WO2019031938A2 - 암 치료를 위한 t 세포의 활성화 방법 - Google Patents

암 치료를 위한 t 세포의 활성화 방법 Download PDF

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WO2019031938A2
WO2019031938A2 PCT/KR2018/009224 KR2018009224W WO2019031938A2 WO 2019031938 A2 WO2019031938 A2 WO 2019031938A2 KR 2018009224 W KR2018009224 W KR 2018009224W WO 2019031938 A2 WO2019031938 A2 WO 2019031938A2
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cell
cancer
cells
hla
seq
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French (fr)
Korean (ko)
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WO2019031938A3 (ko
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김정호
김범석
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Good T Cells Inc
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Good T Cells Inc
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Priority to EP18844804.7A priority Critical patent/EP3666888A4/en
Priority to JP2020507093A priority patent/JP7364237B2/ja
Priority to CN201880052032.2A priority patent/CN110997903B/zh
Priority to US16/638,055 priority patent/US11918634B2/en
Priority to BR112020002816-9A priority patent/BR112020002816A2/pt
Publication of WO2019031938A2 publication Critical patent/WO2019031938A2/ko
Publication of WO2019031938A3 publication Critical patent/WO2019031938A3/ko
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Priority to US18/423,189 priority patent/US20240156927A1/en
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Definitions

  • the present invention relates to a cancer-specific neo-epitope, an antigen-presenting cell loaded with the neo-epitope, and a method of activating T cells for cancer treatment by the antigen presenting cells.
  • gastric cancer cell antigen-related (EBV) -related staphylococcal disease which is caused by accumulation of EBV-associated gastric cancer and gastrointestinal gene mutation, which is typically caused by infection of epstein barr virus Stomach cancer can be classified as.
  • EBV gastric cancer cell antigen-related
  • gastrointestinal gene mutation which is typically caused by infection of epstein barr virus Stomach cancer
  • the treatment for stomach cancer has been known for the longest time, the surgery of cancer tissue is the most effective, chemotherapy and radiotherapy have been done, but when stomach cancer is not found early, cure is a hard disease.
  • clinical trials have been carried out through various biological agents (antibodies, small molecules), there are no therapeutic agents showing good clinical effects.
  • CD8 + T cells CD4 + T cells
  • NK cells have a cell killing effect but lack antigen specificity and thus have various side effects.
  • dendritic cells they do not have a function of directly killing cells, while they transmit antigen specificity to T cells in a patient's body, Is a therapeutic agent for a vaccine concept that can confer tumor cell specificity to T cells.
  • CD4 + T cells play a role in helping other cells through antigen specificity
  • CD8 + T cells are known to be the best cells with antigen specificity and apoptosis.
  • cancer cells do not produce proper immune responses because they do not secrete substances that inhibit the immune response in the body or present antigens essential for the production of antibodies against cancer cells.
  • dendritic cells not only act as observers for detecting antigens coming from the inside of the body or from the outside of the body, but also move rapidly to the secondary lymphoid organs with the thus recognized and absorbed antigens, T cells in the immune system, which serves as a specialized antigen-presenting cell to present the antigen to the immune cells.
  • Anti-cancer immunotherapy vaccines using dendritic cells have been developed in various ways, and can be divided into ex vivo generated dendritic cell vaccines and in vivo dendritic cell vaccines.
  • dendritic cell vaccine is a method of delivering antigen directly to dendritic cells present in the body.
  • the dendritic cells are separated from the PBMC of the patient, and the antigen to be presented to the separated dendritic cells is transferred. Through this, the dendritic cells are activated and then injected into the patient, Thereby allowing the antigen to be transferred to the cell.
  • the dendritic cell culture method and the antigen delivery method are important in vivo, and as an antigen presentation method currently used, the DNA of the antigen to be presented is transfected with a virus or nucleofection Or by antigen binding to an antibody targeting dendritic cells to target dendritic cells.
  • dendritic cell vaccine Currently, the most serious problems of dendritic cell vaccine are effective anti-cancer immune cells in the cancerous microenvironment where severe chronic inflammation in the body, Warburg effect, immunosuppressive cytokine, immunosuppressed T cells and dendritic cells are present. Is very difficult to activate.
  • EBV epstein-barr virus
  • Another object of the present invention is to provide an antigen presenting cell capable of activating T cells for cancer treatment, in which the neo-epitope epitope of the present invention is loaded.
  • a cancer antigen epitope there is provided a cancer antigen epitope.
  • the " cancer-specific epitope” is derived from a protein antigen existing only in cancer cells but not in normal cells.
  • the cancer-specific epitope includes at least one epitope recognized by a T cell receptor, preferably an epitope present in an epstein barr virus (EBV) positive cancer cell.
  • EBV virus Epstein-Barr virus latent membrane protein 2, LMP2a
  • LMP2a Epstein-Barr virus latent membrane protein 2, LMP2a
  • the " Epstein-Barr virus latent membrane protein 2 (LMP2a)" is one of several EBV genes expressed in all type II and III disease / malignant tumors.
  • LMP2a It acts as a negative regulator of B cell-receptor signaling and is a transmembrane protein that promotes cell survival through sequestering of tyrosine kinases.
  • the HLA-A2 restricted peptide is an epitope-specific cytotoxic T lymphocyte detectable in 60-75% of individuals in vitro and the most immunogenic LMP epitope in latent disease.
  • the CLGGLLTMV peptide has long been shown to be a potential target for NPC and HL therapy because the epitope is immunologically vulnerable, along with other EBV potential epitopes, preserved in biopsies inspected from NPC and HL patients.
  • the " Epstein-Barr nuclear antigen 1 " corresponds to a multi-functional, dimeric virus protein related to Epstein-Barr virus. This corresponds to the EBV protein found in all EBV-associated malignant tumors. Which plays an important role in maintaining the conformational state that accompanies the cell when infected with EBV.
  • EBNA-1 corresponds to a glycine-alanine repeat sequence that separates the protein into amino- and carboxy-terminal domains. These sequences serve to stabilize proteins, prevent proteasomal breakdown, and impair antigen processing and MHC class I-restricted antigen expression.
  • EBNA-1 inhibits the response of CD8-restricted cytotoxic T cells to virus-infected cells.
  • EBNA-1 is expressed by the Qp promoter in all latency programs and is the only viral protein expressed in latency program I.
  • the "neo-epitope" refers to an epitope that is not present in a reference such as a normal non-cancerous cell or a germ cell, but is found in a cancer cell.
  • the neo-epitope includes HLA-A, HLA-B, HLA-C, and HLA-T cells so as to have an effect on T cells extracted from human blood, preferably memory T cells HLA-DRB1, HLA-DRB1, HLA-DRB1, HLA-DRB1, HLA-DRB1, HLA-DRB1, HLA-DRB1, HLA- DRB5, HLA-DM, HLA-DOA and HLA-DOB loci.
  • HLA-type which is the most frequently expressed by Koreans, for example, HLA-A * 2402, HLA-A * A0201, HLA-A * 3303, HLA-A * 1101, HLA-A * 0206, HLA-A * 3101, HLA-B * 5101, HLA- , HLA-B * 5801, and HLA-B * 3501.
  • the neo-epitope may be a neo-epitope of an LMP2a antigen, which is a peptide represented by any one of SEQ ID NOs: 1-115, having a high binding affinity for HLA-A * 2402; Or a neo-epitope of the EBNA-1 antigen, which is a peptide represented by any one of SEQ ID NOS: 152 to 184, having high binding affinity for HLA-A * 3101.
  • LMP2a antigen which is a peptide represented by any one of SEQ ID NOs: 1-115, having a high binding affinity for HLA-A * 2402
  • a neo-epitope of the EBNA-1 antigen which is a peptide represented by any one of SEQ ID NOS: 152 to 184, having high binding affinity for HLA-A * 3101.
  • NetMHC 3.4 (URL: www.cbs.dtu.dk/services/NetMHC- 3.4 /) may be used, but is not limited thereto.
  • HLA or " human leukocyte antigen” in the present invention refers to a human gene that encodes an MHC (main histocompatibility complex) protein on the surface of a cell responsible for modulation of the immune system.
  • HLA-I or "HLA class I” refers to a human MHC class I gene comprising HLA-A, HLA-B, HLA-C, HLA-E, HLA-F, HLA- Quot;
  • HLA-II or "HLA class II” refers to HLA-DPA1, HLA-DPB1, HLA-DQA1, HLA-DQB1, HLA- DRA1, HLA-DRB1, HLA- DRB3, HLA- DM, HLA-DOA and HLA-DOB loci.
  • the cancer is preferably an epstein-barr virus (EBV) positive cancer, an EBV-positive gastric cancer, an EBV positive cervical cancer, an EBV positive Burkitt's lymphoma, an EBV-positive T cell lymphoma ), EBV-positive breast cancer, EBV-positive leiomyosarcomas, EBV-positive smooth muscle tumors, EBV-positive Hodgkin lymphoma, EBV-positive benign breast cancer, or PTLD after EBV- , But may preferably be EBV-positive stomach cancer.
  • EBV epstein-barr virus
  • EBV Epstein-Barr virus
  • the nucleic acid molecule of the present invention includes all of the nucleic acid molecules translated into a polynucleotide sequence as known to those skilled in the art by the amino acid sequence of the polypeptide provided herein. Therefore, various polynucleotide sequences by ORF (open reading frame) can be produced, and these are all included in the nucleic acid molecule of the present invention.
  • ORF open reading frame
  • an expression vector in which the isolated nucleic acid molecule provided by the present invention is inserted.
  • the " vector " is a nucleic acid molecule capable of transporting another nucleic acid to which a nucleic acid molecule is linked.
  • a vector plasmid
  • Another type of vector is a phage vector.
  • Another type of vector is a viral vector, and additional DNA segments can be ligated to the viral genome.
  • Some vectors can autonomously replicate in the host cells into which they are introduced (e. G., Bacterial vectors are episomal mammalian vectors with bacterial replication origin). Other vectors (e.
  • Non-episomal mammalian vectors can be incorporated into the genome of the host cell while being introduced into the host cell, thereby replicating with the host genome.
  • some vectors can direct expression of the genes to which they are linked at the activation level.
  • Such a vector is referred to herein as a " recombinant expression vector " or simply an " expression vector ".
  • expression vectors useful in recombinant DNA techniques are often present in the form of plasmids.
  • plasmid and vector can be used interchangeably because the plasmid is the most commonly used form of vector.
  • the expression vector in the present invention include commercially available pCDNA vector, F, R1, RP1, Col, pBR322, ToL, Ti vector; Cosmids; Lambda, lambdoid, M13, Mu, p1 P22, Q ⁇ , T-even, T2, T3, T7 and the like; Plant virus, but not limited thereto.
  • Any expression vector known to the person skilled in the art as an expression vector can be used in the present invention, and the selection of the expression vector depends on the nature of the intended host cell.
  • the vector contains one or more selectable markers, but is not limited thereto, and a vector containing no selectable marker can be used to select the product according to whether the product is produced or not. Selection of the selection marker is selected by the desired host cell, and the present invention is not limited thereto since it uses a method already known to those skilled in the art.
  • the nucleic acid molecule of the present invention can be fused by inserting a tag sequence into an expression vector.
  • tags include, but are not limited to, hexa-histidine tags, hemagglutinin tags, myc tags, or flag tags, all of which are known to those skilled in the art and that facilitate purification.
  • a host cell transfected with the expression vector provided in the present invention.
  • the " host cell” includes individual cells or cell cultures that may or may not be a recipient of the vector (s) for incorporation of the polypeptide insert.
  • the host cell contains the offspring of a single host cell and the offspring may not necessarily be identical (morphologically or in a genomic DNA complement) to the original parental cell because of natural, accidental or deliberate mutations.
  • Host cells include cells transfected in vivo with the polypeptide (s) herein.
  • the host cell may include cells of mammalian, plant, insect, fungal or cellular origin, for example, bacterial cells such as Escherichia coli, Streptomyces, Salmonella typhimurium; Yeast cells, fichia pastoris, and the like; Insect cells such as Drosophila and Spodoptera Sf9 cells; CHO (Chinese hamster ovary cells), SP2 / 0 (mouse myeloma), human lymphoblastoid, COS, NSO (mouse osteoma), 293T, Bowmanella cells, HT-1080, BHK (Baby Hamster Kidney cells), HEK (Human Embryonic Kidney cells), or PERC.6 (human retinal cells); Or plant cells, but is not limited thereto, and cells usable as a host cell known to a person skilled in the art are all usable.
  • bacterial cells such as Escherichia coli, Streptomyces, Salmonella typhimurium
  • a cancer antigen epitope provided in the present invention, a nucleic acid molecule encoding the tumor antigen, an expression vector inserted with the nucleic acid molecule, or a host cell transformed with the expression vector And more particularly to a composition for activating T cells.
  • activation of a T cell refers to the activation of a T cell receptor that recognizes at least one tumor antigen peptide, a single clone (e. G., Encoding the same TCR) or a polyclone , With clones encoding different TCRs).
  • Activated T cells include but are not limited to one or more selected from the group consisting of cytotoxic T cells, assisted T cells, natural killer T cells, gamma delta T cells, regulatory T cells and memory T cells Or more, but may be preferably memory T cells.
  • the activated T cells can be used to treat a cancerous or a tumorous condition or to prevent cancer recurrence, progression, or metastasis by avoiding the defense mechanism of cancer cells.
  • antigen presenting cells may be loaded with a cancer antigen epitope provided by the present invention.
  • the antigen-presenting cells may include at least one of dendritic cells (DC), B cells and macrophages, but may be dendritic cells.
  • DC dendritic cells
  • B cells B cells
  • macrophages but may be dendritic cells.
  • the " dendritic cells” are members of various groups of morphologically similar cell types found in lymphoid or non-lymphoid tissues. These cells are characterized by their unique form and high expression levels of Surface Class I and Class II MHC molecules, proteins that present antigen peptides to T cells.
  • DCs, other APCs, and T cells may be isolated or derived (e. G., Differentiated) from peripheral blood and from multiple tissue sources conveniently, such as peripheral blood mononuclear cells (PBMC) derived from peripheral blood.
  • PBMC peripheral blood mononuclear cells
  • the antigen-presenting cells induce the differentiation and proliferation of cancer antigen-specific T cells, preferably memory T cells, thereby treating the cancerous or tumorous condition by avoiding the defense mechanism of cancer cells, Can be prevented.
  • a cancer antigen epitope provided by the present invention.
  • a fusion protein comprising a dendritic cell-specific antibody or fragment thereof.
  • the fusion protein provided by the present invention enables the cancer-specific epitope provided by the present invention to be loaded into dendritic cells.
  • Examples of the dendritic cell-specific antibody in the present invention include DCIR, MHC class I, MHC class II, CD1, CD2, CD3, CD4, CD8, CD11b, CD14, CD15, CD16, CD19, CD20, , CD40, CD43, CD44, CD45, CD54, CD56, CD57, CD58, CD83, CD86, CMRF-44, CMRF-56, DCIR, DC-ASPGR, CLEC-6, CD40, BDCA-2, MARCO, DEC-205 , Clec9A, 33D1, mannose receptor, Langerin, DECTIN-1, B7-1, B7-2, IFN- ⁇ receptor, IL-2 receptor, ICAM-1, Fc ⁇ receptor, LOX-1 , Or an ASPGR-specific antibody.
  • the cancer-specific epitope may be conjugated to the dendritic cell-specific antibody or a fragment thereof.
  • conjugate refers to any substance formed by joining two moieties together. Representative conjugates according to the present invention include those formed by combining antigen and antibody and TLR agonist together.
  • conjugation refers to the process of forming a conjugate and is generally referred to as a physical coupling, e.g., covalent bond, co-ordinal covalent bond, or a second bond, der Waals bonding force.
  • the process of linking an antigen to an antibody can also be accomplished using a non-covalent association [dancerin-cohesin association], such as U.S. Patent Publication No. 20100135994, Related] or by direct chemical linkage by forming a peptide or chemical bond.
  • the antigen-presenting cell may include at least one of dendritic cells, B cells, and macrophages, but may be a dendritic cell.
  • the dendritic cells can be obtained from a variety of sources including a self-source, that is, a desired individual, and preferably a peripheral blood mononuclear cell (PBMC) , More preferably by isolating mononuclear cells from the individual-derived PBMC and contacting them with a plurality of cytokines.
  • a self-source that is, a desired individual
  • PBMC peripheral blood mononuclear cell
  • the kind of the cytokine that induces the differentiation of the monocyte into dendritic cells is not particularly limited, but may include, for example, at least one of GM-CSF and IL-4.
  • the above-mentioned " objective individual” means an individual who has developed cancer or has a high possibility of developing cancer.
  • the cancer-specific epitope of the present invention can be loaded into the antigen-presenting cell.
  • Immature dendritic cells generally capture antigens through endocytosis through phagocytosis or receptors, process antigens through a series of processes in cells, and then present antigenic peptides to MHC and present them to T lymphocytes.
  • dendritic cells become more mature and lose receptors used for phagocytosis and intracellular entry, increase the expression of MHC class I, II, co-stimulatory molecules, cell adhesion molecules, and express new chemokine receptors T lymphocyte-rich regions of the surrounding lymph nodes and presenting antigen to the T lymphocyte leads to T lymphocyte immune response.
  • the antigen-presenting cell in order to load the cancer-specific epitope into the antigen-presenting cell, may be contacted with the cancer-specific epitope of the present invention.
  • antigen presenting cells e. G., Dendritic cells
  • derived e.g., differentiated
  • TLR agonists include, but are not limited to, poly IC, MALP, and R848.
  • the antigen-presenting cell in order to load the cancer-specific epitope into the antigen-presenting cell, is transfected with an expression vector, preferably a plasmid, into which the nucleic acid molecule encoding the cancer-specific epitope is inserted, (nucleofection).
  • an expression vector preferably a plasmid
  • said nucleofection can be generated by any useful means in the art, including, for example, the Amaxa (R) nucleofection system or the InVitrogen (R) nucleophage system.
  • the cancer-specific epitope provided by the present invention.
  • a fusion protein comprising a dendritic cell-specific antibody or fragment thereof.
  • the present invention relates to a T cell activated by antigen presenting cells.
  • the T cell may be a monoclonal (e. G. Encoding the same TCR) or a polyclonal (e. G., Having a clone encoding a different TCR) with a T cell receptor that recognizes a tumor antigen peptide.
  • a cell population may include, but is not limited to, one or more selected from the group consisting of a cytotoxic T cell, a secondary T cell, a natural killer T cell, a ⁇ T cell, a regulatory T cell, and a memory T cell It may contain one or more subtypes of T cells, but may be preferably memory T cells.
  • the above-mentioned " memory T cells” are T cells differentiated from T cells or activated T cells that have previously reacted with their specific antigens.
  • Tumor-specific memory T cells constitute a small part of the total T cell volume, but they perform an important function in the monitoring of tumor cells for the entire life span of an individual.
  • memory T cells are immediately activated and clonally expanded.
  • Activated and proliferated T cells differentiate into effector T cells, killing tumor cells with high efficiency.
  • Memory T cells are important for establishing and maintaining long-term tumor antigen-specific responses of T cells.
  • the activated T cells preferably activated memory T cells, specifically recognize the antigen of cancer cells and treat the cancerous or tumorous condition by avoiding the defense mechanism of cancer cells, Can be prevented.
  • a method of activating T cells by antigen presenting cells provided by the present invention.
  • the T cells may be co-cultured with the cancer-specific epitope-loaded antigen-presenting cells of the present invention in order to activate the T cells.
  • the T cells can be obtained from a variety of sources including a self-source, that is, a desired individual, and preferably obtained from a peripheral blood mononuclear cell (PBMC) derived from peripheral blood, More preferably from the non-adherent portion of the peripheral blood mononuclear cells.
  • PBMC peripheral blood mononuclear cell
  • the non-adherent portion of the PBMC can be obtained by density gradient centrifugation of a peripheral blood sample and can be obtained by centrifuging it with at least one cytokine (e.g. IL -2).
  • the T cell may be a monoclonal (e. G. Encoding the same TCR) or a polyclonal (e. G., Having a clone encoding a different TCR) with a T cell receptor that recognizes a tumor antigen peptide.
  • a cell population may include, but is not limited to, one or more selected from the group consisting of a cytotoxic T cell, a secondary T cell, a natural killer T cell, a ⁇ T cell, a regulatory T cell, and a memory T cell It may contain one or more subtypes of T cells, but may be preferably memory T cells.
  • the T cell and the antigen presenting cell may be derived from an individual having the same individual, for example, a cancer, preferably an EBV positive cancer (for example, a low grade to an intermediate grade cancer) It is not.
  • a cancer preferably an EBV positive cancer (for example, a low grade to an intermediate grade cancer) It is not.
  • the T cells are incubated with the antigen presenting cells of the present invention at 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, or 30 days, and preferably 1 to 21 days, 1 to 14 days, 2 to 10 days, 2 to 5 days, 2 to 5 days, 3 days, 5 days, 7 days, 10 days, 14 days, 16 days, 18 days, or 21 days.
  • At least one cytokine is added to coexist the T cells and the antigen presenting cells of the present invention to promote activation, maturation and / or proliferation of T cells, and then to differentiate into T cells Can be primed.
  • exemplary cytokines that can be used at this stage include IL-2, IL-4, IL-7, IL-15, IL- (IL-21), combinations thereof, and the like.
  • a fusion protein comprising a cytokine and an immunoglobulin heavy chain constant region is co-cultured in the co-culture of the T cell and the antigen presenting cell of the present invention to promote activation, maturation and / or proliferation of T cells T cells can then be primed for subsequent differentiation into memory T cells.
  • Interleukin-2 IL-2
  • interleukin-4 IL-4
  • interleukin-12 IL-12
  • IL-18 tumor necrosis factor TNF
  • GMCSF granulocyte macrophage colony stimulating factor
  • the immunoglobulin heavy chain constant region may also be an immunoglobulin heavy chain constant region selected from the group consisting of an immunoglobulin hinge region, and optionally, a CH2 domain, a CH3 domain, and a CH4 domain or a combination thereof, but is not limited thereto.
  • the immunoglobulin heavy chain constant region may be selected from the group consisting of immunoglobulins belonging to any of the five immunoglobulin classes referred to in the art as IgA (Ig?), IgD (Ig?), IgE , But may preferably be an immunoglobulin heavy chain constant region derived from an IgG class.
  • a ligand which binds to a cell surface protein that is highly expressed in memory T cells when co-cultured with the T cell and the antigen presenting cell of the present invention; And immunoglobulin heavy chain constant regions may be added to facilitate activation, maturation, and / or proliferation of T cells and subsequent priming of T cells for differentiation into memory T cells.
  • cell surface proteins highly expressed in the memory T cells may be CD27, CXCR3 or CD62L.
  • the ligand capable of binding to CD27 may be CD70
  • the ligand capable of binding to CXCR3 may be CXCR9 or CXCR10
  • the ligand capable of binding to CD62L may be GlyCAM-1, CD34, MadCAM-1 or PSGL -1, but is not limited thereto.
  • the immunoglobulin heavy chain constant region may be selected from the group consisting of immunoglobulins belonging to any of the five immunoglobulin classes referred to in the art as IgA (Ig?), IgD (Ig?), IgE , But may preferably be an immunoglobulin heavy chain constant region derived from an IgG class.
  • an immunotherapeutic agent comprising an antigen-presenting cell loaded with a cancer-specific epitope provided by the present invention as an active ingredient.
  • the immunotherapeutic agent according to the present invention can increase the immune response or selectively elevate a part of the immune response desirable for the treatment or prevention of cancer, for example, in a particular disease.
  • cancer-specific epitope-loaded antigen-presenting cells provided by the present invention; And / or an activated T cell as an active ingredient, or a pharmaceutical composition for preventing or treating cancer.
  • the term " cancer" refers to or indicates a physiological condition characterized by cell growth that is not typically regulated in mammals.
  • the cancer to be prevented, ameliorated or treated in the present invention is an epstein-barr virus (EBV) -positive cancer, EBV-positive gastric cancer, EBV-positive cervical cancer, EBV-positive Burkitt's lymphoma, T-cell lymphomas, EBV-positive breast cancer, EBV-positive leiomyosarcomas, EBV-positive smooth muscle tumors, EBV-positive Hodgkin lymphoma, EBV- Lymphocyte proliferative disease (PTLD), but may be, but is not limited to, EBV-positive gastric cancer.
  • EBV-positive gastric cancer EBV-positive cervical cancer
  • EBV-positive Burkitt's lymphoma T-cell lymphomas
  • EBV-positive breast cancer EBV-positive leiomyosarcomas
  • EBV-positive smooth muscle tumors EBV-positive Hodgkin lymphoma
  • the antigen-presenting cells provided in the present invention can induce the differentiation and proliferation of EBV-positive cancer antigen-specific T cells, preferably memory T cells, and the activated memory T cells are capable of preventing cancer cell defense mechanism Or to treat a tumorous condition or to prevent cancer recurrence, progression or metastasis.
  • the anti-cancer vaccine according to the present invention may include both an immunization method performed by a single administration and an immunization method performed by continuous administration.
  • " prevention Or any act that suppresses or delays the symptoms, without limitation.
  • treatment may include, without limitation, any action that improves or alleviates the symptoms of cancer using the pharmaceutical composition of the present invention.
  • the pharmaceutical composition may be in the form of capsules, tablets, granules, injections, ointments, powders or beverages.
  • the pharmaceutical composition may be a human.
  • the pharmaceutical composition according to the present invention may be formulated into oral formulations, such as powders, granules, capsules, tablets, aqueous suspensions, etc., external preparations, suppositories and sterilized injection solutions according to a conventional method, .
  • the pharmaceutical compositions of the present invention may comprise a pharmaceutically acceptable carrier.
  • the pharmaceutically acceptable carrier may be a binder, a lubricant, a disintegrant, an excipient, a solubilizing agent, a dispersing agent, a stabilizer, a suspending agent, a coloring matter, a perfume or the like in the case of oral administration.
  • a solubilizing agent, an isotonic agent, a stabilizer and the like may be mixed and used.
  • a base In the case of topical administration, a base, an excipient, a lubricant, a preservative and the like may be used.
  • Formulations of the pharmaceutical compositions of the present invention may be prepared in various manners by mixing with pharmaceutically acceptable carriers as described above.
  • oral administration may be in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, etc.
  • injections they may be formulated in unit dosage ampoules or in multiple dosage forms have.
  • suitable carriers, excipients and diluents for formulation include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltoditol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, Cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate or mineral oil. Further, it may further include a filler, an anticoagulant, a lubricant, a wetting agent, a flavoring agent, an emulsifying agent, an antiseptic, and the like.
  • the route of administration of the pharmaceutical composition according to the present invention is not limited to the oral route, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, Sublingual or rectal. Oral or parenteral administration is preferred.
  • parenteral includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.
  • the pharmaceutical compositions of the present invention may also be administered in the form of suppositories for rectal administration.
  • the pharmaceutical composition of the present invention may be administered orally or parenterally depending on various factors including the activity, age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and severity of the particular disease to be prevented or treated, And the dose of the pharmaceutical composition may be appropriately selected by a person skilled in the art depending on the condition of the patient, the body weight, the degree of disease, the type of administration, the route of administration and the period of time, and is preferably from 0.0001 to 50 mg / kg Or 0.001 to 50 mg / kg. The administration may be carried out once a day or divided into several times. The dose is not intended to limit the scope of the invention in any way.
  • the pharmaceutical composition according to the present invention can be formulated into pills, dragees, capsules, solutions, gels, syrups, slurries, and suspensions.
  • an antigen-presenting cell in which a cancer-specific epitope provided in the present invention is loaded into a desired individual, in order to prevent or treat cancer; And / or < / RTI > administering an activated T cell.
  • the cancer is an epstein-barr virus (EBV) positive cancer, including EBV-positive gastric cancer, EBV-positive cervical cancer, EBV-positive Burkitt's lymphoma, EBV-positive T cell lymphoma, , EBV-positive breast cancer, EBV-positive leiomyosarcomas, EBV-positive smooth muscle tumors, EBV-positive Hodgkin lymphoma, EBV-positive nasopharyngeal cancer, or EBV-positive lymphocyte proliferative disease (PTLD) But preferably is, but is not limited to, EBV-positive stomach cancer.
  • EBV-positive gastric cancer including EBV-positive cervical cancer, EBV-positive Burkitt's lymphoma, EBV-positive T cell lymphoma, , EBV-positive breast cancer, EBV-positive leiomyosarcomas, EBV-positive smooth muscle tumors, EBV-positive Hodgkin lymphoma, EBV-positive nasopharyngeal
  • the dosage, schedule and route of administration of the cancer-specific epitope-loaded antigen presenting cells or activated T cells provided by the present invention can be determined according to the size and condition of the individual, and according to standard pharmaceutical practice.
  • Exemplary routes of administration include intravenous, intraarterial, intraperitoneal, intrapulmonary, intravascular, intramuscular, intratracheal, subcutaneous, intrathecal, intrathecal, or transdermal.
  • the dose of a cell to be administered to an individual may vary depending on, for example, the particular type of cell being administered, the route of administration, and the particular type and stage of the cancer being treated.
  • the amount should be sufficient to bring about the desired response, such as a therapeutic response to cancer, without severe toxic or adverse events.
  • the amount of activated T cells or antigen presenting cells (such as dendritic cells) to be administered is a therapeutically effective amount.
  • the amount of cell (e.g., a dendritic cell or activated T cell loaded with a cancer specific epitope) is compared to the corresponding tumor size, number of cancer cells, or tumor growth rate in the same individual prior to treatment, Or at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100% The number of tumor cells, the number of cancer cells, or the rate of growth of the tumor.
  • the effect can be scaled using standard methods such as in vitro assays with purified enzyme, cell-based assays, animal models or human experiments.
  • the cancer-specific epitope is loaded antigen-presenting cells (e.g. dendritic cells) of the invention 1 ⁇ 10 5 ⁇ 5 ⁇ 10 5, 5 ⁇ 10 5 ⁇ 1 ⁇ 10 6, 1 ⁇ 10 6 ⁇ 2 ⁇ 10 6, 2 ⁇ 10 6 ⁇ 3X10 6 , 3X10 6 to 4X10 6 , 4X10 6 to 5X10 6 , 5X10 6 to 6X10 6 , 6X10 6 to 7X10 6 , 7X10 6 to 8X10 6 , 8X10 6 to 1X10 8 , 1X10 6 to 3X10 6 , 3X10 6 to 5X10 6 , 5 ⁇ 10 6 to 7 ⁇ 10 6 , 2 ⁇ 10 6 to 4 ⁇ 10 6 , 1 ⁇ 10 6 to 5 ⁇ 10 6, or 5 ⁇ 10 6 to 1 ⁇ 10 7 cells / individual.
  • antigen-presenting cells e.g. dendritic cells
  • the cancer-specific epitope is loaded antigen-presenting cells (e.g. dendritic cells) of the invention 1 ⁇ 10 4 ⁇ 5 ⁇ 10 4, 5 ⁇ 10 4 ⁇ 1 ⁇ 10 5, 1 ⁇ 10 5 ⁇ 2 ⁇ 10 5, 2 ⁇ 10 5 ⁇ 4 ⁇ 10 5 1X10 5 to 6X10 5 , 6X10 5 to 8X10 5 , 8X10 5 to 1X10 6 , 1X10 6 to 2X10 6 , 2X10 6 to 1X10 7 , 1X10 4 to 1X10 5 , 1X10 5 to 1X10 6 , 1X10 6 to 1X10 7 , 1X10 4 to 1 ⁇ 10 6, or 1 ⁇ 10 5 to 1 ⁇ 10 7 cells / kg.
  • antigen-presenting cells e.g. dendritic cells
  • 1 ⁇ 10 8 to 5 ⁇ 10 8, 5 ⁇ 10 8 to 9 ⁇ 10 8, 9 ⁇ 10 8 to 1 ⁇ 10 9, 1 ⁇ 10 9 to 2 ⁇ 10 9, 2 ⁇ 10 9 to 3 ⁇ 10 9, 3 ⁇ 10 9 to 4X10 9 , 4X10 9 to 5X10 9 , 5X10 9 to 6X10 9 , 6X10 9 to 1X10 10 , 1X10 9 to 3X10 9 , 3X10 9 to 5X10 9 , 5X10 9 to 7X10 9 , 7X10 9 to 1X10 10 , 1X10 9 to 5X10 9 , 5 ⁇ 10 9 to 1 ⁇ 10 10, 3 ⁇ 10 9 to 7 ⁇ 10 9, 1 ⁇ 10 10 to 1.5 ⁇ 10 10, 1 ⁇ 10 10 to 10 or 2 ⁇ 10 1 ⁇ 10 9 1 ⁇ 10 to any one of the may be administered at a dose of cells / object of 10, but limited to, It is not.
  • the activated T cells of the present invention 1 ⁇ 10 7 to 1 ⁇ 10 8, 1 ⁇ 10 8 to 2 ⁇ 10 8, 2 ⁇ 10 8 to 4 ⁇ 10 8, 4 ⁇ 10 8 to 6 ⁇ 10 8, 6 ⁇ 10 8 to 8 ⁇ 10 8, 8 ⁇ 10 8 to 1X10 9 , 1X10 9 to 2X10 9 , 2X10 9 to 4X10 9 , 4X10 9 to 1X10 10 , 2X10 8 to 6X10 8 , 6X10 8 to 1X10 9 , 1X10 8 to 2X10 8 , 2X10 8 to 2X10 9 , 1X10 7 to 1X10 8 , 1 ⁇ 10 8 to 1 ⁇ 10 9, 1 ⁇ 10 9 to 10 or 1 ⁇ 10 1 ⁇ 10 7 to 9 1 ⁇ 10 gae be administered at a dose of any one of the cells / kg of, but is not limited to this.
  • the cancer-specific epitope-loaded antigen presenting cells e.g., dendritic cells
  • a stabilizing agent or excipient such as human albumin upon administration of the activated T cells
  • the dosage and administration schedule of the cancer-specific epitope-loaded antigen presenting cells may be adjusted throughout the course of treatment based on the judgment of the administering physician.
  • the activated T cells are treated at a dose of about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 or 1 month after the administration of the antigen, May be administered simultaneously, but are not limited thereto.
  • the administration of the cancer-specific epitope-loaded antigen-presenting cells may be used alone or in combination with other therapies such as surgery, radiation therapy, gene therapy, Stem cell transplantation, hormone therapy, target therapy, cryotherapy, ultrasound therapy, photodynamic therapy, chemotherapy, and the like.
  • other therapies such as surgery, radiation therapy, gene therapy, Stem cell transplantation, hormone therapy, target therapy, cryotherapy, ultrasound therapy, photodynamic therapy, chemotherapy, and the like.
  • a person at greater risk of developing a proliferative disease may be treated for inhibiting and / or delaying the onset of the disease.
  • Epstein-Barr Virus (EBV) positive cancer-specific epitope provided by the present invention can be used to rapidly and effectively differentiate and proliferate cancer antigen-specific T cells, preferably memory T cells, via antigen-presenting cells loaded with dendritic cells Induced memory T cells can be used to treat Epstein-Barr virus (EBV) positive or tumorous conditions or to prevent cancer recurrence, progression or metastasis by avoiding the defense mechanisms of cancer cells.
  • EBV Epstein-Barr virus
  • adoptive T cell therapy has required a long period of 3 to 6 months to produce a large number of T cells for the treatment of cancer patients, which is a serious problem in the cell production process in immune cell therapy.
  • FIG. 1 shows ELISPOT of each neo-epitope in order to confirm the degree of T cell activation of the neo-epitope derived from EBNA-1 in the SNU719 cell line according to an embodiment of the present invention.
  • FIG. 2 is a graph showing ELISPOT of each neo-epitope in order to confirm the level of activation of EB-1-derived neo-epitope T cells in EBV-infected MKN74 cell line according to an embodiment of the present invention.
  • FIG. 3 shows the results of ELISPOT for each neo-epitope in order to confirm the degree of T cell activation of LMP-2A-derived neo-epitope in SNU719 cell line according to an embodiment of the present invention.
  • FIG. 4 shows ELISPOT of each neo-epitope in order to confirm the degree of T cell activation of the neo-epitope derived from LMP-2A in the EBV-infected MKN74 cell line according to an embodiment of the present invention.
  • FIG. 5 is a graph showing the effect of EBNA-1-derived neo-epitope on SNU-719 cell line according to HLA type in order to confirm the target cancer cell killing activity of EBV-positive gastric cancer cell antigen of human derived memory T cells prepared according to one embodiment of the present invention (Cr51 release assay) for three selected neo-epitopes, respectively.
  • FIG. 6 is a graph showing the effect of the EBNA-1-derived neo-oncogene on the EBV-infected MKN74 cell line according to the HLA type in order to confirm the target cancer cell killing activity of the EBV-positive gastric cancer cell antigen of the human- (Cr51 release assay) for each of the three neo-epitopes selected from among the epitopes.
  • FIG. 7 is a graph showing the effect of LMP-2A-derived neo-oncogene on SNU-719 cell line according to HLA type in order to confirm the target cancer cell apoptosis activity of EBV-positive gastric cancer cell antigen in human-derived memory T cells prepared according to an embodiment of the present invention. (Cr51 release assay) for each of the three neo-epitopes selected from among the epitopes.
  • FIG. 8 is a graph showing the effect of HLA-type EBV-infected MKN74 cell line on human-derived memory T cells of human-derived memory T cells according to an embodiment of the present invention. (Cr51 release assay) for each of the three neo-epitopes selected from among the epitopes.
  • FIG. 9 is a graph showing the results of immunoblot analysis of three EBV-negative MKN74 cell lines selected from three EBV-negative neoplastic epithelial cells of human-derived memory T cells, And the Cr51 release assay for the neo-epitope, respectively.
  • FIG. 10 is a graph showing the results of immunoblot analysis of three EBV-negative MKN74 cell lines selected from three EBV-negative neoplastic epithelial cells of EBV-positive gastric cancer cell antigens of human-derived memory T cells prepared according to an embodiment of the present invention And the Cr51 release assay for the neo-epitope, respectively.
  • FIG. 11 is a graph showing the cell-specificity of LMP-2A-derived neo-epitope among EBV-positive gastric cancer cell antigens of human-derived memory T cells prepared according to an embodiment of the present invention. And the Cr51 release assay for the neo-epitope, respectively.
  • FIG. 12 is a graph showing the cell-specificity of LMP-2A-derived neo-epitope among EBV-positive gastric cancer cell antigens of human-derived memory T cells prepared according to an embodiment of the present invention. And the Cr51 release assay for the neo-epitope, respectively.
  • FIG. 13 is a graph showing the neo-epitope specificity in the BALB / c nude mouse xenograft model (SNU-719) in order to examine the in vivo anticancer effect of the neo-epitope derived from EBNA-1 according to an embodiment of the present invention The results of experiments on the effect of red cell cytotoxic T cells are shown.
  • FIG. 14 is a graph showing the neo-epitope specificity in the BALB / c nude mouse xenograft model (EBV-infected MKN74) in order to examine the in vivo anticancer effect of the neo-epitope derived from EBNA-1 according to an embodiment of the present invention The results of experiments on the effect of red cell cytotoxic T cells are shown.
  • Figure 15 is a graph showing the neo-epitope specificity in an animal model of BALB / c nude mouse xenograft (SNU-719) in order to examine the in vivo anticancer effect of the neo-epitope derived from LMP-2A according to an embodiment of the present invention The results of experiments on the effect of red cell cytotoxic T cells are shown.
  • 16 is a graph showing the neo-epitope specificity in BALB / c nude mouse xenograft model (EBV-infected MKN74) in order to examine the in vivo anticancer effect of neo-epitope derived from LMP-2A according to an embodiment of the present invention The results of experiments on the effect of red cell cytotoxic T cells are shown.
  • an epstein-barr virus (EBV) positive tumor-specific neo-epitope represented by any one of SEQ ID NOS: 1-184.
  • an antigen presenting cell in which the cancer-specific neo-epitope provided in the present invention is loaded.
  • the present invention relates to a T cell activated by antigen presenting cells.
  • cancer-specific epitope-loaded antigen-presenting cells provided by the present invention; And / or an activated T cell as an active ingredient, or a pharmaceutical composition for preventing or treating cancer.
  • HLA-A * 0206 HLA-A * 3303 were identified as HLA-A * 2402, HLA-A * A0201 and HLA-A * * 3101 and a peptide sequence expected to have high binding affinity with HLA-B * 5101, HLA-B * 4403, HLA-B * 5401, HLA-B * 5801 and HLA-B * 3501.
  • HLA typing of the present EBV + gastric cancer cell line was performed to investigate the HLA type of each cell line, and LMP-2A and EBNA-2, which are present only in EBV + gastric cancer cells and induce malignant tumor by EBV virus, 1 protein was predicted by the NetMHC program and predicted for each HLA type and neo - epitope with high binding affinity. The results are shown in Tables 1 and 2, respectively.
  • HLA-A * 2402, HLA-A * A0201, HLA-A * 3303, HLA-A * 1101, HLA- Neo-epitopes with high binding affinity for -A * 3101, HLA-B * 5101, HLA-B * 4403, HLA-B * 5401, HLA-B * 5801 or HLA- HLA binding affinities were predicted by IC 50 (nM) values.
  • IC 50 nM
  • the neo-epitope thus selected was synthesized as a peptide.
  • GM-CSF and IL-4 cytokines were cultured for 2 days in a culture medium.
  • the PBMCs from healthy human blood were separated into monocytes and leukocytes by flow cytometry.
  • the cells were incubated with anti-CD3 / CD28 antibody for 3 days and then cultured in a culture medium containing IL-2 cytokine.
  • the neo-epitope peptide selected as described above is transferred to DCs differentiated into dendritic cells by electrophoresis.
  • the neo-epitope was expressed on the surface of the dendritic cells, followed by culturing in a culture medium containing the anti-CD3 / CD28 antibody in the ratio of 1:20 (dendritic cell: leukocyte) Lt; / RTI > In co-culture, the culture medium contained IL-4, a cytokine that increases the antigen-presenting function of dendritic cells, and cytokines such as IL-2 and IL-7, which are cytokines that help to convert T cells into memory cells. Cain cocktails were mixed and cultured. The expression level of IFN-y in the activated T cells after 16 hours was measured by ELISPOT and shown in Figs. However, the negative control peptide used in the above experiment was an EBNA-1 and an amino acid sequence 9-mer (sequence: GGSRERARG) of LMP-2A protein not extracted through NetMHC in EBNA-1 and LMP-2A.
  • IFNr is secreted in T cells cultured with dendritic cells loaded with the neo-epitope peptide of the present invention, as compared with the control, irrespective of the binding affinity of the peptide to HLA.
  • Cytotoxic T lymphocytes can be activated by neo-epitope-loaded dendritic cells selected by the HLA-A type of each cell line in Tables 1 and 2, Activated T cells were found to have antigen specificity to recognize neo - epitopes of neoplastic origin.
  • the cells were co-cultured for 72 hours as described in 2. above, and then a cell extractor (MACS) using a magnet capable of extracting IFNr cytokine-releasing T cells was used to select memory T cells presented with antigen via dendritic cells And extracted EBV antigen-specific memory T cells.
  • the extracted memory T cells were cultured in a medium containing IL-2, IL-7, and IL-15 cytokines in order to maintain memory function and to increase the number of cells, Respectively.
  • the activated T cells were co-cultured with SNU-719 cell line, EBV-positive gastric cancer cell line, and EBV-infected MKN74 cell line, and the lysis of cancer cells was confirmed by Cr51 release assay, The results are shown in FIG. 5 to FIG. 8.
  • Co-culture with an MKN-74 cell line, an EBV-negative gastric cancer cell confirmed the lysis of cancer cells by Cr51 release assay, 9-12.
  • the negative control peptide used in the above experiment was an EBNA-1 and an amino acid sequence 9-mer (sequence: GGSRERARG) of LMP-2A protein not extracted through NetMHC in EBNA-1 and LMP-2A.
  • the neo-epitope-activated T cells according to the present invention have excellent hemolytic activity of EBV-positive gastric cancer cells, while the hemolytic activity of EBV-negative gastric cancer cells is insignificant. That is, T cells activated with dendritic cells loaded with the EBV cancer-specific antigen neo-epitope according to the present invention can specifically show hemolysis of EBV-positive cancer cells.
  • the neo-epitope-activated T cells of the present invention showed a tendency to increase in the hemolytic activity depending on the concentration of the mixture when co-cultured with EBV-positive gastric cancer cells.
  • the neo-epitope-activated T cells according to the present invention significantly reduced the size of EBV-positive gastric cancer compared to the control group.
  • the binding affinity with HLA The higher the rate of gastric cancer size reduction.
  • the neo-epitope selected by the HLA-A type of each cell line is excellent in the activity of enhancing the activity of T cells.
  • the binding affinity by bioinformatics is increased (that is, the IC 50 value is lowered It was confirmed that the activity for the improvement of the T cell activity and the cancer cell death was increased.
  • the neo-epitope shown in Tables 1 and 2 can enhance the activity of T cells using dendritic cells, and that the therapeutic effect of the target cancer will be also excellent.
  • the present invention relates to a cancer-specific neo-epitope, an antigen-presenting cell loaded with the neo-epitope, and a method of activating T cells for cancer treatment by the antigen presenting cells.

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