Pharmaceutical composition for treating or preventing cancer
Patent Information
- Application Number
- JP2024566059
- Authority / Receiving Office
- JP · JP
- Patent Type
- Applications
- Filing Date
- 2025-05-19
- Publication Date
- 2025-07-29
Abstract
Description
Pharmaceutical composition for treating or preventing cancer
[0001] The present disclosure relates to a pharmaceutical composition for treating or preventing cancer. More specifically, the present disclosure relates to a pharmaceutical composition for treating or preventing cancer expressing KitaKyushu Lung Cancer Antigen 1 (KK-LC-1), in which a peptide or the like is administered in combination with T cells.
[0002] KitaKyushu Lung Cancer Antigen 1 (KK-LC-1) is a cancer antigen expressed in various cancers such as lung cancer, gastric cancer, breast cancer, and liver cancer, and is expressed only in the testis among normal tissues. Patent Document 1 discloses a cancer immunotherapy reagent using a peptide derived from KK-LC-1.
[0003] International Publication No. 2017 / 089756
[0004] The main object of the present disclosure is to provide techniques that can be used for immunotherapy against cancers that express KK-LC-1.
[0005] To solve the above problems, the present disclosure provides the following [1] to
[23] . [1] A pharmaceutical composition for treating or preventing cancer expressing KK-LC-1 in a subject, in which a peptide, a polynucleotide encoding the peptide, or a vector containing the polynucleotide is administered in combination with T cells, wherein the peptide and the T cells have the following combination (1) or (2) depending on the human leukocyte antigen (HLA) type of the subject: (1) A combination of a peptide comprising the amino acid sequence of SEQ ID NO: 1 and T cells expressing a T cell receptor (TCR) having a β chain comprising the complementarity-determining region 3 (CDR3) of SEQ ID NO: 2, when the subject's HLA type is HLA*C14. (2) A combination of a peptide comprising the amino acid sequence of SEQ ID NO: 3 and T cells expressing a TCR having a β chain comprising the CDR3 of SEQ ID NO: 4, 5, or 6, when the subject's HLA type is HLA*B15. [2] A pharmaceutical composition for administering a combination of a peptide, a polynucleotide encoding the peptide, or a vector containing the polynucleotide, and T cells to a subject for the treatment or prevention of cancer expressing KK-LC-1, wherein the peptide and the T cells have the following combination (1) or (2): (1) A combination of a peptide comprising the amino acid sequence of SEQ ID NO: 1 and T cells expressing a TCR having a β chain comprising CDR3 of SEQ ID NO: 2. (2) A combination of a peptide comprising the amino acid sequence of SEQ ID NO: 3 and T cells expressing a TCR having a β chain comprising CDR3 of SEQ ID NO: 4, 5, or 6. [3] The pharmaceutical composition of [2], wherein the HLA type of the subject is HLA*C14 in the combination of (1), or HLA*B15 in the combination of (2). [4] The pharmaceutical composition of [3], wherein the HLA type of the subject is HLA*C14:02 in the combination of (1), and HLA*B15:01 in the combination of (2). [5] The pharmaceutical composition of any of [1] to [4], wherein the cancer is lung cancer, stomach cancer, breast cancer, or liver cancer.
[0006] [6] A pharmaceutical composition comprising a peptide, a polynucleotide encoding the peptide, or a vector comprising the polynucleotide, which is administered in combination with T cells for the treatment or prevention of cancer expressing KK-LC-1 in a subject, wherein the peptide is (1) or (2) below: (1) A peptide comprising the amino acid sequence of SEQ ID NO: 1, which is administered in combination with T cells expressing a TCR having a β chain comprising a CDR3 of SEQ ID NO: 2. (2) A peptide comprising the amino acid sequence of SEQ ID NO: 3, which is administered in combination with T cells expressing a TCR having a β chain comprising a CDR3 of SEQ ID NO: 4, 5, or 6. [7] A pharmaceutical composition for the treatment or prevention of cancer expressing KK-LC-1 in a subject, which comprises a peptide, a polynucleotide encoding the peptide, or a vector comprising the polynucleotide, wherein the peptide is (1) or (2) below: (1) A peptide comprising the amino acid sequence of SEQ ID NO: 1. (2) A peptide comprising the amino acid sequence of SEQ ID NO: 3. [8] The pharmaceutical composition of [6] or [7], which is a cancer vaccine. [9] The pharmaceutical composition of any of [6] to [8], wherein the cancer is lung cancer, stomach cancer, breast cancer, or liver cancer.
[10] A peptide comprising the amino acid sequence of SEQ ID NO: 1 or 3, a polynucleotide encoding the peptide, or a vector comprising the polynucleotide.
[0007]
[11] A pharmaceutical composition comprising T cells, which is administered in combination with a peptide, a polynucleotide encoding the peptide, or a vector comprising the polynucleotide, for the treatment or prevention of cancer that expresses KK-LC-1 in a subject, wherein the T cells are either (1) or (2) below: (1) T cells expressing a TCR having a β chain comprising a CDR3 of SEQ ID NO: 2, which are administered in combination with a peptide comprising the amino acid sequence of SEQ ID NO: 1. (2) T cells expressing a TCR having a β chain comprising a CDR3 of SEQ ID NO: 4, 5, or 6, which are administered in combination with a peptide comprising the amino acid sequence of SEQ ID NO: 3.
[12] A pharmaceutical composition for the treatment or prevention of cancer that expresses KK-LC-1 in a subject, which comprises T cells, wherein the T cells are either (1) or (2) below: (1) T cells expressing a TCR having a β chain comprising a CDR3 of SEQ ID NO: 2. (2) T cells expressing a TCR having a β chain comprising a CDR3 of SEQ ID NO: 4, 5, or 6.
[13] The pharmaceutical composition according to
[11] or
[12] , wherein the cancer is lung cancer, stomach cancer, breast cancer, or liver cancer.
[14] A polynucleotide encoding a TCR having a β chain comprising CDR3 of SEQ ID NO: 2, 4, 5, or 6, or a vector comprising the polynucleotide.
[0008]
[15] A method for treating or preventing cancer expressing KK-LC-1 in a subject, comprising the step of administering to the subject a combination of a peptide, a polynucleotide encoding the peptide, or a vector containing the polynucleotide, and T cells, wherein the peptide and the T cells have the following combination (1) or (2) depending on the human leukocyte antigen (HLA) type of the subject: (1) A combination of a peptide comprising the amino acid sequence of SEQ ID NO: 1 and T cells expressing a TCR having a β chain comprising CDR3 of SEQ ID NO: 2. (2) A combination of a peptide comprising the amino acid sequence of SEQ ID NO: 3 and T cells expressing a TCR having a β chain comprising CDR3 of SEQ ID NO: 4, 5, or 6.
[16] A method for treating or preventing cancer that expresses KK-LC-1 in a subject, comprising the steps of: determining the HLA type of the subject; and administering a peptide, a polynucleotide encoding the peptide, or a vector containing the polynucleotide, in combination with T cells, wherein: (1) if the subject's HLA type is HLA*C14, a peptide comprising the amino acid sequence of SEQ ID NO: 1 is administered in combination with T cells expressing a TCR having a β chain comprising CDR3 of SEQ ID NO: 2, and (2) if the subject's HLA type is HLA*B15, a peptide comprising the amino acid sequence of SEQ ID NO: 3 is administered in combination with T cells expressing a TCR having a β chain comprising CDR3 of SEQ ID NO: 4, 5, or 6.
[17] The method of
[15] or
[16] , wherein the subject's HLA type is HLA*C14:02 in (1), or HLA*B15:01 in (2).
[18] The method according to any one of
[15] to
[17] , wherein the cancer is lung cancer, stomach cancer, breast cancer, or liver cancer.
[0009]
[19] A method for treating or preventing cancer that expresses KK-LC-1 in a subject, comprising the step of administering to the subject a peptide, a polynucleotide encoding the peptide, or a vector containing the polynucleotide, wherein the peptide is either (1) or (2) below: (1) A peptide comprising the amino acid sequence of SEQ ID NO: 1. (2) A peptide comprising the amino acid sequence of SEQ ID NO: 3.
[20] A method for treating or preventing cancer that expresses KK-LC-1 in a subject, comprising the steps of determining the HLA type of the subject, and administering to the subject a peptide, a polynucleotide encoding the peptide, or a vector containing the polynucleotide, wherein the peptide is either (1) or (2) below: (1) A peptide comprising the amino acid sequence of SEQ ID NO: 1 when the subject's HLA type is HLA*C14. (2) A peptide comprising the amino acid sequence of SEQ ID NO: 3 when the subject's HLA type is HLA*B15.
[0010]
[21] A method for treating or preventing cancer that expresses KK-LC-1 in a subject, comprising the step of administering T cells to the subject, wherein the T cells are either (1) or (2) below: (1) T cells expressing a TCR having a β chain comprising CDR3 of SEQ ID NO: 2. (2) T cells expressing a TCR having a β chain comprising CDR3 of SEQ ID NO: 4, 5, or 6.
[22] A method for treating or preventing cancer that expresses KK-LC-1 in a subject, comprising the steps of determining the HLA type of the subject and administering T cells to the subject, wherein the T cells are either (1) or (2) below: (1) T cells expressing a TCR having a β chain comprising CDR3 of SEQ ID NO: 2 when the HLA type of the subject is HLA*C14. (2) T cells expressing a TCR having a β chain comprising CDR3 of SEQ ID NO: 4, 5, or 6 when the HLA type of the subject is HLA*B15.
[0011]
[23] Use of a peptide, a polynucleotide encoding the peptide, a vector containing the polynucleotide, or T cells for producing a pharmaceutical composition for treating or preventing cancer expressing KK-LC-1 in a subject, wherein the pharmaceutical composition comprises a combination of the peptide and the T cells of (1) or (2) below: (1) A combination of a peptide comprising the amino acid sequence of SEQ ID NO: 1 and T cells expressing a T cell receptor (TCR) having a β chain comprising CDR3 of SEQ ID NO: 2. (2) A combination of a peptide comprising the amino acid sequence of SEQ ID NO: 3 and T cells expressing a TCR having a β chain comprising CDR3 of SEQ ID NO: 4, 5, or 6.
[0012] In the present disclosure, "immunogenicity" refers to the ability to induce an immune response (immune induction ability), for example, by increasing the cytotoxic T cell (CTL)-inducing activity of antigen-presenting cells and further increasing the cytotoxic activity of CTLs against cancer cells. Furthermore, in the present disclosure, "CTL induction" refers to the induction or proliferation of CTLs that specifically recognize the KK-LC-1 antigen, the differentiation of naive T cells into effector cells capable of killing target cells such as cancer cells (cytotoxic activity), and / or the enhancement of the cytotoxic activity of CTLs, when a peptide according to the present disclosure is presented on the surface of antigen-presenting cells in vitro or in vivo. CTL induction activity can be measured by assessing cytokine (e.g., IFN-γ) production by CTLs. For example, the CTL induction activity may be measured by evaluating the increase in cytokine-producing cells induced from precursor cells by antigen-presenting cells such as peripheral blood mononuclear cells stimulated with the peptides according to the present disclosure using known highly sensitive immunoassays such as the ELISPOT (Enzyme-Linked ImmunoSpot) method or the ELISA (Enzyme-Linked ImmunoSorbent Assay) method. 51The CTL-inducing activity of a test substance can be measured by known techniques such as the Cr release method. When the CTL-inducing activity of a test substance is significantly increased compared to a control substance, for example, when the increase is 5% or more, 10% or more, 20% or more, 30% or more, 40% or more, and preferably 50% or more, the test substance can be determined to have CTL-inducing activity.
[0013] The present disclosure provides techniques that can be used for immunotherapy against cancers that express KK-LC-1.
[0014] 1 shows the results of detecting antigen-specific responses in co-culture of B-APCs loaded with KK-LC-1 peptide and TexTCR-expressing cells expressing TexTCR (pt.2-ex08TCR). 2 shows the results of detecting antigen-specific responses in co-culture of HLA-expressing cells loaded with peptide CT83-12 (RFQRNTGEM) and TexTCR-expressing cells expressing TexTCR (pt.2-ex08TCR). 3 shows the results of detecting antigen-specific responses in co-culture of B-APCs loaded with KK-LC-1 peptide and TexTCR-expressing cells expressing TexTCR (pt.1-ex08TCR, pt.1-ex15TCR, or pt.2-ex09TCR). 4 shows the amino acid sequences of the full-length β and α chains and CDRs of TexTCR (pt.2-ex08TCR). 5 shows the amino acid sequences of the full-length β and α chains and CDRs of TexTCR (pt.1-ex08TCR). The amino acid sequences of the full-length β and α chains and CDRs of TexTCR (pt.1-ex15TCR) are shown. The amino acid sequences of the full-length β and α chains and CDRs of TexTCR (pt.2-ex09TCR) are shown.
[0015] [Peptide] The peptide according to the present disclosure comprises the amino acid sequence of SEQ ID NO: 1 or 3. The peptide according to the present disclosure is presented by HLA of antigen-presenting cells and recognized by TCR of T cells. Therefore, the peptide according to the present disclosure can be effectively used in immunotherapy for cancers expressing KK-LC-1.
[0016] The amino acid sequence of SEQ ID NO: 1 corresponds to positions 23-31 from the N-terminus of the full-length KK-LC-1 amino acid sequence. Peptides comprising the amino acid sequence of SEQ ID NO: 1 are HLA*C14-restricted, particularly HLA*C14:02-restricted. Therefore, peptides comprising the amino acid sequence of SEQ ID NO: 1 can be suitably used for CTL induction in subjects with an HLA type of HLA*C14, particularly HLA*C14:02. The amino acid sequence of SEQ ID NO: 3 corresponds to positions 76-84 from the N-terminus of the full-length KK-LC-1 amino acid sequence. Peptides comprising the amino acid sequence of SEQ ID NO: 3 are HLA*B15-restricted, particularly HLA*B15:01-restricted. Therefore, peptides comprising the amino acid sequence of SEQ ID NO: 3 can be suitably used for CTL induction in subjects with an HLA type of HLA*B15, particularly HLA*B15:01.
[0017] The peptide according to the present disclosure may comprise all or part of the amino acid sequence of SEQ ID NO: 1 or 3, and the total length of the peptide is preferably 8-11 amino acids for presentation by HLA. The peptide according to the present disclosure preferably comprises the entire amino acid sequence of SEQ ID NO: 1 or 3, and particularly preferably consists of the amino acid sequence of SEQ ID NO: 1 or 3.
[0018] The peptides according to the present disclosure may be modified in the amino acid residues constituting the amino acid sequence or in parts thereof. Modifications include, but are not limited to, glycosylation, side chain oxidation, and phosphorylation. Furthermore, the peptides according to the present disclosure may be substituted, inserted, deleted, or added with one or more amino acid residues, as long as they retain immunogenicity. When peptides are administered directly into the body, depending on the route of administration, the termini of the peptide may be digested in the digestive organs or other sources, resulting in changes. Therefore, the peptides according to the present disclosure may exist in the form of a precursor in which one or more amino acid residues are added to the N-terminus and / or C-terminus.
[0019] The peptides according to the present disclosure can be replaced by polynucleotides encoding the peptides, vectors containing the polynucleotides, or antigen-presenting cells that present on their surface a complex of the peptide and an HLA molecule. The peptides according to the present disclosure induce CTLs by being presented to the HLA of antigen-presenting cells, and the induced CTLs damage cancer cells. However, administration of these polynucleotides, vectors, and antigen-presenting cells can also induce CTLs in a manner similar to administration of the peptides.
[0020] [T Cells] T cells according to the present disclosure express a TCR having a β chain comprising a CDR3 of any one of SEQ ID NOs: 2, 4-6. In the binding of a complex of an HLA molecule and an antigenic peptide presented thereon to a TCR, CDR3 is involved in the recognition of the antigenic peptide, and the affinity to the antigenic peptide is determined particularly by the CDR3 of the β chain. The TCR of T cells according to the present disclosure recognizes the KK-LC-1 peptide presented by HLA. Therefore, T cells according to the present disclosure can be effectively used in immunotherapy for cancers expressing KK-LC-1.
[0021] T cells expressing a TCR having a β chain comprising the CDR3 of SEQ ID NO: 2 can bind to an HLA molecule presenting a peptide comprising the amino acid sequence of SEQ ID NO: 1. The peptide comprising the amino acid sequence of SEQ ID NO: 1 is restricted by HLA*C14 (particularly HLA*C14:02). Therefore, T cells expressing a TCR having a β chain comprising the CDR3 of SEQ ID NO: 2 are preferably administered in combination with a peptide comprising the amino acid sequence of SEQ ID NO: 1, and more preferably administered together with the peptide to a subject with an HLA type of HLA*C14 (particularly HLA*C14:02).
[0022] An example of a T cell expressing a TCR having a β chain comprising the CDR3 of SEQ ID NO: 2 is one that further comprises, as the complementarity-determining regions of the β chain, an HLA-binding region (CDR1) of SEQ ID NO: 17 and an HLA-binding region (CDR2) of SEQ ID NO: 18, and, as the complementarity-determining regions of the α chain, an HLA-binding region (CDR1) of SEQ ID NO: 19, an HLA-binding region (CDR2) of SEQ ID NO: 20, and an HLA-binding region (CDR3) of SEQ ID NO: 21. A T cell expressing a TCR having a β chain comprising the CDR3 of SEQ ID NO: 2 may comprise the amino acid sequence of SEQ ID NO: 22 as the full-length sequence of the β chain and the amino acid sequence of SEQ ID NO: 23 as the full-length sequence of the α chain.
[0023] T cells expressing a TCR having a β chain comprising a CDR3 of SEQ ID NO: 4, 5, or 6 can bind to an HLA molecule presenting a peptide comprising the amino acid sequence of SEQ ID NO: 3. A peptide comprising the amino acid sequence of SEQ ID NO: 3 is restricted by HLA-B15 (particularly HLA-B15:01). Therefore, T cells expressing a TCR having a β chain comprising a CDR3 of SEQ ID NO: 4, 5, or 6 are preferably administered in combination with a peptide comprising the amino acid sequence of SEQ ID NO: 3, and more preferably administered together with the peptide to a subject with an HLA type of HLA-B15 (particularly HLA-B15:01).
[0024] An example of a T cell expressing a TCR having a β chain comprising the CDR3 of SEQ ID NO: 4 is one that further comprises, as the complementarity-determining regions of the β chain, an HLA-binding region (CDR1) of SEQ ID NO: 24 and an HLA-binding region (CDR2) of SEQ ID NO: 25, and, as the complementarity-determining regions of the α chain, an HLA-binding region (CDR1) of SEQ ID NO: 26, an HLA-binding region (CDR2) of SEQ ID NO: 27, and an HLA-binding region (CDR3) of SEQ ID NO: 28. T cells expressing a TCR having a β chain comprising the CDR3 of SEQ ID NO: 4 may comprise the amino acid sequence of SEQ ID NO: 29 as the full-length sequence of the β chain and the amino acid sequence of SEQ ID NO: 30 as the full-length sequence of the α chain.
[0025] An example of a T cell expressing a TCR having a β chain comprising the CDR3 of SEQ ID NO: 5 is one that further comprises, as the complementarity-determining regions of the β chain, an HLA-binding region (CDR1) of SEQ ID NO: 31 and an HLA-binding region (CDR2) of SEQ ID NO: 32, and, as the complementarity-determining regions of the α chain, an HLA-binding region (CDR1) of SEQ ID NO: 33, an HLA-binding region (CDR2) of SEQ ID NO: 34, and an HLA-binding region (CDR3) of SEQ ID NO: 35. A T cell expressing a TCR having a β chain comprising the CDR3 of SEQ ID NO: 5 may comprise the amino acid sequence of SEQ ID NO: 36 as the full-length sequence of the β chain and the amino acid sequence of SEQ ID NO: 37 as the full-length sequence of the α chain.
[0026] An example of a T cell expressing a TCR having a β chain comprising the CDR3 of SEQ ID NO: 6 is one that further comprises, as the complementarity-determining regions of the β chain, an HLA-binding region (CDR1) of SEQ ID NO: 38 and an HLA-binding region (CDR2) of SEQ ID NO: 39, and as the complementarity-determining regions of the α chain, an HLA-binding region (CDR1) of SEQ ID NO: 40, an HLA-binding region (CDR2) of SEQ ID NO: 41, and an HLA-binding region (CDR3) of SEQ ID NO: 42. T cells expressing a TCR having a β chain comprising the CDR3 of SEQ ID NO: 6 may comprise the amino acid sequence of SEQ ID NO: 43 as the full-length β chain sequence, and the amino acid sequence of SEQ ID NO: 44 as the full-length α chain sequence.
[0027] The T cells of the present disclosure may be T cells in which the above-mentioned TCR is expressed by gene transfer (TCR gene-transfected T cells). Peripheral blood lymphocytes derived from a subject in need of cancer treatment or prevention are transformed with a vector containing a polynucleotide encoding a TCR, and the resulting TCR gene-transfected T cells are expanded and then infused back into the subject. The polynucleotide encoding the TCR or a vector containing the same may be introduced into peripheral blood lymphocytes by a conventionally known method, such as lipofection, electroporation, microinjection, cell fusion, DEAE-dextran, or calcium phosphate.
[0028] Furthermore, the T cells of the present disclosure can be replaced by T cells (CAR-T) expressing a CAR containing an antigen-recognition region derived from an antibody that binds to a complex of the peptide of the present disclosure and an HLA molecule. The antigen-recognition region is generally an scFv.
[0029] [Pharmaceutical Composition] The pharmaceutical composition according to the present disclosure is a pharmaceutical composition in which the above-mentioned peptide, a polynucleotide encoding the peptide, or a vector comprising the polynucleotide is administered in combination with T cells, wherein the peptide and the T cells have the following combination (1) or (2): (1) A combination of a peptide comprising the amino acid sequence of SEQ ID NO: 1 and T cells expressing a TCR having a β chain comprising a CDR3 of SEQ ID NO: 2. (2) A combination of a peptide comprising the amino acid sequence of SEQ ID NO: 3 and T cells expressing a TCR having a β chain comprising a CDR3 of SEQ ID NO: 4, 5, or 6.
[0030] In another aspect, the pharmaceutical composition according to the present disclosure may contain only the peptide or only the T cells described in (1) or (2) above.
[0031] A peptide comprising the amino acid sequence of SEQ ID NO: 1 is presented on HLA molecules of HLA*C14 (particularly HLA*C14:02) and recognized by T cells expressing a TCR having a β chain comprising a CDR3 of SEQ ID NO: 2. Therefore, a peptide comprising the amino acid sequence of SEQ ID NO: 1 and T cells expressing a TCR having a β chain comprising a CDR3 of SEQ ID NO: 2 can be administered in combination to a subject with an HLA type of HLA*C14 (particularly HLA*C14:02) and can be used particularly effectively in the treatment or prevention of cancers expressing KK-LC-1.
[0032] A peptide comprising the amino acid sequence of SEQ ID NO: 3 is presented on HLA molecules of HLA-B15 (particularly HLA-B15:01) and recognized by T cells expressing a TCR having a β chain comprising a CDR3 of SEQ ID NO: 4, 5, or 6. Therefore, a peptide comprising the amino acid sequence of SEQ ID NO: 3 and T cells expressing a TCR having a β chain comprising a CDR3 of SEQ ID NO: 4, 5, or 6 can be administered in combination to a subject with an HLA type of HLA-B15 (particularly HLA-B15:01) and used particularly effectively in the treatment or prevention of cancers expressing KK-LC-1.
[0033] Cancers to which the pharmaceutical compositions of the present disclosure can be applied are not particularly limited as long as they express KK-LC-1, and may be, for example, lung cancer, stomach cancer, breast cancer, or liver cancer.
[0034] The pharmaceutical composition according to the present disclosure can be used not only for cancer treatment but also for cancer prevention. For example, by administering the pharmaceutical composition according to the present disclosure to a healthy human body, CTLs are induced, and the induced CTLs remain in the body, so that when cancer cells appear, they can damage the cancer cells. Similarly, by administering the pharmaceutical composition according to the present disclosure to a human body after cancer treatment, the recurrence of cancer can be prevented.
[0035] In the pharmaceutical composition according to the present disclosure, the peptide and the T cells may be in the same formulation or in separate formulations. When the peptide and the T cells are in separate formulations, the formulation containing the peptide and the formulation containing the T cells may be administered to a subject simultaneously or separately.
[0036] The dose of peptide and T cells can be appropriately determined depending on the patient's age, weight, administration method, etc. so as to achieve the desired immunogenicity.
[0037] The pharmaceutical compositions of the present disclosure may also contain other components known to be used in cancer treatment, such as chemokines, cytokines, tumor necrosis factors, chemotherapeutic agents, and the like.
[0038] The pharmaceutical compositions of the present disclosure may contain various additives. Examples of additives include preservatives and buffers. Preservatives include sodium bisulfite, sodium bisulfate, sodium thiosulfate, benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric acetate, phenylmercuric nitrate, methylparaben, polyvinyl alcohol, phenylethyl alcohol, ammonia, dithiothreitol, and beta-mercaptoethanol. Buffers include sodium carbonate, sodium borate, sodium phosphate, sodium acetate, and sodium bicarbonate.
[0039] The pharmaceutical composition according to the present disclosure, in an embodiment containing a peptide but not T cells, can be used as a cancer vaccine. The vaccine may also contain inactive ingredients to enhance its efficacy. Examples of inactive ingredients include adjuvants and toxoids. Examples of adjuvants include precipitating adjuvants such as aluminum hydroxide, aluminum phosphate, and calcium phosphate, and oil-based adjuvants such as Freund's complete adjuvant and Freund's incomplete adjuvant.
[0040] In an embodiment containing a peptide but not T cells, the pharmaceutical composition of the present disclosure is intended for administration to the human body as well as for use outside the body. Specifically, the pharmaceutical composition of the present disclosure may be used to stimulate antigen-presenting cells in vitro or ex vivo to increase CTL-inducing activity. For example, the pharmaceutical composition of the present disclosure may be used in cancer dendritic cell therapy, in which antigen-presenting cells, such as dendritic cells, derived from a subject in need of cancer treatment or prevention are contacted with the composition and then the antigen-presenting cells are returned to the subject's body. The peptide may be introduced into the antigen-presenting cells by, for example, lipofection or injection. Alternatively, a polynucleotide encoding the peptide or a vector containing the polynucleotide may be introduced into the antigen-presenting cells by, for example, lipofection, electroporation, microinjection, cell fusion, DEAE-dextran, or calcium phosphate to express the peptide.
[0041] A vector refers to a nucleic acid construct that allows the expression of mRNA, protein, or polypeptide in a host cell. Known vectors such as plasmids and viruses may be used as the vector.
[0042] [Therapeutic / Preventive Method and Companion Diagnostics] The cancer therapeutic or preventive method according to the present disclosure comprises the step of administering the above-described peptide, a polynucleotide encoding the peptide, or a vector comprising the polynucleotide in combination with T cells, wherein the peptide and the T cells have the following combination (1) or (2): (1) A combination of a peptide comprising the amino acid sequence of SEQ ID NO: 1 and T cells expressing a TCR having a β chain comprising a CDR3 of SEQ ID NO: 2. (2) A combination of a peptide comprising the amino acid sequence of SEQ ID NO: 3 and T cells expressing a TCR having a β chain comprising a CDR3 of SEQ ID NO: 4, 5, or 6.
[0043] The administration of a peptide, a polynucleotide encoding the peptide, or a vector containing the polynucleotide (hereinafter collectively referred to as "peptide") and the administration of T cells may be administered in the same formulation or in separate formulations. The administration of the peptide and the administration of the T cells may be carried out simultaneously or separately. Furthermore, the administration routes of the peptide and the T cells may be the same or different.
[0044] In another aspect, the method for treating or preventing cancer according to the present disclosure may include a procedure of administering only the peptide described in (1) or (2) above, a polynucleotide encoding the peptide, or a vector containing the polynucleotide, or only T cells.
[0045] The cancer treatment or prevention method according to the present disclosure may include a step of determining the HLA genotype of the subject prior to the step of administering the peptide and / or T cells. The HLA genotype can be determined using a conventionally known genetic analysis method.
[0046] Optimized therapeutic effects can be expected when a peptide comprising the amino acid sequence of SEQ ID NO: 1 and T cells expressing a TCR having a β chain comprising a CDR3 of SEQ ID NO: 2 are administered to a subject having an HLA type of HLA*C14 (particularly HLA*C14:02). Optimized therapeutic effects can be expected when a peptide comprising the amino acid sequence of SEQ ID NO: 3 and T cells expressing a TCR having a β chain comprising a CDR3 of SEQ ID NO: 4, 5, or 6 are administered to a subject having an HLA type of HLA-B15 (particularly HLA-B15:01). Therefore, a high therapeutic effect can be expected by determining the subject's HLA genotype prior to administering the peptide and / or T cells, and selecting a peptide, T cells, or a combination thereof according to the subject's HLA type.
[0047] Some or all of the above embodiments can also be described as follows, but are not limited to the following. Regarding the configurations of the inventions described below, a configuration according to one category of inventions can also be dependent on another category of inventions. [1] A pharmaceutical composition for administering a combination of a peptide, a polynucleotide encoding the peptide, or a vector containing the polynucleotide, and T cells for the treatment or prevention of cancer expressing KK-LC-1 in a subject, wherein the peptide and the T cells have the following combination (1) or (2) depending on the human leukocyte antigen (HLA) type of the subject: (1) When the HLA type of the subject is HLA*C14, a combination of a peptide comprising the amino acid sequence of SEQ ID NO: 1 and T cells expressing a T cell receptor (TCR) having a β chain including the complementarity-determining region 3 (CDR3) of SEQ ID NO: 2. (2) A combination of a peptide comprising the amino acid sequence of SEQ ID NO: 3 and T cells expressing a TCR having a β chain comprising CDR3 of SEQ ID NO: 4, 5, or 6, when the HLA type of the subject is HLA*B15. [2] A pharmaceutical composition for administering a combination of a peptide, a polynucleotide encoding the peptide, or a vector comprising the polynucleotide, and T cells for the treatment or prevention of cancer expressing KK-LC-1 in a subject, wherein the peptide and the T cells have the following combination (1) or (2): (1) A combination of a peptide comprising the amino acid sequence of SEQ ID NO: 1 and T cells expressing a TCR having a β chain comprising CDR3 of SEQ ID NO: 2. (2) A combination of a peptide comprising the amino acid sequence of SEQ ID NO: 3 and T cells expressing a TCR having a β chain comprising CDR3 of SEQ ID NO: 4, 5, or 6. [3] The pharmaceutical composition of [2], wherein the HLA type of the subject is HLA*C14 in the combination of (1), and HLA*B15 in the combination of (2). [4] The pharmaceutical composition of [3], wherein the HLA type of the subject is HLA*C14:02 in the combination of (1), and HLA*B15:01 in the combination of (2). [5] The pharmaceutical composition of any of [1] to [4], wherein the cancer is lung cancer, stomach cancer, breast cancer, or liver cancer.[6] A pharmaceutical composition comprising a peptide, a polynucleotide encoding the peptide, or a vector comprising the polynucleotide, which is administered in combination with T cells for the treatment or prevention of cancer expressing KK-LC-1 in a subject, wherein the peptide is (1) or (2) below: (1) A peptide comprising the amino acid sequence of SEQ ID NO: 1, which is administered in combination with T cells expressing a TCR having a β chain comprising a CDR3 of SEQ ID NO: 2. (2) A peptide comprising the amino acid sequence of SEQ ID NO: 3, which is administered in combination with T cells expressing a TCR having a β chain comprising a CDR3 of SEQ ID NO: 4, 5, or 6. [7] A pharmaceutical composition for the treatment or prevention of cancer expressing KK-LC-1 in a subject, which comprises a peptide, a polynucleotide encoding the peptide, or a vector comprising the polynucleotide, wherein the peptide is (1) or (2) below: (1) A peptide comprising the amino acid sequence of SEQ ID NO: 1. (2) A peptide comprising the amino acid sequence of SEQ ID NO: 3. [8] The pharmaceutical composition of [6] or [7], which is a cancer vaccine. [9] The pharmaceutical composition of any of [6] to [8], wherein the cancer is lung cancer, stomach cancer, breast cancer, or liver cancer.
[10] A peptide comprising the amino acid sequence of SEQ ID NO: 1 or 3, a polynucleotide encoding the peptide, or a vector comprising the polynucleotide.
[11] A pharmaceutical composition comprising T cells to be administered in combination with a peptide, a polynucleotide encoding the peptide, or a vector comprising the polynucleotide for the treatment or prevention of cancer expressing KK-LC-1 in a subject, wherein the T cells are (1) or (2) below. (1) T cells expressing a TCR having a β chain comprising a CDR3 of SEQ ID NO: 2, which are administered in combination with a peptide comprising the amino acid sequence of SEQ ID NO: 1. (2) T cells expressing a TCR having a β chain comprising a CDR3 of SEQ ID NO: 4, 5, or 6, which are administered in combination with a peptide comprising the amino acid sequence of SEQ ID NO: 3.
[12] A pharmaceutical composition for the treatment or prevention of cancer expressing KK-LC-1 in a subject, comprising T cells, wherein the T cells are (1) or (2) below.(1) T cells expressing a TCR having a β chain comprising a CDR3 of SEQ ID NO: 2. (2) T cells expressing a TCR having a β chain comprising a CDR3 of SEQ ID NO: 4, 5, or 6.
[13] The pharmaceutical composition of
[11] or
[12] , wherein the cancer is lung cancer, gastric cancer, breast cancer, or liver cancer.
[14] A polynucleotide encoding a TCR having a β chain comprising a CDR3 of SEQ ID NO: 2, 4, 5, or 6, or a vector comprising the polynucleotide.
[15] A method for treating or preventing cancer expressing KK-LC-1 in a subject, comprising the step of administering to the subject a combination of a peptide, a polynucleotide encoding the peptide, or a vector comprising the polynucleotide, and T cells, wherein the peptide and the T cells have the following combination (1) or (2) depending on the human leukocyte antigen (HLA) type of the subject: (1) A combination of a peptide comprising the amino acid sequence of SEQ ID NO: 1 and T cells expressing a TCR having a β chain comprising a CDR3 of SEQ ID NO: 2. (2) A combination of a peptide comprising the amino acid sequence of SEQ ID NO: 3 and T cells expressing a TCR having a β chain comprising CDR3 of SEQ ID NO: 4, 5, or 6.
[16] A method for treating or preventing cancer that expresses KK-LC-1 in a subject, comprising the steps of: determining the HLA type of the subject; and administering a peptide, a polynucleotide encoding the peptide, or a vector comprising the polynucleotide, in combination with T cells, wherein: (1) when the HLA type of the subject is HLA*C14, a peptide comprising the amino acid sequence of SEQ ID NO: 1 is administered in combination with T cells expressing a TCR having a β chain comprising CDR3 of SEQ ID NO: 2; and (2) when the HLA type of the subject is HLA*B15, a peptide comprising the amino acid sequence of SEQ ID NO: 3 is administered in combination with T cells expressing a TCR having a β chain comprising CDR3 of SEQ ID NO: 4, 5, or 6.
[17] The method of
[15] or
[16] , wherein the HLA type of the subject is HLA*C14:02 in (1) above, and HLA*B15:01 in (2) above.
[18] Any of the methods of
[15] to
[17] , wherein the cancer is lung cancer, stomach cancer, breast cancer, or liver cancer.
[19] A method for treating or preventing cancer that expresses KK-LC-1 in a subject, comprising the step of administering to the subject a peptide, a polynucleotide encoding the peptide, or a vector containing the polynucleotide, wherein the peptide is either (1) or (2) below: (1) A peptide comprising the amino acid sequence of SEQ ID NO: 1. (2) A peptide comprising the amino acid sequence of SEQ ID NO: 3.
[20] A method for treating or preventing cancer that expresses KK-LC-1 in a subject, comprising the steps of determining the HLA type of the subject, and administering to the subject a peptide, a polynucleotide encoding the peptide, or a vector containing the polynucleotide, wherein the peptide is either (1) or (2) below: (1) A peptide comprising the amino acid sequence of SEQ ID NO: 1 when the subject's HLA type is HLA*C14. (2) A peptide comprising the amino acid sequence of SEQ ID NO: 3 when the subject's HLA type is HLA*B15.
[21] The method of
[20] , wherein the HLA type of the subject is HLA*C14:02 in (1), and HLA*B15:01 in (2).
[22] A method for treating or preventing cancer that expresses KK-LC-1 in a subject, comprising the step of administering T cells to the subject, wherein the T cells are either (1) or (2) below: (1) T cells expressing a TCR having a β chain comprising a CDR3 of SEQ ID NO: 2. (2) T cells expressing a TCR having a β chain comprising a CDR3 of SEQ ID NO: 4, 5, or 6.
[23] A method for treating or preventing cancer that expresses KK-LC-1 in a subject, comprising the steps of determining the HLA type of the subject and administering T cells to the subject, wherein the T cells are either (1) or (2) below: (1) T cells expressing a TCR having a β chain comprising a CDR3 of SEQ ID NO: 2 when the HLA type of the subject is HLA*C14. (2) When the HLA type of the subject is HLA*B15, T cells expressing a TCR having a β chain comprising CDR3 of SEQ ID NO: 4, 5, or 6.
[24] The method of
[23] , wherein the HLA type of the subject is HLA*C14:02 in (1) above, or HLA*B15:01 in (2) above.
[24] The method according to any one of
[19] to
[23] , wherein the cancer is lung cancer, stomach cancer, breast cancer, or liver cancer.
[0048] 1. Construction of HLA gene expression vectors. The HLA genes for HLA types A*24:02, A*26:03, B*15:01, B*51:01, C*07:02, and C*14:02 were cloned into the expression vector (pcDNA3.1(+)) to construct the HLA gene expression vectors pcDNA3.1(+) / HLA-A*24:02, pcDNA3.1(+) / HLA-A*26:03, pcDNA3.1(+) / HLA-B*15:01, pcDNA3.1(+) / HLA-B*51:01, pcDNA3.1(+) / HLA-C*07:02, and pcDNA3.1(+) / HLA-C*14:02.
[0049] 2. HLA gene transfection into HEK293T cells. 5 μL of Lipofectamine 2000 (Thermo Fisher Scientific) was added to OPTI-MEM medium (250 μL) and incubated for 5 minutes. The cells were then mixed with OPTI-MEM medium (250 μL) containing an HLA gene expression vector (2.5 μg) and allowed to stand for 20 minutes. 8 × 10 5 HEK293T cells were added and cultured for 6 hours. The medium was then replaced and cultured for an additional 2 days to obtain HLA-expressing cells.
[0050] 3. TCR Gene Transfer into Jurkat Cells. A synthetic gene was created by combining the β-chain cDNA and α-chain cDNA of a TCR (TexTCR) identified from tumor-infiltrating lymphocytes of a lung cancer patient with the self-cleaving peptide (P2A) coding sequence. The synthetic gene was inserted into the retroviral vector pMX-IRES-puro (CELL BIOLABS INC) (pMX-IRES-puro / TexTCR). Retroviral producer cells were transfected with pMX-IRES-puro / TexTCR (2.5 μg) using Lipofectamine 2000 and cultured. Phoenix-GP cells (ATCC, CRL-3215) transfected with the GALV gene were used as retroviral producer cells. The medium was changed 6 hours after the start of culture and the cells were cultured for an additional 3 days. The culture supernatant was filtered through a 0.8 μm filter to obtain the virus solution.
[0051] 1x10 CD8-expressing Jurkat cells without TCR expression in 1 mL of retrovirus solution 5 The cells were suspended and mixed with polybrene (8 μg / ml), then transferred to a 12-well plate and infected by spin infection (1,000 g, 1 hour, 32°C). After 4 hours, 2 ml of medium was added per well. Two days after infection, the cells were harvested, suspended in fresh medium, and cultured with puromycin (1 μg / ml). Two weeks later, TCR expression was confirmed using a flow cytometer to obtain TexTCR-expressing CD8-expressing Jurkat cells.
[0052] 4. KK-LC-1 Peptide The KK-LC-1 peptide having the following amino acid sequence was synthesized. A 20 mg / mL solution of the peptide was prepared using DMSO, and the solution was diluted appropriately before use. CT83-S1: ILNNFPHSI (SEQ ID NO: 7) CT83-S2: RQKRILVNL (SEQ ID NO: 3) CT83-K1: SILCALIVF (SEQ ID NO: 8) CT83-K2: IVFWKYRRF (SEQ ID NO: 9) CT83-K3: LVRPSSSGL (SEQ ID NO: 10) Ichi010_MP41: YCWEYFLSL (SEQ ID NO: 11) CT83-7: VRPSSGLI (SEQ ID NO: 12) CT83-8: YLLLASSIL (SEQ ID NO: 13) CT83-9: NFPHSIARQ (SEQ ID NO: 14) CT83-10: LVELEHTLL (SEQ ID NO: 15) CT83-11: LLLASSILC (SEQ ID NO: 16) CT83-12: RFQRNTGEM (SEQ ID NO: 1)
[0053] 5. Detection of antigen-specific responses. TexTCR-expressing cells were genetically modified to express luciferase under the control of TCR signaling. Specifically, a solution (2 μg / μL) of a vector (pGL4.30[luc2P / NFAT-RE / Hygro]) containing the NFAT (nuclear factor of activated T cells) response element and the luciferase gene was prepared. TexTCR-expressing CD8-expressing Jurkat cells were washed with PBS and suspended in electroporation buffer. 2 × 10 5 The concentration was adjusted to 11 μL per cell. 1 μL of vector solution and 11 μL of cell solution were mixed, loaded onto a Neon Tip, and inserted into a Neon Tube containing 3 mL of buffer. Electroporation (Thermo Fisher Scientific, Neon transfection system) was performed at 1200 V for 5 ms. After gene transfection, the cells were suspended in 100 μL of antibiotic-free medium.
[0054] Target cells were loaded with KK-LC-1 peptide (20 μg / ml) and seeded in 96-well plates (2 × 10 4In addition to the HLA-expressing cells prepared in step 1 above, the patient's autologous B-cell antigen-presenting cells (B-APCs) were used as target cells. B-APCs were 5 × 10 4 TexTCR-expressing CD8-expressing Jurkat cells (5 × 10 4 After 14 hours of co-culture, 50 μL of luciferase substrate solution (Promega, Steady-Glo Luciferase Assay System) was added to each well and incubated for 10 minutes at room temperature. 70 μL of the mixture was transferred to a half-area white plate (Greiner, LUMITRAC 675075), and luminescence was measured using an EnSpire multimode plate reader (PerkinElmer).
[0055] 6. Results The results of detecting antigen-specific responses in co-culture of peptide-loaded B-APCs with TexTCR-expressing cells expressing TexTCR (pt.2-ex08TCR) are shown in Figure 1. Antigen-specific responses mediated by the peptide CT83-12 (RFQRNTGEM) were detected.
[0056] Figure 2 shows the results of detecting antigen-specific responses in co-culture of HLA-expressing cells loaded with peptide CT83-12 (RFQRNTGEM) and TexTCR-expressing cells expressing TexTCR (pt.2-ex08TCR). It was revealed that antigen-specific responses mediated by peptide CT83-12 (RFQRNTGEM) and TexTCR (pt.2-ex08TCR) were HLA-C14:02 restricted. Note that "None" in the figure indicates results for EK293T cells without HLA gene transfection.
[0057] Figure 3 shows the results of detecting antigen-specific responses in cocultures of peptide-loaded B-APCs with TexTCR-expressing cells expressing TexTCR (pt.1-ex08TCR, pt.1-ex15TCR, or pt.2-ex09TCR). For peptide CT83-S2(RQKRILVNL), antigen-specific responses mediated by all three TexTCRs were detected. Peptide CT83-S2(RQKRILVNL) is known to be HLA-B15:01 restricted.
[0058] The combinations of HLA types, peptides, and TCRs that induced antigen-specific responses are shown in Table 1. The full-length amino acid sequences and CDR amino acid sequences of the β and α chains of pt.2-ex08TCR, pt.1-ex08TCR, pt.1-ex15TCR, and pt.2-ex09TCR are shown in Figures 4-7.
[0059]
[0060] SEQ ID NO: 1: Amino acid sequence of peptide CT83-12 SEQ ID NO: 2: Amino acid sequence of the β chain CDR3 of pt.2-ex08TCR SEQ ID NO: 3: Amino acid sequence of peptide CT83-S2 SEQ ID NO: 4: Amino acid sequence of the β chain CDR3 of pt.1-ex08TCR SEQ ID NO: 5: Amino acid sequence of the β chain CDR3 of pt.1-ex15TCR SEQ ID NO: 6: Amino acid sequence of the β chain CDR3 of pt.2-ex09TCR SEQ ID NO: 7: Amino acid sequence of peptide CT83-S1 SEQ ID NO: 8: Amino acid sequence of peptide CT83-K1 SEQ ID NO: 9: Amino acid sequence of peptide CT83-K2 SEQ ID NO: 10: Amino acid sequence of peptide CT83-K3 SEQ ID NO: 11: Amino acid sequence of peptide Ichi010_MP41 SEQ ID NO: 12: Amino acid sequence of peptide CT83-7 SEQ ID NO: 13: Amino acid sequence of peptide CT83-8 SEQ ID NO: 14: Amino acid sequence of peptide CT83-9 SEQ ID NO: 15: Amino acid sequence of peptide CT83-10 SEQ ID NO: 16: Amino acid sequence of peptide CT83-11 SEQ ID NO: 17: Amino acid sequence of β chain CDR1 of pt.2-ex08TCR SEQ ID NO: 18: Amino acid sequence of β chain CDR2 of pt.2-ex08TCR SEQ ID NO: 19: Amino acid sequence of α chain CDR1 of pt.2-ex08TCR SEQ ID NO: 20: Amino acid sequence of α chain CDR2 of pt.2-ex08TCR SEQ ID NO: 21: Amino acid sequence of α chain CDR3 of pt.2-ex08TCR SEQ ID NO: 22: Full length amino acid sequence of β chain of pt.2-ex08TCR SEQ ID NO: 23: Full length amino acid sequence of α chain of pt.2-ex08TCR SEQ ID NO: 24: Amino acid sequence of β chain CDR1 of pt.1-ex08TCR SEQ ID NO: 25: Amino acid sequence of β chain CDR2 of pt.1-ex08TCR SEQ ID NO: 26: Amino acid sequence of α chain CDR1 of pt.1-ex08TCR SEQ ID NO: 27: Amino acid sequence of α chain CDR2 of pt.1-ex08TCR SEQ ID NO: 28: Amino acid sequence of α chain CDR3 of pt.1-ex08TCR SEQ ID NO: 29: Full length amino acid sequence of β chain of pt.1-ex08TCR SEQ ID NO: 30: Full length amino acid sequence of α chain of pt.1-ex08TCR SEQ ID NO: 31: Amino acid sequence of β chain CDR1 of pt.1-ex15TCR SEQ ID NO: 32: Amino acid sequence of β chain CDR2 of pt.1-ex15TCR SEQ ID NO: 33: pt.SEQ ID NO: 34: Amino acid sequence of the α chain CDR2 of the pt.1-ex15TCR SEQ ID NO: 35: Amino acid sequence of the α chain CDR3 of the pt.1-ex15TCR SEQ ID NO: 36: Full length amino acid sequence of the β chain of the pt.1-ex15TCR SEQ ID NO: 37: Full length amino acid sequence of the α chain of the pt.1-ex15TCR SEQ ID NO: 38: Amino acid sequence of the β chain CDR1 of the pt.2-ex09TCR SEQ ID NO: 39: Amino acid sequence of the β chain CDR2 of the pt.2-ex09TCR SEQ ID NO: 40: Amino acid sequence of the α chain CDR1 of the pt.2-ex09TCR SEQ ID NO: 41: Amino acid sequence of the α chain CDR2 of the pt.2-ex09TCR SEQ ID NO: 42: Amino acid sequence of the α chain CDR3 of the pt.2-ex09TCR SEQ ID NO: 43: Full length amino acid sequence of the β chain of the pt.2-ex09TCR SEQ ID NO: 44: Full-length amino acid sequence of the α chain of pt.2-ex09 TCR.
Claims
1. For the treatment or prevention of cancer expressing Kitakyushu Lung Cancer Antigen 1 (KK-LC-1) in a subject, a peptide, a polynucleotide encoding the peptide, or a vector containing the polynucleotide, and T cells, A pharmaceutical composition comprising: The peptide, the polynucleotide encoding the peptide, or the vector containing the polynucleotide and the T cells are administered in combination, A pharmaceutical composition, wherein the peptide and the T cells have the following combination (1) or (2) according to the human leukocyte antigen (HLA) type of the subject. (1) When the HLA type of the subject is HLA*C14, a combination of a peptide comprising the amino acid sequence of SEQ ID NO: 1 and a T cell expressing a T cell receptor (TCR) having a β chain comprising the complementarity-determining region 3 (CDR3) of SEQ ID NO:
2. (2) When the HLA type of the subject is HLA*B15, a combination of a peptide comprising the amino acid sequence of SEQ ID NO: 3 and a T cell expressing a TCR having a β chain comprising the CDR3 of SEQ ID NO: 4, 5 or 6.
2. For the treatment or prevention of cancer expressing KK-LC-1 in a subject, a peptide, a polynucleotide encoding the peptide, or a vector containing the polynucleotide, and T cells, A pharmaceutical composition comprising: The peptide, the polynucleotide encoding the peptide, or the vector containing the polynucleotide and the T cells are administered in combination, A pharmaceutical composition, wherein the peptide and the T cells have the following combination (1) or (2). (1) A combination of a peptide comprising the amino acid sequence of SEQ ID NO: 1 and a T cell expressing a TCR having a β chain comprising the CDR3 of SEQ ID NO:
2. (2) A combination of a peptide comprising the amino acid sequence of SEQ ID NO: 3 and a T cell expressing a TCR having a β chain comprising the CDR3 of SEQ ID NO: 4, 5 or 6.
3. The HLA type of the subject is HLA*C14 in the combination of (1), HLA*B15 in the combination of (2), The pharmaceutical composition according to claim 2.
4. The HLA type of the subject is HLA*C14:02 in the combination of (1), HLA*B15:01 in the combination of (2), The pharmaceutical composition according to claim 3.
5. The pharmaceutical composition according to any one of claims 1 to 4, wherein the cancer is lung cancer, gastric cancer, breast cancer or liver cancer.
6. A pharmaceutical composition comprising a peptide, a polynucleotide encoding the peptide, or a vector comprising the polynucleotide, which is administered in combination with T cells for the treatment or prevention of cancer expressing KK-LC-1 in a subject, The pharmaceutical composition, wherein the peptide is the following (1) or (2). (1) A peptide comprising the amino acid sequence of SEQ ID NO: 1, which is administered in combination with T cells expressing a TCR having a β chain comprising the CDR3 of SEQ ID NO:
2. (2) A peptide comprising the amino acid sequence of SEQ ID NO: 3, which is administered in combination with T cells expressing a TCR having a β chain comprising the CDR3 of SEQ ID NO: 4, 5 or 6.
7. A pharmaceutical composition for the treatment or prevention of cancer expressing KK-LC-1 in a subject, comprising a peptide, a polynucleotide encoding the peptide, or a vector comprising the polynucleotide, The pharmaceutical composition, wherein the peptide is the following (1) or (2). (1) A peptide comprising the amino acid sequence of SEQ ID NO:
1. (2) A peptide comprising the amino acid sequence of SEQ ID NO:
3.
8. The pharmaceutical composition according to claim 6 or 7, which is a cancer vaccine.
9. The pharmaceutical composition according to claim 6 or 7, wherein the cancer is lung cancer, gastric cancer, breast cancer or liver cancer.
10. A peptide comprising the amino acid sequence of SEQ ID NO: 1 or 3, a polynucleotide encoding the peptide, or a vector comprising the polynucleotide.
11. A pharmaceutical composition comprising T cells, which is administered in combination with a peptide, a polynucleotide encoding the peptide, or a vector comprising the polynucleotide for the treatment or prevention of cancer expressing KK-LC-1 in a subject, The pharmaceutical composition, wherein the T cell is the following (1) or (2). (1) A T cell expressing a TCR having a β chain comprising the CDR3 of SEQ ID NO: 2, which is administered in combination with a peptide comprising the amino acid sequence of SEQ ID NO:
1. (2) A T cell expressing a TCR having a β chain comprising the CDR3 of SEQ ID NO: 4, 5 or 6, which is administered in combination with a peptide comprising the amino acid sequence of SEQ ID NO:
3.
12. A pharmaceutical composition for the treatment or prevention of cancer expressing KK-LC-1 in a subject, comprising T cells, A pharmaceutical composition, wherein the T cell is the following (1) or (2). (1) A T cell that expresses a TCR having a β chain containing the CDR3 of SEQ ID NO:
2. (2) A T cell that expresses a TCR having a β chain containing the CDR3 of SEQ ID NO: 4, 5, or 6.
13. A polynucleotide encoding a TCR having a β chain containing the CDR3 of SEQ ID NO: 2, 4, 5, or 6, or a vector containing the polynucleotide.
14. For the manufacture of a pharmaceutical composition for the treatment or prevention of cancer expressing KK-LC-1 in a subject, A peptide, a polynucleotide encoding the peptide, or a vector containing the polynucleotide, or, A T cell, The use of which comprises: The pharmaceutical composition has a combination of the peptide of the following (1) or (2) and the T cell. (1) A combination of a peptide comprising the amino acid sequence of SEQ ID NO: 1 and a T cell expressing a T cell receptor (TCR) having a β chain containing the CDR3 of SEQ ID NO:
2. (2) A combination of a peptide comprising the amino acid sequence of SEQ ID NO: 3 and a T cell expressing a TCR having a β chain containing the CDR3 of SEQ ID NO: 4, 5, or 6.