6, 7, 8, 9, or 10 days prior to the administration of modified immune-responsive cells expressing or presenting xenolytic T cell receptors (TCRs), preferably 7 to 5 days or 7 to 4 days prior. The administration of cyclophosphamide and fludarabine may be performed sequentially and separately, or simultaneously, and the administration may be performed intravenously or by intravenous infusion.

[0127] The present invention further includes, as described above by reference to the method of treatment and related aspects, embodiments and features, administering to a subject a therapeutic regimen comprising a therapeutic regimen comprising a subject comprising an effective amount of modified immune-responsive cells expressing or presenting a heterologous T cell receptor (TCR) that binds to MAGE-A4 or the peptide antigen of MAGE-A4, including GVYDGREHTV, SEQ ID NO: 2, in subjects having cancer and / or tumors of the head and neck or lung, optionally compared to pre-treatment or placebo administration, or compared to no treatment or standard treatment as described herein. (a) Reduce the expression or concentration of MAGE-A4 in the subject, for example, in a biological sample of the subject. (b) Strengthen immune function, (c) reducing tumor growth or tumor growth rate, maintaining tumor size after discontinuation of treatment, or reducing the number or volume of tumors. (d) Increase the levels or concentrations of serum cytokines and / or interferon, (e) improve the persistence of T cells (f) Improve T cell infiltration of the tumor, (g) Inducing changes in disease biomarkers that serve as indicators for effective treatment of head and neck or lung cancer and / or tumors, Provide a method.

[0128] Accordingly, the present invention relates to a method for enhancing immune function, comprising administering to a subject a therapeutic regimen comprising a therapeutic regimen comprising a sufficient amount of modified immune-responsive cells expressing or presenting a heterologous T cell receptor (TCR) that binds to MAGE-A4 or MAGE-A4 peptide antigen or GVYDGREHTV, SEQ ID NO: 2, as described above by reference to the therapeutic method and related aspects, embodiments and features thereof, in subjects having cancer and / or tumors of the head and neck or lung, optionally compared to pre-treatment or placebo administration, or compared to no treatment or treatment including standard treatment as described herein, respectively. (a) CD8 T cells in the subjects have enhanced priming, activation, proliferation and / or cytolytic activity, (b) The number of CD8 T cells was increased in the subjects, (c) In the subject, the expression of MHC class I antigen is selectively elevated in cancer cells and / or tumor cells, and optionally, the expression of MHC class I antigen is not elevated in the subject's PBMC cells. (d) The maturation and activation of antigen-presenting cells are enhanced in the subject, and optionally the antigen-presenting cells are dendritic cells. (e) Serum levels of IL-10 and / or IL-8 are decreased in the subject, (f) The level of T cell infiltration in the cancer and / or tumor of the subject is elevated, (g) The expression level of T cell PD-1 is decreased in the subject's T cells. Provide a method.

[0129] Therefore, by referring to the above and the treated subjects, (a) activation of CD8 T cells is associated with γ-IFN + (b) Maturation of antigen-presenting cells may be characterized by an increase in the frequency of CD8 T cells and / or enhanced cytolytic activity; (b) Maturation of CD83 + (c) Activation of antigen-presenting cells may be characterized by an increased frequency of dendritic cells; (d) CD8 T cells may be antigen-specific CD8 T cells.

[0130] According to the present invention, (a) A kit comprising: an effective amount of modified immune-responsive cells expressing or presenting a heterologous T cell receptor (TCR) that binds to MAGE-A4 or MAGE-A4 peptide antigen or GVYDGREHTV, SEQ ID NO: 2; and a package insert containing instructions for using the modified immune-responsive cells to treat or delay the progression of cancer and / or tumors of the head and neck or lung of a subject; (b) an effective amount of modified immune-responsive cells expressing or presenting a heterologous T cell receptor (TCR) that binds to MAGE-A4 or the peptide antigen of MAGE-A4, or GVYDGREHTV, SEQ ID NO: 2, and the modified immune-responsive cells in subjects having cancer and / or tumors as described herein above. (i) Reduce the expression or concentration of MAGE-A4 in the subject, for example, in a biological sample of the subject. (ii) Strengthen immune function, (iii) reducing tumor growth or tumor growth rate, maintaining tumor size after discontinuation of treatment, or reducing the number or volume of tumors. (iv) Increase the levels or concentrations of serum cytokines and / or interferon, (v) Improve the persistence of T cells (vi) improve T cell infiltration of the tumor, or (vii) Inducing changes in disease biomarkers that serve as indicators for effective treatment of head and neck or lung cancer and / or tumors, A kit including an accompanying document with instructions for use in the method, It will be provided.

[0131] Further aspects of the invention In a further aspect, the present invention provides a method for treating, preventing or delaying the progression of cancer and / or tumor in a subject, comprising administering to the subject a therapeutic regimen comprising a therapeutic regimen comprising a subject comprising a modified amount of immune-responsive cells expressing or presenting a heterologous T-cell receptor (TCR) or chimeric antigen receptor (CAR) that binds to MAGE-A4 (SEQ ID NO: 1), the peptide antigen of MAGE A4, optionally GVYDGREHTV, SEQ ID NO: 2, wherein the cancer and / or tumor is any one of (a) ovarian cancer and / or tumor, (b) urothelial / bladder cancer and / or tumor, (c) melanoma, or (d) sarcoma or synovial sarcoma.

[0132] The cancer and / or tumor is preferably an advanced and / or metastatic and / or inoperable sarcoma, optionally a soft tissue sarcoma, optionally a synovial or myxoid round cell liposarcoma.

[0133] In a further embodiment, heterologous TCRs or CARs may specifically and / or selectively bind to MAGE-A4 (SEQ ID NO: 1), the peptide antigen of MAGE A4, or to the peptide antigen of MAGE A4, including GVYDGREHTV, SEQ ID NO: 2.

[0134] In a further embodiment, the MAGE-A4 peptide antigen, including MAGE-A4 (SEQ ID NO: 1), the MAGE-A4 peptide antigen, or GVYDGREHTV, SEQ ID NO: 2, may be associated with and / or presented by tumors and / or cancer cells or tissues of any one of the following: (a) ovarian cancer and / or tumor, (b) urothelial / bladder cancer and / or tumor, (c) melanoma cancer and / or tumor, or (d) sarcoma or synovial sarcoma. Therefore, (a) ovarian cancer and / or tumor, (b) urothelial / bladder cancer and / or tumor, (c) melanoma cancer and / or tumor, or (d) sarcoma or synovial sarcoma may be cancers and / or tumors that express MAGE-A4 and / or express the MAGE-A4 peptide antigen, including MAGE-A4 or its peptide antigen, or GVYDGREHTV, SEQ ID NO: 2.

[0135] In a further embodiment, the peptide antigen of MAGE-A4, or the peptide antigen of MAGE-A4 including GVYDGREHTV, SEQ ID NO: 2, can be complexed with a peptide-presenting molecule, optionally selected from major histocompatibility complex (MHC) or human leukocyte antigen (HLA), optionally class I or class II, optionally HLA*02, HLA-A*02:01, HLA-A*02:02, HLA-A*02:03, HLA-A*02:04, HLA-A*02:06, HLA-A*02:642 or HLA-A*02:07, preferably HLA-A*02:01 or HLA-A*02. Preferably, the heterologous TCR binds specifically and / or selectively to the peptide antigen and / or the peptide-presenting molecule and / or its complex. Alternatively, and according to further embodiments, MAGE A4 or its peptide antigen, or the peptide antigen of MAGE A4 including GVYDGREHTV, SEQ ID NO: 2, may be presented independently of the peptide-presenting molecule.

[0136] In a further embodiment, the heterologous TCR may include a TCRα chain variable domain and a TCRβ chain variable domain, where, (i) The α-chain variable domain is sequence VSPFSN(αCDR1), amino acids 48-53 of SEQ ID NO: 11 or SEQ ID NO: 5, or sequences having at least 50% sequence identity to them. LTFSEN(αCDR2), amino acids 71-76 of SEQ ID NO: 12 or SEQ ID NO: 5, or sequences having at least 50% sequence identity to them, and CVVSGGTDSWGKLQF(αCDR3), amino acids 111-125 of SEQ ID NO: 13 or SEQ ID NO: 5, or sequences having at least 50% sequence identity to them. Includes a CDR having, (ii) The β-chain variable domain is sequence KGHDR(βCDR1), amino acids 46-50 of SEQ ID NO: 14 or SEQ ID NO: 7, or sequences having at least 50% sequence identity to them. SFDVKD(βCDR2), amino acids 68-73 of SEQ ID NO: 15 or SEQ ID NO: 7, or sequences having at least 50% sequence identity to them, CATSGQGAYEEQFF(βCDR3), amino acids 110-123 of SEQ ID NO: 16 or SEQ ID NO: 7, or sequences having at least 50% sequence identity to them. Includes a CD-R containing [specific feature].

[0137] Therefore, heterogeneous TCRs are (a) The α-chain variable domain contains an amino acid sequence that is at least 80% identical to SEQ ID NO: 9, and / or the β-chain variable domain contains an amino acid sequence that is at least 80% identical to SEQ ID NO: 10, (b) The α-chain variable domain contains the amino acid sequence containing SEQ ID NO: 9 and / or the β-chain variable domain contains SEQ ID NO: 10, (c) The α chain contains an amino acid sequence that is at least 80% identical to SEQ ID NO: 5, and / or the β chain contains an amino acid sequence that is at least 80% identical to SEQ ID NO: 6, or (d) The α chain contains an amino acid sequence including SEQ ID NO: 5, and / or the β chain contains an amino acid sequence including SEQ ID NO: 6. May contain TCRs.

[0138] In a further embodiment, modified immune-responsive cells expressing or presenting a heterologous TCR may further express or present a heterologous coreceptor, optionally the coreceptor being a CD8 coreceptor, optionally the heterologous CD8 coreceptor being a heterodimer or homodimer, a CD8αb heterodimer or a CD8αα homodimer.

[0139] Therefore, heterologous CD8 coreceptors are (a) CDR1 having at least 80% sequence identity to amino acid sequence VLLSNPTSG and SEQ ID NO: 17, CDR2 having at least 80% sequence identity to amino acid sequence YLSQNKPK and SEQ ID NO: 18, and CDR3 having at least 80% sequence identity to amino acid sequence LSNSIM and SEQ ID NO: 19. (b) Amino acid sequence VLLSNPTSG, CDR1 of SEQ ID NO: 17, amino acid sequence YLSQNKPK, CDR2 of SEQ ID NO: 18, and amino acid sequence LSNSIM, CDR3 of SEQ ID NO: 19 (c) an amino acid sequence having at least 80% sequence identity with amino acid numbers 22-235 of SEQ ID NO: 3, or amino acid sequence having at least 80% sequence identity with amino acid numbers 22-135 of SEQ ID NO: 3, (d) Amino acid sequences that have 100% sequence identity with amino acid numbers 22-235 of the sequence of SEQ ID NO: 3, or amino acid sequences that have 100% sequence identity with amino acid numbers 22-135 of SEQ ID NO: 3 It may include.

[0140] In a further embodiment, modified immune-responsive cells expressing or presenting heterologous CARs or TCRs may further express or present one or more heterologous costimulatory ligands, optionally 4-1BBL and / or CD80.

[0141] In a further embodiment, the modified immune-responsive cells are (a) B cells, T cells or natural killer (NK) cells, and (b) T cells, optionally, CD4 + T cells and / or CD8 + A T cell, optionally modified, immune-responsive cell may be a population of CD4+ T cells; or CD8+ T cells; or a mixed population of CD4+ T cells and CD8+ T cells.

[0142] In a further embodiment, the modified immune-responsive cells can be administered continuously or intermittently.

[0143] In a further embodiment, the modified immune-responsive cells may be administered in multiple doses or as a single dose. Thus, a single dose or multiple doses may be administered in one or more dosing cycles, and optionally, the dose may be fixed or variable. The modified immune-responsive cells may be administered in doses of approximately 500 million to 1 billion cells, approximately 2 billion to 5 billion cells, or approximately 6 billion to 10 billion cells.

[0144] In a further embodiment, modified immune-responsive cells are (a) A single dose in each of one or more medication cycles, (b) One or more doses in each of one or more medication cycles, (c) A single dose on the first day of each of one or more medication cycles, (d) One or more doses in each of one or more medication cycles, in which at least one dose is administered on the first day of each cycle. (e) One or more doses in each of one or more medication cycles, in which at least one dose is administered on the first day of each cycle. (f) Single dose It can be administered as such.

[0145] In a further embodiment, if modified immune-responsive cells are administered according to a drug cycle, the drug cycle may last between two and six months or may be continued as the disease progresses.

[0146] In a further embodiment, if modified immune-responsive cells are administered according to a drug cycle, the drug cycle is: (a) Disease progression following prior administration of modified immune-responsive cells, and which may continue 12 weeks or more after prior administration of modified immune-responsive cells, (b) The tumor and / or cancer expresses MAGE-A4 and / or its peptide antigen, and / or (d) MAGE-A4 and / or its peptide antigen are detected in the subject's biological sample and / or exceed the normal range.

[0147] In a further embodiment, if modified immune-responsive cells are administered according to a drug cycle, the drug cycle is: (a) complete or partial response following prior administration of modified immune-responsive cells, or (b) disease stability for a period of four months or more following prior administration of modified immune-responsive cells, followed by disease progression; and (c) continuation of response for 12 weeks or more following prior administration of modified immune-responsive cells. (d) The tumor and / or cancer expresses MAGE-A4 and / or its peptide antigen, and / or (d) MAGE-A4 and / or its peptide antigen are detected in the subject's biological sample and / or exceed the normal range.

[0148] In a further embodiment, the modified immune-responsive cells may be administered intravenously or by intravenous infusion.

[0149] In a further aspect, prior to treatment, the subject may have a disease that is measurable according to the Criteria for Efficacy of Solid Tumors (RECIST) 1.1 and / or histologically confirmed ovarian cancer and / or tumor, urothelial / bladder cancer and / or tumor, or melanoma.

[0150] In a further manner, before treatment, the subject, (a) The HLA-A genotype is HLA-A*02:05 positive, (b) The HLA-A genotype is HLA-A*02:07 with only one HLA-A*02 allele (for example, subjects with HLA alleles A*02:04 and A*02:07 are eligible), (c) The HLA-A genotype is HLA-A* of any A*02 null allele as the sole HLA-A*02 allele, or (d) Having symptomatic CNS metastases, If a subject has one or more of the following conditions, they are deemed ineligible for treatment.

[0151] In a further aspect, subjects may be intolerant to standard treatment, optionally platinum-based systemic chemotherapy, and / or ovarian cancer and / or tumors, urothelial / bladder cancer and / or tumors, melanoma / tumors and / or sarcomas or synovial sarcomas may have previously been unsuccessful with standard treatment, optionally platinum-based systemic chemotherapy.

[0152] In a further aspect, ovarian cancer and / or tumors, urothelial / bladder cancer and / or tumors, melanoma / tumors, or sarcomas or synovial sarcomas may have previously been unsuccessful in treatment with surgery (resection), radiotherapy, targeted therapy, immunotherapy or chemotherapy, or in combination with surgery (resection), radiotherapy, radiotherapy-targeted therapy, checkpoint inhibitors or immunotherapy.

[0153] In a further aspect, ovarian cancer and / or tumors, urothelial / bladder cancer and / or tumors, melanoma / tumors or sarcomas or synovial sarcomas may be primary cancers, secondary cancers, recurrent or refractory cancers or recurrent or locally recurrent or metastatic cancers, unresectable cancers or locally limited or inoperable cancers for which there are no surgical or radiotherapy options, and optionally, the cancer is not a candidate for transplantation or localized therapy.

[0154] In a further embodiment, prior to the administration of modified immune-responsive cells expressing or presenting heterologous T cell receptors (TCRs) or CARs, the subject may optionally receive 500 mg / m². 2 Cyclophosphamide and 20 mg / m² daily for 3 days. 2 Fludarabine doses of 600 mg / m² or 600 mg / m² per day for 3 days. 2 Cyclophosphamide and 30 mg / m³ daily for 3 days. 2 Lymphocyte apheresis chemotherapy, including administration of cyclophosphamide and fludarabine in a dose of 4 doses per day, may be administered optionally 7 to 5 days or 7 to 4 days prior to the administration of modified immune-responsive cells expressing or presenting xenotypic T cell receptors (TCRs) or CARs.

[0155] In a further aspect, the subject may not have received prior treatment for cancer and / or tumors, for example, may be treatment-naive; or the subject may have received prior treatment for cancer and / or tumors and / or the prior treatment for cancer and / or tumors was ineffective. Therefore, prior treatment may include any of the following: (a) Systemic and / or local therapy, optionally one or more of surgery, radiotherapy, cryotherapy, laser therapy, local therapy and / or systemic therapy, for example, one or more of chemotherapy, hormone therapy, targeted drugs, targeted chemotherapy or immunotherapy, (b) PD-L1-binding antagonist or PD-1-binding antagonist, optionally, the PD-1 axis-binding antagonist or PD-L1-binding antagonist is an antibody. (c) Epidermal growth factor receptor antagonist, optionally cetuximab, erlotinib, gefitinib, or afatinib. (d) Chemotherapy containing platinum compounds, optionally lipoplatin, cisplatin, carboplatin, oxaliplatin, nedaplatin, triplatin tetranitrate, phenanthriplatin, satraplatin, picoplatin, (e) optionally comprising a chemotherapeutic agent selected from any or a combination thereof from methotrexate, capecitabine, taxane, anthracycline, paclitaxel, docetaxel, paclitaxel protein-binding particles, doxorubicin, epirubicin, 5-fluorouracil, cyclophosphamide, afatinib, vincristine, etoposide, (f) 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.

[0156] If the method or treatment according to the present invention is for sarcoma or synovial sarcoma, the standard treatment may include, or may be selected from, an anthracycline-centered treatment, for example, an anthracycline monotherapy, for example, doxorubicin, daunorubicin, epirubicin or idarubicin; ifosfamide monotherapy; a combination of an anthracycline and ifosfamide, or a combination of doxorubicin and ifosfamide, or one or more of pazopanib, trabectedin, eribulin, gemcitabine + / - docetaxel or dacarbazine.

[0157] If the method or treatment according to the present invention is for sarcoma or synovial sarcoma, prior treatment may include an anthracycline-centered treatment, for example, an anthracycline monotherapy, for example, doxorubicin, daunorubicin, epirubicin or idarubicin; ifosfamide monotherapy; a combination of an anthracycline and ifosfamide, or a combination of doxorubicin and ifosfamide, or one or more of pazopanib, trabectedin, eribulin, gemcitabine + / - docetaxel or dacarbazine, or one or more of these.

[0158] In a further manner, the subject may not have received prior treatment in the event of a relapse within 12 months of the last treatment or within 6 months of the last treatment.

[0159] In a further aspect, the subject may not have received any prior adjuvant therapy (e.g., postoperative radiotherapy and / or chemotherapy) or local therapy in the event of a relapse within 12 months of the last treatment, or within 6 months of the last treatment.

[0160] In a further embodiment, this treatment is compared to placebo, or to pre-treatment, or to no treatment, or to standard treatment, optionally including platinum-based systemic chemotherapy. (a) Progression-free survival, (b) progression-free period, (c) Duration of response, (d) overall survival; (e) Objective response or objective response rate, (f) Total response or total response rate, (g) Partial response or partial response rate (h) Complete response or complete response rate; (i) Disease stability rate or median disease stability, (j) median progression-free survival, (k) median progression-free interval, (l) median duration of response, or (m) Median overall survival rate; (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 disease stability rate or median disease stability It can effectively extend or improve.

[0161] In a further embodiment, this treatment can effectively extend or improve progression-free survival (or median progression-free survival) by 20 weeks or more, optionally 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 weeks or 50 weeks or more, optionally without reaching the median overall survival, preferably in the subject according to a further embodiment. Methods for treating or preventing cancer and / or tumors or delaying their progression relate to sarcomas or synovial sarcomas, and are, for example, compared to placebo, or to prior treatment, or to no treatment, or to treatment including standard treatment as described herein, and optionally to treatment including one or more of pazopanib, trabectedin, eribulin, gemcitabine+ / -, docetaxel, or dacarbazine. Preferably, the PFS for the treatment of sarcomas or synovial sarcomas according to the present invention or further embodiments thereof is 20 weeks or more, and optionally 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 weeks or 50 weeks or more.

[0162] In a further embodiment, the treatment can effectively extend or improve the overall response rate (ORR), preferably, the further embodiment of the method for treating or preventing or delaying the progression of a subject's cancer and / or tumor relates to sarcoma or synovial sarcoma, and is, for example, compared to placebo, or to prior treatment, or to no treatment, or to treatment including standard treatment as described herein, and optionally to treatment comprising one or more of pazopanib, trabectedin, eribulin, gemcitabine+ / -, docetaxel, or dacarbazine. Preferably, the ORR is improved 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 times compared to treatment including standard treatment as described herein, and optionally to treatment comprising one or more of pazopanib, trabectedin, eribulin, gemcitabine+ / -, docetaxel, or dacarbazine. Preferably, ORR is a value selected from 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 16%, 20%, 25%, 30%, 35%, 40%, 45%, 46%, 50%, 60%, 70%, 80%, 90%, or more, preferably 40%, 42%, 43%, 45%, 46%, 47%, or more, with respect to the treatment of sarcoma or synovial sarcoma according to the present invention or further embodiments. ORR may be, for example, the value of the increase in the sum of the longest diameters (SLDs) of one or more target lesions or tumors of a subject or a group of subjects, or the median thereof.

[0163] In a further embodiment, preferably, a method for treating or preventing cancer and / or tumors or delaying their progression in a subject according to a further embodiment relates to sarcoma or synovial sarcoma, and the treatment can effectively produce a BOR of 20%, 25%, 30%, 35%, 40%, 45%, 46%, 50%, 60%, 70%, 80%, 90%, or more, preferably 40% or more, preferably 43% or more, for example, a BOR in partial response or disease stabilization.

[0164] In a further embodiment, preferably, a method for treating or preventing or delaying the progression of cancer and / or tumors in a subject according to a further embodiment relates to sarcoma or synovial sarcoma, and the treatment can effectively produce a BOR of 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 3%, 35%, 40%, 45%, 50%, or more, preferably 6% or more, preferably 6.3%, for example, a BOR in a progressive disease.

[0165] In some embodiments, further aspects include modified immune-responsive cells expressing or presenting a heterologous T-cell receptor (TCR) or chimeric antigen receptor (CAR) that binds to MAGE-A4 (SEQ ID NO: 1), the peptide antigen of MAGE-A4, optionally GVYDGREHTV, SEQ ID NO: 2, for use in a subject to treat, prevent or delay the progression of cancer and / or tumors, wherein cancer and / or tumors are any one of (a) ovarian cancer and / or tumors, (b) urothelial / bladder cancer and / or tumors, (c) melanoma, or (d) sarcoma or synovial sarcoma.

[0166] In certain embodiments of further models, the present invention includes administering a therapeutic regimen comprising an effective amount of immune-responsive cells to a subject.

[0167] The present invention will be further described by reference to the following drawings and embodiments. [Brief explanation of the drawing]

[0168] [Figure 1] This figure shows the best overall response rate in head and neck cancer and lung cancer after MAGE-A4c1032 T cell injection (Table: RECIST v1.1). [Figure 2]This figure shows CT data demonstrating a 50% reduction in target lesions in lung cancer 12 weeks after MAGE-A4c1032 T cell infusion in a cohort of subjects who received an injection of 10 billion cells. The upper panel shows tumor reduction, and the lower panel shows intrapleural fluid reduction. [Figure 3] This figure shows a table of data indicating response as assessed by RECIST v1.1, representing the percentage change in the reduction of lesion SLC from baseline, i.e., the percentage change in the sum of the diameters measured in the target lesion (sum of diameter = sum of the longest diameters for non-nodular lesions, sum of the shortest diameters for nodular lesions). [Figure 4] This figure shows the progression-free survival (PFS) and overall survival (OS) of sarcoma (synovial sarcoma) treated with MAGE-A4c1032 T cell injection. [Figure 5] This figure shows the best overall response in sarcoma (synovial sarcoma) after MAGE-A4c1032 T cell injection: RECIST v1.1. [Figure 6] A comparison of efficacy observed in the treatment of synovial sarcoma; (a) standard treatment, (b) response rate in sarcoma (synovial sarcoma) after MAGE-A4c1032 T cell infusion: a table showing the percentage change from baseline SLD to RECIST v1.1. [Figure 7] This figure shows a CT scan demonstrating a partial response (PR) 24 weeks after transduction of transduced T cells: CT data (lesions are circled) from a subject with head and neck cancer expressing MAGE-A4 (biopsy showed invasive SCC and left arytenoid SCC), prior treatment regimens included cisplatin, carboplatin + doxetaxel, and pembrolizumab. Baseline scans showed a 47 mm SLD (LN (lymph node) lesion in the thoracic target lesion and NT lesion in the neck). The subject received injections of 3.83 × 10⁹ transduced cells (ADP-A2M4 SPEAR T cells). At week 24, a 36% reduction in the SLD of the lesion from the baseline measurement was recorded. [Figure 8]This figure shows CT scans indicating a partial response (PR) 20 weeks after transduction of transduced T cells in a lung cancer subject, along with data summarized in a table for the same subject: CT data from a subject with stage IV squamous NSLCL (PD-L1, ROS1) (measurement scales are attached to the lesions). Biopsy showed expression of MAGE-A4 antigen [IHC level: +1 (0%); +2 (5%); +3 (95%)]. Previous cancer treatments included surgery, systemic therapy (including chemotherapy, targeted therapy, and immunotherapy); carboplatin / paclitaxel / denosumab; nivolumab; nivolumab and ipilimumab; docetaxel and ramucirumab; and radiotherapy. The subject received an injection of 6.5 × 10⁹ transduced T cells (ADP-A2M4 SPEAR T cells). At week 20, a 41.7% reduction in the lesion's SLD (Single Least Disease) was recorded from the baseline measurement. [Modes for carrying out the invention] [Examples]

[0169] [Example 1] In HLA-A2+ subjects with MAGE-A4-positive head and neck tumors and lung tumors, MAGE-A4, MAGE-A4 c1032 A Phase I open-label clinical trial evaluating the safety and antitumor activity of autologous T cells expressing a T-specific enhanced TCR.

[0170] method In subjects with HLA-A*02 and MAGE-A4-positive, inoperable locally advanced or metastatic head and neck cancer or lung cancer, genetically modified MAGE-A4 c1032 The human trials of T cells are described below.

[0171] The disease was a measurable disease that was histologically or cytogenetically confirmed and / or documented according to RECIST v1.1 criteria. Subjects who were eligible based on HLA type and met the MAGE-A4 criteria were screened for overall health status, activity indicators, and disease stage. After screening, subjects who met all eligibility criteria underwent leukocyte apheresis to obtain cells for the production of autologous T cells possessing MAGE-A4 TCRs. Eligible subjects had an ECOG Performance Status of 0 to 1, sufficient organ function and measurable disease prior to lymphocyte apheresis, and the following: (a) Inoperable or metastatic (advanced) squamous cell carcinoma of the head and neck. The patient has previously received, is intolerant to, or has refused platinum-based chemotherapy as adjuvant treatment for a locally advanced or metastatic primary tumor. The patient may have received prior immunotherapy. There are no restrictions on the type of previous anticancer therapy. (b) Diagnosis of histologically or cytologically confirmed advanced NSCLC (stage IIIB or IV) or recurrent disease. Having squamous cell carcinoma, adenosquamous carcinoma, or large cell carcinoma. Having received at least one previous systemic therapy. In subjects whose tumor is known to have an EGFR mutation or ALK gene rearrangement, prior treatment with an EGFR inhibitor or ALK tyrosine kinase inhibitor has been unsuccessful (progressive disease or unacceptable toxicity), respectively. In subjects with a ROS-1 positive tumor, ALK inhibitor (crizotinib) has not been effective. May have received PD-1 inhibitors. There are no restrictions on the type of prior anticancer therapy.

[0172] Exclusion of subjects is primarily based on HLA-A genotype: the subject is HLA-A*02:05 positive; the subject has HLA-A*02:07 as their sole HLA-A*02 allele (e.g., subjects with HLA alleles A*02:04 and A*02:07 are eligible); the subject has any A*02 null allele as their sole HLA-A*02 allele (denoted as "N", e.g., A*-2:32N). Subjects to be excluded include those with symptomatic central nervous system metastases.

[0173] Following leukocyte removal, the cells were subsequently treated with MAGE-A4 antigen (specifically, specific MAGE-A4 antigenic peptide, SEQ ID NO: 2). c1032 Transduction is performed using T cells (SEQ ID NOs. 5 and 7), and the cells are enlarged and cryopreserved for later use. MAGE-A4 c1032 Once T cells were obtained, the subjects received lymphocyte depletion chemotherapy with cyclophosphamide and fludarabine from day -7 to day -5 or from day -7 to day -4, followed by the injection of transduced cells on day 1.

[0174] Each of the three subject cohorts was administered 100 million to 5 billion transdextrin cells, without dose escalation: Dosage for 100 million cells (cyclophosphamide: 500 mg / m²) 2 (d) × 3 days; (Fludarabine: 20 mg / m²) 2 / d)×3 days Dosage for 1 billion cells (cyclophosphamide: 500 mg / m²) 2 (d) × 3 days; (Fludarabine: 20 mg / m²) 2 / d)×3 days Dosage for 5 billion cells (cyclophosphamide: 600 mg / m²) 2 (d) × 3 days; (Fludarabine: 30 mg / m²) 2 / d)×4 days

[0175] Subjects will be hospitalized for 7 days after injection to monitor safety, T cell persistence, and cytokine production. CT and MRI scans will be performed at weeks 4, 8, 16, and 24, and thereafter every 3 months until disease progression or discontinuation due to early intervention. A long-term annual follow-up study is planned for 15 years.

[0176] Subjects who receive T-cell infusions are considered to have completed the intervention phase of the study if they subsequently experience disease progression or die before disease progression. A second T-cell infusion may be administered voluntarily, and the subject remains in the intervention phase until further disease progression occurs. Once progression is confirmed, no further efficacy evaluations other than overall survival will be performed. All subjects who complete the intervention phase of the study will enter a long-term follow-up (LTFU) phase to observe delayed adverse events (AEs) for 15 years after infusion, in accordance with FDA and EMA regulations. The study will be considered complete when the last surviving subject completes the LTFU.

[0177] MAGE-A4 c1032 To assess the safety and tolerability of T, the occurrence of dose-limiting toxicity (DLT) is monitored, and the optimal acceptable dose range, adverse events (AEs) and serious adverse events (SAEs); clinical laboratory evaluations including blood chemistry, hematological tests and coagulation tests; and cardiac evaluations including electrocardiogram and cardiac troponin are determined.

[0178] During the study period, MAGE-A4 will be evaluated as a biomarker for tumor MAGE-A4 expression and antitumor activity. This involves assessing the antigen expression level at the tumor level at baseline and the MAGE-A4 level. c1032 This is done to correlate with T-cell injection. MAGE-A4 expression in tumors after treatment is evaluated over time to determine tumor immunity or MAGE-A4 c1032 Resistance to T was determined. Furthermore, serum cytokine levels were measured and their association with cytokine release syndrome (CRS) and other adverse events (AEs) was evaluated. In addition, MAGE-A4 c1032 After T cell infusion, MAGE-A4 c1032T-vector copy count and MAGE-A4 c1032 MAGE-A4 is measured by the number of transduced T cells. c1032 The persistence of transduced cells was assessed by measuring the persistence of serum levels of T cells engineered by T. The mean expression of specific surface markers on genetically modified T cells in subject blood and tumor samples was measured by fluorescence intensity. The death and cytokine profiles of genetically modified T cells were evaluated using flow cytometry in blood and tumor samples. Biomarkers of subject samples included polymorphisms in cytokine genes and cytokine production.

[0179] MAGE-A4 c1032 To evaluate the antitumor activity of T, the following endpoint was monitored according to RECIST v1.1: overall response rate (ORR), defined as the percentage of subjects who achieved a complete response (CR) or partial response (PR). Other endpoints monitored included duration of response (DoR), disease stability (SD), progression-free survival (PFS), and overall survival (OS). The efficacy of the treatment was evaluated by assessing the duration of response and overall survival. The following intervals were also evaluated: (a) Evaluation of the effectiveness of the treatment by assessing the time from the day of the initial T-cell infusion to the first recorded CR or PR finding and the time to the first response. (b) From the date on which a complete response (CR) or partial response (PR) was first recorded until the first recorded progression of the disease or death from any cause. (c) From the date on which the first finding of stable disease (SD) was recorded until the first recording of disease progression or death from any cause. (d) The date of the first T-cell infusion and the earliest date of death from the disease, progression, or any other cause. (e) From the day of the first T-cell injection until the day of death from any cause.

[0180] Evaluation of treatment effectiveness based on the number and proportion of subjects with long-term follow-up adverse events (AEs), malignancies, neuropathy, rheumatic or other autoimmune diseases, hematological disorders, and infections.

[0181] The subjects were further monitored for safety and tolerability responses through clinical laboratory evaluations including blood chemistry, hematological and coagulation tests, as well as for adverse events (AEs), including anti-MAGE-A4 TCR antibodies, serious adverse events (SAEs), dose-limiting toxicity (DLTs), NCI CTCAEs, optimal tolerable dose ranges, and evaluation of the persistence of genetically modified T cells in the periphery and the retention of heterologous TCR expression in T cell PBMCs using PCR-based assays.

[0182] The same test was conducted on subjects with ovarian cancer, melanoma, urothelial / bladder cancer, and sarcoma (synovial sarcoma) using MAGE-A4. c1032 We have also expanded our research to include treatment with T, and the data is shown below.

[0183] result The data shown in Figure 1 is 5 × 10 9 pieces~10×10 9 MAGE-A4 for individual cells (5 billion to 10 billion cells) c1032 For patients with head and neck cancer and lung cancer who received T-cell infusion doses, the best overall response is defined as the best response recorded from the T-cell infusion date to disease progression, based on the RECIST v1.1 response criteria. These data support the responses observed in subjects with head and neck cancer and lung cancer.

[0184] The data in Figure 2 show CT scans of a 42-year-old male subject who was diagnosed at age 25 and recently developed metastatic disease. The subject had moderate MAGE-A4 expression at baseline (16% 1+, 37% 2+, 41% 3+) and a large tumor burden; the baseline SLD was 20 cm and contained approximately 10 billion SPEAR MAGE-A4 c1032Upon initial T-cell infusion, side effects were minimized to grade 2 CRS (cytokine release syndrome) and cytopenia, consistent with those typically experienced by cancer patients undergoing cytotoxic chemotherapy and / or cancer immunotherapy. For lung cancer, the tumor showed a reduction of over 45% according to RECIST 1.1, and shortness of breath symptoms disappeared with treatment. The shortness of breath was due to fluid in the pleural cavity, shown in the lower left of Figure 2, which has disappeared in the lower right. Figure 2 also shows that at baseline, a large tumor displaced major vessels and compressed the right lung, but the upper right scan 12 weeks after treatment shows a dramatic reduction in tumor size and the absence of non-target lesions. The lower right scan of Figure 2 shows lung dilation.

[0185] The data in Figure 3 show the tumor response for cohort subjects with different cancers expressing MAGE-A4, and the percentage change in the total diameter of target lesions over a measurement period of several weeks following the T-cell infusion day. This data supports the efficacy of the response at 24 weeks or 6 months for tumor size reduction (36% reduction) with head and neck cancer treatment.

[0186] Data from individual subjects with ovarian cancer, urothelial / bladder cancer, and melanoma also showed that MAGE-A4 is determined by the percentage change in the total diameter of the target lesion, based on the sum of the longest diameters (SLD) for non-nodular lesions and the sum of the shortest diameters for nodular lesions. c1032 Tumor size reduction was demonstrated after T-cell therapy (injection of 5 to 10 billion cells); response was evaluated by RECIST 1.1. According to this data, MAGE-A4 c1032 At 12 weeks after infusion of T-mediated T cells, ovarian cancer tumor SLD was reduced by approximately 9%, and MAGE-A4 c1032 Six weeks after infusion of T-mediated T cells, melanoma tumor SLD was reduced by approximately 21%, and MAGE-A4 c1032Six weeks after the injection of T cells manipulated by T, the tumor SLD of urothelial / bladder cancer decreased by approximately 67% (Figure 3). Thus, this data indicates the therapeutic effects and the reduction of target tumors observed in patients with ovarian cancer, urothelial / bladder cancer, and melanoma.

[0187] As a conclusion above, the data from this clinical trial shows that the efficacy confirmed in subjects with head and neck cancer and lung cancer was observed, and tumor shrinkage was also observed in patients with ovarian cancer, bladder cancer, and melanoma.

[0188] Sequence SEQ ID NO: 1, MAGE A4

[0189]

Chem.

[0190] SEQ ID NO: 2, MAGE A4 peptide GVYDGREHTV

[0191] SEQ ID NO: 3; (CD8α) CDR is in bold underlined, signal sequence is in italic underlined

[0192]

Chem.

[0193] SEQ ID NO: 4; (CDʋα)

[0194]

Chem.

[0195] SEQ ID NO: 5; (MAGE A4 TCRα chain) CDR is in bold underlined

[0196]

Chem.

[0197] Accession number 6; (MAGE A4 TCR α-chain coding sequence)

[0198]

Chem.

[0199] Accession number 7; (MAGE A4 TCR β-chain) CDRs are in bold and underlined

[0200]

Chem.

[0201] Accession number 8; (MAGE A4 TCR β-chain coding sequence)

[0202]

Chem.

[0203] Accession number 9; (MAGE A4 TCR α-chain variable region) 136 AA - CDRs are in bold and underlined MKKHLTTFLVILWLYFYRGNGKNQVEQSPQSLIILEGKNCTLQCNYT VSFSSN LRWYKQDTGRGPVSLTI LTFSEN TKSNGRYTATLDADTKQSSLHITASQLSDSASYI CVVSGGTDSWGKLQF GAGTQVVVTPD

[0204] Accession number 10; (MAGE A4 TCR β-chain variable region) 133 AA - CDRs are in bold and underlined MASLLFFCGAFYLLGTGSMDADVTQTPRNRITKTGKRIMLECSQT KGHDR MYWYRQDPGLGLRLIYY SFDVKD INKGEISDGYSVSRQAQAKFSLSLESAIPNQTALYF CATSGQGAYEEQFF GPGTRLTVLE

[0205] Accession number 11; CDR1 of MAGE A4 TCR α-chain, (residues 48 - 53) VSFSSN

[0206] Sequence ID 12; CDR2 MAGE A4 TCRα chain, (residues 71-76) LTFSEN

[0207] Sequence ID 13; CDR3 MAGE A4 TCRα chain, (residues 111-125) CVVSGGTDSWGKLQF

[0208] Sequence ID 14; CDR1 MAGE A4 TCRβ chain, (residues 46-50) KGHDR

[0209] Sequence ID 15; CDR2 MAGE A4 TCRβ chain, (residues 68-73) SFDVKD

[0210] Sequence ID 16; CDR3 MAGE A4 TCRβ chain, (residues 110-123) CATSGQGAYEEQFF

[0211] Sequence ID 17; CDR1 CD8α (residues 45-53) VLLSNPTSG

[0212] Sequence ID 18; CDR2 CD8α (residues 72-79) YLSQNKPK

[0213] Sequence ID 19; CDR3 CD8α (residues 118-123) LSNSIM The inventions described in the original claims of this application are listed below. [Invention 1] A method for treating, preventing, or delaying the progression of cancer and / or tumor in a subject, comprising administering to the subject a therapeutic regimen comprising a therapeutic regimen comprising a subject comprising an effective amount of modified immune-responsive cells expressing or presenting a heterologous T cell receptor (TCR) that binds to a peptide antigen of MAGE A4, including GVYDGREHTV, SEQ ID NO: 2, wherein the cancer and / or tumor is a cancer and / or tumor of the head and neck or a cancer and / or tumor of the lung. [Invention 2] The method according to invention 1 or 2, wherein the peptide antigen of MAGE A4 comprises the sequence GVYDGREHTV, SEQ ID NO: 2. [Invention 3] The method according to invention 1 or 2, wherein the heterologous TCR specifically and / or selectively binds to the peptide antigen. [Invention 4] The method according to any one of inventions 1 to 3, wherein the peptide antigen is associated with cancer and / or tumors of the head and neck or lung cancer and / or tumors, and / or is presented by tumor and / or cancer cells or tissue. [Invention 5] The method according to any one of Inventions 1 to 4, wherein the cancer and / or tumor is a cancer and / or tumor expressing MAGE A4, and / or expressing MAGE A4 or its peptide antigen, or a MAGE A4 peptide antigen including GVYDGREHTV, SEQ ID NO: 2. [Invention 6] The method according to any one of inventions 1 to 5, wherein the peptide antigen forms a complex with a peptide-presenting molecule, optionally with major histocompatibility complex (MHC) or human leukocyte antigen (HLA), optionally with class I or class II. [Invention 7] The method according to Invention 6, wherein the peptide-presenting molecule is HLA-A*02, and optionally selected from HLA*02, HLA-A*02:01, HLA-A*02:02, HLA-A*02:03, HLA-A*02:04, HLA-A*02:06, HLA-A*02:642, or HLA-A*02:07, preferably HLA-A*02:01 or HLA-A*02. [Invention 8] The method according to any one of inventions 1 to 6, wherein the heterologous TCR specifically and / or selectively binds to the peptide antigen and / or the peptide-presenting molecule and / or its complex. [Invention 9] The method according to any one of Inventions 1 to 5, wherein the peptide antigen is presented independently of the peptide-presenting molecule. [Invention 10] The heterologous TCR comprises a TCRα chain variable domain and a TCRβ chain variable domain, (i) The α chain variable domain is sequence VSPFSN(αCDR1), amino acids 48-53 of SEQ ID NO: 11 or SEQ ID NO: 5, or sequences having at least 50% sequence identity to them. LTFSEN(αCDR2), amino acids 71-76 of SEQ ID NO: 12 or SEQ ID NO: 5, or sequences having at least 50% sequence identity to them, and CVVSGGTDSWGKLQF(αCDR3), amino acids 111-125 of SEQ ID NO: 13 or SEQ ID NO: 5, or sequences having at least 50% sequence identity to them. Includes a CDR having, (ii) The β-chain variable domain is sequence KGHDR(βCDR1), amino acids 46-50 of SEQ ID NO: 14 or SEQ ID NO: 7, or sequences having at least 50% sequence identity to them. SFDVKD(βCDR2), amino acids 68-73 of SEQ ID NO: 15 or SEQ ID NO: 7, or sequences having at least 50% sequence identity to them, CATSGQGAYEEQFF(βCDR3), amino acids 110-123 of SEQ ID NO: 16 or SEQ ID NO: 7, or sequences having at least 50% sequence identity to them. Includes a CDR having The method according to any one of inventions 1 to 9. [Invention 11] The aforementioned different TCRs, (a) The α-chain variable domain contains an amino acid sequence having at least 80% identity with SEQ ID NO: 9, and / or the β-chain variable domain contains an amino acid sequence having at least 80% identity with SEQ ID NO: 10, (b) The α-chain variable domain comprises an amino acid sequence containing SEQ ID NO: 9 and / or the β-chain variable domain comprises SEQ ID NO: 10, (c) The α chain contains an amino acid sequence having at least 80% identity with SEQ ID NO: 5, and / or the β chain contains an amino acid sequence having at least 80% identity with SEQ ID NO: 6, (d) The α chain comprises an amino acid sequence containing SEQ ID NO: 5, and / or the β chain comprises an amino acid sequence containing SEQ ID NO: 6. A method according to any one of inventions 1 to 10, including TCR. [Invention 12] The method according to any one of inventions 1 to 11, wherein the modified immune-responsive cells expressing or presenting a heterologous TCR further express or present a heterologous coreceptor, optionally the coreceptor being a CD8 coreceptor. [Invention 13] The method according to Invention 12, wherein the heterogeneous CD8 coreceptor is a heterodimer or homodimer, a CD8αb heterodimer or a CD8αα homodimer. [Invention 14] The aforementioned heterologous CD8 coreceptor, (a) CDR1 having at least 80% sequence identity to amino acid sequence VLLSNPTSG and SEQ ID NO: 17, CDR2 having at least 80% sequence identity to amino acid sequence YLSQNKPK and SEQ ID NO: 18, and CDR3 having at least 80% sequence identity to amino acid sequence LSNSIM and SEQ ID NO: 19. (b) Amino acid sequence VLLSNPTSG, CDR1 of SEQ ID NO: 17, amino acid sequence YLSQNKPK, CDR2 of SEQ ID NO: 18, and amino acid sequence LSNSIM, CDR3 of SEQ ID NO: 19 (c) an amino acid sequence having at least 80% sequence identity with amino acid numbers 22-235 of SEQ ID NO: 3, or amino acid sequence having at least 80% sequence identity with amino acid numbers 22-135 of SEQ ID NO: 3, (d) Amino acid sequences that have 100% sequence identity with amino acid numbers 22-235 of the sequence of SEQ ID NO: 3, or amino acid sequences that have 100% sequence identity with amino acid numbers 22-135 of SEQ ID NO: 3 A method according to invention 10 or 11, comprising any one of the following. [Invention 15] The method according to any one of Inventions 1 to 14, wherein the modified immune-responsive cells expressing or presenting a heterologous TCR further express or present a heterologous costimulatory ligand, optionally 4-1BBL or CD80. [Invention 16] The modified immune-responsive cells are (a) B cells, T cells or natural killer (NK) cells, (b) T cells, optionally CD4 + T cells and / or CD8 + A method according to any one of Inventions 1 to 15, wherein the cell is a T cell. [Invention 17] The method according to any one of inventions 1 to 16, wherein the modified immune-responsive cells are a population of CD4+ T cells, or CD8+ T cells, or a mixed population of CD4+ T cells and CD8+ T cells. [Invention 18] The method according to any one of inventions 1 to 17, wherein the modified immune-responsive cells are administered continuously or intermittently. [Invention 19] The method according to any one of Inventions 1 to 18, wherein the modified immune-responsive cells are administered in multiple doses or in a single dose. [Invention 20] The method according to Invention 19, wherein the single dose or multiple doses are administered in one or more drug cycles, and optionally the doses may be fixed or variable. [Invention 21] The method according to any one of Inventions 1 to 20, wherein the modified immune-responsive cells are administered in a dose between approximately 500 million and 1 billion cells, approximately 2 billion and 5 billion cells, or approximately 6 billion and 10 billion cells. [Invention 22] The modified immune-responsive cells (a) A single dose in each of one or more medication cycles, (b) One or more doses in each of one or more medication cycles, (c) A single dose on the first day of each of one or more medication cycles, (d) One or more doses in each of one or more medication cycles, in which at least one dose is administered on the first day of each cycle. (e) One or more doses in each of one or more medication cycles, in which at least one dose is administered on the first day of each cycle. (f) Single dose A method according to any one of inventions 1 to 21, administered as such. [Invention 23] The method according to any one of inventions 20 to 22, wherein the drug administration cycle is between two months and six months or continues as the disease progresses. [Invention 24] The aforementioned medication cycle, (a) Disease progression following a previous administration of modified immune-responsive cells, and continuing for 12 weeks or more after the previous administration of said modified immune-responsive cells, (b) The tumor and / or cancer expresses MAGE-A4 and / or its peptide antigen, and / or (d) MAGE-A4 and / or its peptide antigen are detected in the subject's biological sample and / or exceed the normal range. The method according to any one of inventions 20 to 23. [Invention 25] The aforementioned medication cycle, (a) complete or partial response following prior administration of modified immune-responsive cells, or (b) disease stability for a period of four months or more following prior administration of said modified immune-responsive cells, followed by no disease progression; and (c) continued for 12 weeks or more following prior administration of said modified immune-responsive cells. (d) The tumor and / or cancer expresses MAGE-A4 and / or its peptide antigen, and / or (d) MAGE-A4 and / or its peptide antigen are detected in the subject's biological sample and / or exceed the normal range. The method according to any one of inventions 20 to 23. [Invention 26] The method according to any one of inventions 1 to 25, wherein the modified immune-responsive cells are administered intravenously or by intravenous injection. [Discussion 27] The method according to any one of Inventions 1 to 26, wherein, prior to treatment, the subject has a US East Coast Clinical Oncology Group (ECOG) score of 0 to 1 and / or has a measurable disease and / or histologically confirmed head, neck, or lung cancer / tumor according to the Criteria for Efficacy of Solid Infections (RECIST) 1.1. [Invention 28] Before treatment, the subject, (a) The HLA-A genotype is HLA-A*02:05 positive, (b) The HLA-A genotype is HLA-A*02:07 with only one HLA-A*02 allele (for example, subjects with HLA alleles A*02:04 and A*02:07 are eligible), (c) The HLA-A genotype is HLA-A* of any A*02 null allele as the sole HLA-A*02 allele, or (d) Symptomatic CNS metastases The method according to any one of inventions 1 to 27, wherein the subject is excluded from treatment if he or she has any one or more of the following conditions. [Invention 29] The method according to any one of Inventions 1 to 28, wherein the subject is intolerant to standard treatment, or optionally to platinum-based systemic chemotherapy. [Invention 30] The method according to any one of Inventions 1 to 29, wherein the head and neck or lung cancer and / or tumor has previously been unsuccessful in treatment with standard therapy, optionally with platinum-based systemic chemotherapy. [Invention 31] The method according to any one of Inventions 1 to 30, wherein the cancer and / or tumor of the head and neck or lung has previously been unsuccessful in treatment with surgery (resection), radiotherapy, targeted therapy, immunotherapy or chemotherapy, or chemotherapy in combination with surgery (resection), radiotherapy, radiotherapy-targeted therapy, checkpoint inhibitors or immunotherapy. [Invention 32] The method according to any one of Inventions 1 to 31, wherein the subject has cancer and / or a tumor of the head and neck or lung, or the cancer and / or tumor of the head and neck or lung is a primary cancer, secondary cancer, recurrent cancer, refractory cancer, recurrent cancer, locally recurrent cancer, or metastatic cancer, unresectable cancer, locally localized cancer for which there are no surgical or radiotherapy options, or inoperable cancer, and the cancer is optionally not subject to transplantation or localized therapy. [Invention 33] The method according to any one of inventions 1 to 32, wherein the cancer and / or tumor of the head and neck is squamous cell head and neck carcinoma or head and neck squamous cell carcinoma (HNSCC), and optionally metastatic and / or progressive and / or locally progressive and / or recurrent squamous cell head and neck carcinoma or head and neck squamous cell carcinoma (HNSCC). [Invention 34] The method according to any one of Inventions 1 to 32, wherein the lung cancer and / or tumor is NSCLC, squamous NSCLC, adenosquamous NSCLC, or large cell carcinoma, optionally one of metastatic and / or progressive and / or locally progressive and / or recurrent NSCLC, squamous NSCLC, adenosquamous NSCLC, or large cell carcinoma. [Invention 35] The method according to any one of inventions 1 to 34, wherein the subject undergoes lymphocyte apheresis chemotherapy before administration of the modified immune-responsive cells expressing or presenting a heterologous T cell receptor (TCR). [Invention 36] The aforementioned lymphocyte-depleting chemotherapy involves cyclophosphamide and fludarabine, optionally administered at 500 mg / m². 2 Cyclophosphamide and 20 mg / m² daily for 3 days. 2 Fludarabine doses of 600 mg / m² or 600 mg / m² per day for 3 days. 2 Cyclophosphamide and 30 mg / m³ daily for 3 days. 2 The method according to invention 35, comprising administration at a dose of / d x 4 days. [Invention 37] The method according to invention 35 or 36, wherein the lymphocyte apheresis chemotherapy is administered 7 to 5 days or 7 to 4 days before the administration of the modified immune-responsive cells expressing or presenting a heterologous T cell receptor (TCR). [Invention 38] The method according to any one of Inventions 1 to 37, wherein the subject has not received prior treatment for cancer and / or tumors. [Invention 39] The method according to any one of Inventions 1 to 37, wherein the subject has received prior treatment for cancer and / or tumors, and / or prior treatment for cancer and / or tumors has not been effective. [Invention 40] The method according to Invention 39, wherein the prior treatment includes, optionally, one or more systemic and / or local therapies, surgery, radiotherapy, cryotherapy, laser therapy, local therapy and / or systemic therapy, for example, one or more chemotherapy, hormone therapy, targeted drugs, targeted chemotherapy or immunotherapy. [Invention 41] The method according to Invention 40, wherein the 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 42] The method according to Invention 40, wherein the prior treatment comprises an epidermal growth factor receptor antagonist, and optionally comprises any one of cetuximab, erlotinib, gefitinib, or afatinib. [Invention 43] The method according to Invention 40, wherein the prior treatment includes chemotherapy comprising a platinum compound, which is arbitrarily selected from lipoplatin, cisplatin, carboplatin, oxaliplatin, nedaplatin, triplatin tetranitrate, phenantriplatin, satraplatin, and picoplatin. [Invention 44] The method according to Invention 40, wherein the prior treatment comprises chemotherapy comprising a chemotherapeutic agent selected from any or a combination thereof from methotrexate, capecitabine, taxane, anthracycline, paclitaxel, docetaxel, paclitaxel protein-binding particles, doxorubicin, epirubicin, 5-fluorouracil, cyclophosphamide, afatinib, vincristine, and etoposide. [Invention 45] The method according to Invention 40, wherein the prior treatment includes 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 46] The method according to any one of inventions 40 to 45, wherein the subject has not received prior treatment in the event of a relapse within 12 months of the last treatment or within 6 months of the last treatment. [Invention 47] The method according to any one of Inventions 40 to 45, wherein the subject has not received any prior adjuvant therapy (e.g., postoperative radiotherapy and / or chemotherapy) or local treatment in the event of a relapse within 12 months of the last treatment or within 6 months of the last treatment. [Invention 48] Compared to placebo, or compared to pre-treatment, or compared to no treatment, or compared to standard treatment, optionally including platinum-based systemic chemotherapy, the treatment is, (a) Progression-free survival, (b) progression-free period, (c) Duration of response, (d) overall survival; (e) Objective response or objective response rate, (f) Total response or total response rate, (g) Partial response or partial response rate (h) Complete response or complete response rate; (i) Disease stability rate or median disease stability, (j) median progression-free survival, (k) median progression-free interval, (l) median duration of response, or (m) Median overall survival rate; (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 disease stability rate or median disease stability A method according to any one of inventions 1 to 47, which effectively extends or improves.

Claims

1. A pharmaceutical composition for use in a method to treat, prevent, or delay the progression of cancers and / or tumors of the head and neck expressing MAGE-A4, or cancers and / or tumors of the lung expressing MAGE-A4, in a subject, The pharmaceutical composition comprises modified T cells that express or present a heterologous T cell receptor (TCR) that binds to the MAGE-A4 peptide GVYDGREHTV (SEQ ID NO: 2). The method includes administering a therapeutic regimen containing an effective amount of the modified T cells to the subject. The aforementioned pharmaceutical composition.

2. The pharmaceutical composition according to claim 1, wherein the heterogeneous TCR specifically and / or selectively binds to the MAGE-A4 peptide.

3. (a) The MAGE-A4 peptide is a peptide-presenting molecule, optionally, the peptide-presenting molecule is complexed with (i) a major histocompatibility complex (MHC) or human leukocyte antigen (HLA), optionally, class I or class II, or (ii) HLA-A*02, optionally selected from HLA-A*02:01, HLA-A*02:02, HLA-A*02:03, HLA-A*02:04, HLA-A*02:06, HLA-A*02:642 or HLA-A*02:07, preferably HLA-A*02:01 or HLA-A*02, optionally, the heterologous TCR binds specifically and / or selectively to the MAGE-A4 peptide and / or the peptide-presenting molecule and / or its complex, (b) The MAGE-A4 peptide is presented independently of the peptide-presenting molecule. The pharmaceutical composition according to claim 1 or 2.

4. The aforementioned different TCRs, (a) comprising a TCRα chain variable domain and a TCRβ chain variable domain, (i) The α chain variable domain is sequence VSPFSN (αCDR1) (amino acids 48-53 of SEQ ID NO: 11 or SEQ ID NO: 5), LTFSEN (αCDR2) (amino acids 71-76 of SEQ ID NO: 12 or SEQ ID NO: 5), and CVVSGGTDSWGKLQF (αCDR3) (amino acids 111-125 of SEQ ID NO: 13 or SEQ ID NO: 5) Includes a CD-R having, (ii) The β-chain variable domain is sequence KGHDR (βCDR1) (amino acids 46-50 of SEQ ID NO: 14 or SEQ ID NO: 7), SFDVKD(βCDR2) (amino acids 68-73 of SEQ ID NO: 15 or SEQ ID NO: 7), and CATSGQGAYEEQFF(βCDR3) (amino acids 110-123 of SEQ ID NO: 16 or SEQ ID NO: 7) Includes a CD-R having and / or (b) (i) The α-chain variable domain comprises an amino acid sequence containing the α-chain variable domain of SEQ ID NO: 9, and / or the β-chain variable domain comprises the β-chain variable domain of SEQ ID NO: 10, or (ii) The α chain comprises an amino acid sequence including the α chain of SEQ ID NO: 5, and / or the β chain comprises an amino acid sequence including the β chain of SEQ ID NO:

7. Including TCR, A pharmaceutical composition according to any one of claims 1 to 3.

5. The modified T cells further express or present heterologous coreceptors, optionally (a) The heterogeneous coreceptor is a CD8 coreceptor. (b) The heterogeneous coreceptor is a CD8 coreceptor, and the CD8 coreceptor is a heterodimer or homodimer, a CD8αb heterodimer or a CD8αα homodimer, or (c) The heterogeneous coreceptor is a CD8 coreceptor, and the CD8 coreceptor is (i) CDR1 of amino acid sequence VLLSNPTSG (SEQ ID NO: 17), CDR2 of amino acid sequence YLSQNKPK (SEQ ID NO: 18), and CDR3 of amino acid sequence LSNSIM (SEQ ID NO: 19), or (ii) Amino acid sequences that have 100% sequence identity with amino acid numbers 22-235 of the sequence of SEQ ID NO: 3, or amino acid sequences that have 100% sequence identity with amino acid numbers 22-135 of SEQ ID NO: 3 including, A pharmaceutical composition according to any one of claims 1 to 4.

6. (a) The modified T cells further express or present a heterostimulatory ligand, optionally 4-1BBL or CD80, and / or (b) The modified T cells are a population of CD4+ T cells, or CD8+ T cells, or a mixed population of CD4+ T cells and CD8+ T cells. A pharmaceutical composition according to any one of claims 1 to 5.

7. The modified T cells described above (a) administered continuously or intermittently, (b) administered as multiple doses or as a single dose, (c) administered intravenously or by intravenous infusion, A pharmaceutical composition according to any one of claims 1 to 6.

8. The modified T cells described above (a) administered in multiple doses or a single dose, wherein the single dose or multiple doses are administered in one or more dosing cycles, and optionally the dose is a fixed dose or a variable dose. (b) administered in doses between approximately 500 million and 1 billion cells, approximately 2 billion and 5 billion cells, or approximately 6 billion and 10 billion cells, and / or (c) (i) A single dose in each of one or more medication cycles, (ii) One or more doses in each of one or more medication cycles, (iii) A single dose on the first day of each of one or more medication cycles, (iv) One or more doses in each of one or more medication cycles, with at least one dose administered on the first day of each cycle. (v) One or more doses in each of one or more medication cycles, in which at least one dose is administered on the first day of each cycle, (vi) Single dose It is administered as follows: Optionally, the medication cycle may last between two and six months, or may be continued as the disease progresses. A pharmaceutical composition according to any one of claims 1 to 7.

9. (i) The drug administration cycle continues after disease progression following a previous administration of the modified T cells, and 12 weeks or more after the previous administration of the modified T cells, (ii) The drug administration cycle continues for at least 12 weeks after (a) a complete or partial response following a previous administration of the modified T cells, or (b) disease stability for at least 4 months following a previous administration of the modified T cells, with no subsequent disease progression; and (c) at least 12 weeks after a previous administration of the modified T cells. The pharmaceutical composition according to claim 8.

10. (a) Before treatment, the subject The East Coast Cancer Clinical Trials Group (ECOG) is 0 to 1, and / or Patients with a measurable disease according to the Solid Tumor Efficacy Assessment Criteria (RECIST) 1.1, and / or histologically confirmed head and neck cancer and / or tumors or lung cancer and / or tumors, (b) Before treatment, the subject (i) The HLA-A genotype is HLA-A*02:05 positive, (ii) The HLA-A genotype is HLA-A*02:07 with only one HLA-A*02 allele (for example, subjects with HLA alleles A*02:04 and A*02:07 are eligible). (iii) The HLA-A genotype is HLA-A* of any A*02 null allele as the sole HLA-A*02 allele, or (iv) Symptomatic CNS metastasis If a subject has any one or more of the following conditions, the subject is excluded from treatment, and / or (c) The subject is intolerant to standard treatment, or optionally to platinum-based systemic chemotherapy. A pharmaceutical composition according to any one of claims 1 to 9.

11. (a) The head and neck cancer and / or tumor or lung cancer and / or tumor has previously been unsuccessful in treatment with standard therapy, optionally with platinum-based systemic chemotherapy, (b) The head and neck cancer and / or tumor or lung cancer and / or tumor has previously been unsuccessful in treatment with surgery (resection), radiotherapy, targeted therapy, immunotherapy, chemotherapy, or combination chemotherapy with surgery (resection), radiotherapy, targeted radiotherapy, checkpoint inhibitors, or immunotherapy, (c) The subject has cancer and / or tumors of the head and neck or cancer and / or tumors of the lung, or the cancer and / or tumors of the head and neck or lung are primary cancer, secondary cancer, recurrent cancer, refractory cancer, recurrent cancer, locally recurrent cancer, metastatic cancer, unresectable cancer, locally limited cancer, cancer for which there are no surgical or radiotherapy options, or inoperable cancer, and the cancer is optionally not a candidate for transplantation or localized therapy. (d) The head and neck cancer and / or tumor is squamous cell head and neck cancer or head and neck squamous cell carcinoma (HNSCC), and optionally is metastatic, progressive, locally progressive and / or recurrent squamous cell head and neck cancer or head and neck squamous cell carcinoma (HNSCC), and / or (e) The lung cancer and / or tumor is NSCLC, squamous NSCLC, adenosquamous NSCLC, or large cell carcinoma, optionally one of metastatic, progressive, locally progressive, and / or recurrent NSCLC, squamous NSCLC, adenosquamous NSCLC, or large cell carcinoma. A pharmaceutical composition according to any one of claims 1 to 10.

12. Prior to the administration of the modified T cells, the subject underwent lymphocyte apheresis chemotherapy, and optionally, the lymphocyte apheresis chemotherapy was administered. (i) Cyclophosphamide and fludarabine, optionally, 500 mg / m² ２ Cyclophosphamide and 20 mg / m³ daily for 3 days. ２ Fludarabine doses of 600 mg / m³ per day for 3 days, or 600 mg / m³. ２ Cyclophosphamide and 30 mg / m³ daily for 3 days. ２ / d x 4 days of administration of fludarabine, and / or (ii) Administered 7 to 5 days or 7 to 4 days before the administration of the modified T cells A pharmaceutical composition according to any one of claims 1 to 11.

13. The aforementioned subject, (a) Not having received prior treatment for cancer and / or tumors, (b) Having received prior treatment for cancer and / or tumors, and / or prior treatment for cancer and / or tumors has not been effective, Optionally, the prior treatment includes systemic and / or local therapy, optionally one or more of surgery, radiotherapy, cryotherapy, laser therapy, local therapy and / or systemic therapy, for example, one or more of chemotherapy, hormone therapy, targeted drugs, targeted chemotherapy or immunotherapy. A pharmaceutical composition according to any one of claims 1 to 12.

14. The subject has received prior treatment for cancer and / or tumors, and / or the prior treatment for cancer and / or tumors has not been effective. The aforementioned prior treatment, (i) comprising a PD-L1-binding antagonist or a PD-1-binding antagonist, wherein optionally the PD-1 axis-binding antagonist or the PD-L1-binding antagonist is an antibody. (ii) comprising an epidermal growth factor receptor antagonist, optionally comprising cetuximab, erlotinib, gefitinib, or afatinib, (iii) Chemotherapy comprising a platinum compound, optionally selected from any of the following: lipoplatin, cisplatin, carboplatin, oxaliplatin, nedaplatin, triplatin tetranitrate, phenantriplatin, satraplatin, and picoplatin. (iv) Chemotherapy comprising a chemotherapeutic agent selected from any or a combination thereof from methotrexate, capecitabine, taxane, anthracycline, paclitaxel, docetaxel, paclitaxel protein-binding particles, doxorubicin, epirubicin, 5-fluorouracil, cyclophosphamide, afatinib, vincristine, etoposide, or (v) 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. At their discretion, the subject may (a) In the event of a relapse within 12 months of the last treatment or within 6 months of the last treatment, the person has not received prior treatment, or (b) In the case of a relapse within 12 months of the last treatment, or within 6 months of the last treatment, the patient has not received any prior adjuvant therapy (e.g., postoperative radiotherapy and / or chemotherapy) or local therapy. The pharmaceutical composition according to claim 13.

15. Compared to placebo, or compared to pre-treatment, or compared to no treatment, or compared to standard treatment, optionally including platinum-based systemic chemotherapy, the treatment is, (a) Progression-free survival, (b) progression-free period, (c) Duration of response, (d) overall survival rate; (e) Objective response or objective response rate, (f) Total response or total response rate, (g) Partial response or partial response rate (h) Complete response or complete response rate; (i) Disease stability rate or median disease stability, (j) median progression-free survival, (k) median progression-free interval, (l) Median duration of response, (m) Median overall survival rate; (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 disease stability rate or median disease stability A pharmaceutical composition according to any one of claims 1 to 14, which effectively extends or improves.

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