Cancer stem cell targeted cancer vaccines

Abstract

To provide cancer stem cell targeted cancer vaccines, and methods for treatment of and vaccination against cancer.SOLUTION: A method for treating, preventing or managing cancer in a subject in need thereof comprises administering, to the subject, (i) a first pharmaceutical composition comprising an IL-13Rα2 peptide, an EphA2 peptide, at least one survivin peptide, tetanus toxoid helper T cell epitope, and an emulsifier, and (ii) a second pharmaceutical composition comprising an immunomodulatory agent.SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001] 1. Introduction Provided herein are peptide-based cancer stem cell targeted vaccines and A method for treating cancer comprising administering to a subject in need thereof a vaccine that targets cancer stem cells. In a preferred embodiment, the vaccine is administered to patients with brain tumors. Also provided herein are dosages and administration schedules for the vaccine. Also provided herein is a method for administering a vaccine comprising a cancer antigen-derived Such agents as peptides, helper peptides, adjuvants, emulsifiers and / or immunostimulants A cancer stem cell-targeting agent that is combined or administered as a component of the administration method. Also provided herein are vaccine components for this patient population. A patient population to which a cancer vaccine can be administered. The vaccine targeted to cancer stem cells of the present invention , and also targets tumor bulk cells (the non-cancer stem cells of the tumor). [Background technology]

[0002] 2. background Cancer is one of the most important health conditions. The Canadian Cancer Society's Cancer Facts and Figures 2003 estimates that this year, more than 13 million people will be diagnosed with cancer. Americans are expected to be diagnosed with cancer. In 2002, the National Institutes of Health reported that pulmonary circulation is the second leading cause of death after heart disease, accounting for one in four deaths. estimated the total cost of cancer at $171.6 billion, of which $61 billion was direct expenditures. is widely expected to increase as the U.S. age population increases, and the The impact is even greater. Current cancer treatment methods established in the 1970s and 1980s Other modalities, including chemotherapy, radiation therapy, and more recently targeted therapies, have not changed dramatically. These treatments, including CT scans, are used to treat the most advanced stages of common cancers. In particular, these treatments target the cancer stem cells rather than the Rather, it primarily targets tumor bulk cells.

[0003] More specifically, to date, conventional cancer diagnosis and treatment has focused primarily on rapidly growing tumors. In an attempt to selectively detect and eliminate tumor cells (i.e., cells forming the tumor bulk), Standard tumor delivery methods are often primarily used to treat tumors without excessive toxicity, but with minimal radiation. The maximum dose of a therapy or chemotherapeutic agent, often referred to as the “maximum tolerated dose” (MTD) or “maximum These studies are designed to administer doses that are referred to as “no observed adverse events” (NOAELs). Many conventional cancer chemotherapy regimens (e.g., alkylating agents such as cyclophosphamide, 5-fluorouracil, metabolic antagonists such as lauracil, plant alkaloids such as vincristine) and conventional This type of radiation therapy primarily works by interfering with the cellular mechanisms involved in cell growth and DNA replication. These drugs exert their toxic effects on cancer cells. Chemotherapy protocols also Enhancement efforts often involve the administration of a combination of chemotherapy agents. Despite the availability of agents, these treatments have many drawbacks (e.g., Stockdale, 1998, “Principles of Cancer Patient Management” “Intient Management,” Scientific Amerikan Medicine Erican Medicine, Vol. 3, Rubenstein and Federman (See, e.g., Ed., Chapter 12, Section X.) For example, chemotherapy drugs target rapidly growing cells ( Toxic due to non-specific side effects in the body (whether normal or malignant) For example, chemotherapy drugs are known to cause significant side effects, including bone marrow suppression, immunosuppression, and gastrointestinal disorders. These drugs cause unpleasant and often dangerous side effects.

[0004] Cancer stem cells are a unique tumor subpopulation (often 0.1-10% or so) that is more tumorigenic compared to the remaining 90% or so of the tumor (i.e., the tumor bulk) and is relatively are generally slower growing or dormant and are often relatively slower than the tumor bulk. Conventional treatments and administration methods are primarily directed at acute chemotherapy-resistant subpopulations. Designed to attack fast-growing cells (i.e., those cancer cells that comprise the tumor bulk). If the tumor is infected, the often slow-growing cancer stem cells can grow into the faster-growing tumor bulk. Cancer may be relatively more resistant to conventional treatments and administration methods than Stem cells mediate cancer stem cells' relative chemotherapy resistance, such as multidrug resistance and anti-apoptotic pathways. The above may indicate that the cancer is at an advanced stage (i.e. In most patients, This constitutes a key reason for the failure of standard oncology treatment and administration methods to ensure long-term efficacy. Sometimes, cancer stem cells are the tumor-initiating cells (i.e., they form the tumor bulk). These are precursor cells to cancer cells, including the ovarian cancer cells.

[0005] Cancer stem cells have been identified in a wide variety of cancer types. Using a CT memory system, Bonnet et al. identified leukocytes with the distinctive phenotype CD34+CD38−. Diseased cells can be isolated, and then when transplanted into immunodeficient mice, These cells (known as leukemia cells) are capable of recapitulating the leukemia from which they were derived. <1% of leukemias) and is different from the remaining 99+% of the leukemia bulk. For example, "Human acute myeloid leukemia is a hierarchical process that originates from undifferentiated hematopoietic progenitor cells. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell,” Nature Medicine (Nature Medicine), vol. 3, pp. 730-737, 1997. Cancer stem cells are found in less than 1 in 10,000 leukemia cells, yet this low The frequency population was then analyzed in strictly combined immunodeficient / non-obese diabetic (NOD / SCID) mice. Can give rise to human leukemias with the same histological phenotype as in the original tumor It was possible to transfer the cells sequentially.

[0006] Brain tumors are an attractive tumor type for targeting cancer stem cells with immunotherapy. Kondo et al. isolated a small population of cells from the C6-glioma cell line, which is a type 2 glioma that is immunodeficient. In mice, the ability to self-replicate and repopulate gliomas has led to the development of cancer stem cell populations. Kondo et al., "Cancer stem cell proliferation and differentiation in C6-glioma cell line." Persistence of a small population of cancer stem-like cells ike cells in the C6 glioma cell line,” Proceedings of the National Proc. Natl. Acad. Sci. USA ), Vol. 101, pp. 781-786, 2004. In this study, Kondo et al. The cell line contains a population of cancer stem cells that endows the cell line with the ability to engraft in immunodeficient mice. Singh et al. identified brain tumor stem cells. Unlike tumor cells, CD133+ cancer stem cells were able to induce tumors ( This, in turn, can be transplanted. “Identification of human brain tumor initiating cells” , Nature, Vol. 432, pp. 396-401, 2004; Singh et al., "Nervous System Tumors Cancer stem cells in nervous system tumors, oncogenes Oncogene, vol. 23, pp. 7267-7273, 2004; Singh et al., "Cancer in Human Brain Tumors," "Identification of a cancer stem cell in human brain tumors" See Cancer Res., vol. 63, pp. 5821-5828, 2003.

[0007] Immunotherapy is a promising new approach in the treatment of cancer. The therapy activates the immune system to target and kill tumor cells with less toxicity than standard cancer treatments. Immunotherapy may help to activate tumor immunity via memory T cells. Provides durable responses and prolonged survival through tumor-specific immunosuppression. Using autologous cells or dendritic cells (DCs) pulsed with synthetic peptides for T cell epitopes, Such antigen-specific approaches have been shown to be effective. Presentation of immunogenic T cell-epitopes and antigen-specific T cell precursors Stimulation of the immune system can occur efficiently with the use of specific antigen-peptides. It has the unique potential to mobilize responses that are highly specific to protein antigens. The aim of this is to specifically recognize and attack antigens expressed by cancer cells. To achieve this targeted defense, cancer vaccines are designed to stimulate the immune system. The cells of the immune system that donate are called lymphocytes. In particular, cytotoxic T cells (CD4+ T cells) These immune cells specifically target cancer cells that express cancer antigens that are recognized by these immune cells. It has the ability to kill.

[0008] Cancer vaccines are designed to activate cytotoxic T cells and target cancer cells. Tumor lysates, single epitopes or multiple Cancer vaccines that may contain epitopes can be administered to patients by a variety of routes, including the following 1) or 2): 1) harvesting autologous dace exposed to antigen peptides in vitro and then or 2) by reinjecting the antigen peptide into the patient (e.g., via nasal injection); Through direct injection (e.g. subcutaneous administration).

[0009] GM-CSF enhances immune responses to cancer antigens through multiple mechanisms. Increase T cell cytotoxicity (e.g., Tarr, Medical Oncology, Med Oncol, 1996. GM-CSF also inhibits the expression of antigen-presenting cells ( They also induce the migration and maturation of T cells, including dendritic cells (DCs), which mediate the activity of cytotoxic T cells. GM-CSF is also important in activating the immune response to optimize a robust antitumor response. This biases the immune system towards a Th1 phenotype.

[0010] IL-13Rα2 is expressed in a wide range of cancer types, but not in normal tissues. It is known that IL-13Rα2 is not involved in the regulation of the IL-13 receptor (IL-13Rα2) in the brain, It is expressed in mesothelioma, esophageal, Hodgkin's disease, prostate, breast and colon cancers (Debi Debinski and Gibo, Mol Med, 2000 Wykosky et al., Molecular Cancer Research, 20 05; Wykosky et al., Clin Can Res. 2003; Wykosky et al., Molecular Cancer Research es), 2007). Human leukocyte antigen (HLA)-derived interleukin (IL)-13 receptor α2 A2-restricted cytotoxic T lymphocyte (CTL) epitopes have recently been identified (Okano et al., 2002), Therefore, the identified epitope (IL-13α2 345-353 ) is a peptide-based The peptide IL-13α2 is an attractive component of a vaccine that targets the 345-353 Using C By generating unique CTL lines by stimulation of D8+ cells, IL-13α2-positive, HLA-A2-positive It was shown that glioma cells were efficiently lysed in an antigen-specific manner. 2006) was IL-13α2 345-353 A mutant peptide of the formula: Increased affinity for LA-A2 and generated stronger (more robust) T cell responses (i.e. We identified a peptide with two amino acid substitutions that is more immunogenic than the peptides we made. To achieve this, Okano et al. replaced the amino acid at position 1 with alanine and the amino acid at position 9 with valency. The resulting mutant peptides expressed IL-13α2 345-353:1A9V Called T cells stimulated with the mutant peptide were shown to be able to kill glioma cells. was more effective than wild-type stimulated T cells. The mutant peptide is an attractive component of a brain tumor vaccine.

[0011] EphA2 is a member of the Eph family of receptor tyrosine kinases, which are EphA2 and EphB are two major classes of EphA proteins, which are expressed by ligands (respectively). The family is distinguished by its specificity for ephrin-A and ephrin-B. EphA2 is frequently overexpressed in advanced cancers as well as in metastatic lesions. Malignant glial cells are involved in the regulation of gliomas and are often functionally dysregulated (Kinch et al., 2003). Due to the aggressive and invasive nature of this tumor, EphA2 was expressed in this tumor. EphA2 may be a potential target for glioma vaccines. It is also expressed in breast, prostate, lung and colon cancers (Debinski and Gibo, Mol Med, 2000; Wykoski, ky et al., Molecular Cancer Research (Mol Can Res), 2005; Wykosky et al., Clin Can Res, 2003; (Wykosky et al., Mol Can Res, 2007). EphA T cell immune epitopes in 2 have been identified and are being used as potential targets and for the treatment of cancer immunity. It has been characterized as a surrogate marker for other forms of therapy (Alves et al. , 2003 and Tatsumi et al., 2003 ).

[0012] Survivin is an apoptosis inhibitor protein that is overexpressed in most human cancers. It is a cellular enzyme whose inhibition leads to enhanced apoptosis (e.g., blank-blank Blanc-Brude et al., Nat. Med., vol. 8, pp. 987-994, 2011. Survivin expression is associated with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (AML). In various hematological malignancies, including leukemia (ALL), as well as in lung, esophageal, breast, pancreatic, It has been shown in ovarian, melanoma, colon, hepatocellular, gastric and bladder cancers (Li et al. , Cancer Res, 1999; Grabowski et al., Brit. Br J Can, 2003; Tanaka et al., Clinical Chem. Cancer Research (Clin Can Res), 2000; Nath et al., Anticancer Research ( Antican Res, 2002; Sato et al., Cancer, 2001; Sarela ) et al., British Journal of Cancer (Br J Can), 2002; Cohen ( Cohen et al., Modern Pathology, 2003; Naor et al., American Am J Dermatopath, 2008; Salera Sarela et al., Gut, 2000; Ikeguchi et al., Diagnostic Molecular Diagn Mol Pathol, 2002; Ito et al., Hepatopathology. Pathology, 2000; Yu et al., British Journal of Cancer Br J Can, 2002; Lu et al., Cancer Res, 1998 Lehner et al., Applied Immunohistochemistry and Molecular Appl Immunohis Mol Morphol, 2002; Mori et al., International (Int J Hematol, 2002). This expression pattern Survivin also inhibits glioblastoma cells, making it an attractive cancer vaccine target. It is expressed in cancer stem cells in a variety of cancers, including myocardial infarction, renal cancer, prostate cancer, and colon / colon cancer. It has been shown that the IL-1 receptor agonist is a cytotoxic antagonist (Liu et al., Molecular Cancer 2013). r), Vol. 5, Paper 67, 2006; Nishizawa et al., Cancer Res, 2012 Liao et al., Cancer Res, Vol. 70, Paper 18, 2010 In a separate study, Andersen et al. (Cancer Research Research, 61, 2001) has demonstrated that survivin is a cytotoxic T cell-specific antigen that is recognized by peripheral T cells in cancer patients. Moreover, Andersen et al. By making substitutions in the amino acids of the peptide, it is possible to make the peptide more immunogenic than the wild-type peptide. Analogs of these peptides that are potent and cytotoxic to cancer cells have been identified. In addition, Bernatchez et al. (vaccination) identified activated T cells that Chin, Vol. 29, No. 16, 2011) is an additional survivin analog peptide that has immunogenicity (including sequence no. 9 provided herein) and capable of cytotoxicity against cancer cells. Those that could be activated were identified.

[0013] The vaccine targeting cancer stem cells of the present invention also targets tumor bulk cells (non-cancer stem cells of the tumor). These vaccines target genes expressed by both cancer stem cells and tumor bulk cells. The peptides used herein may contain peptides derived from tumor-associated antigens. As used herein, the terms "cancer stem cell targeted vaccine" and "cancer vaccine" are synonymous. Used in. Summary of the Invention

[0014] 3. overview Provided herein are patient populations to which the vaccine may be administered and methods for administering the vaccine to target cancer stem cells. and their components, dosage, route of administration, schedule, and method of administration. Among the components included herein are administered tumor associated antigens and cancer stem cell associated antigens, and peptides derived from these antigens, as well as immunomodulatory agents (adjuvants and Also known as colorants, emulsifiers, and emulsifiers, as well as combinations of these ingredients.

[0015] The present invention relates to a multi-epitope vaccine, wherein the epitopes are derived from a tumor antigen. The epitope peptide is injected subcutaneously (for example) and then circulates through the lymph nodes. The antigen then enters the peripheral lymph nodes (e.g., maxillary or inguinal nodes) where it is collected. The peptides are then "spread" onto the cell surface through a process known as cytotoxicity. T cells systematically interact with the peptide in the lymph nodes and This method is the activation of antigen-specific cytotoxic T cells. This leads to activation and expansion of T cells, making them capable of killing cancer cells. Additional compounds called immune adjuvants can also be used to boost immunity. To enhance the immune system, GM-CSF can be administered in combination with a cancer vaccine. It is one such immunomodulatory agent that has been shown to be effective when used in conjunction with Imiquimod has been shown to be effective when used in conjunction with cancer vaccines. Such immunomodulatory agents include:

[0016] In one aspect, provided herein is a peptide derived from IL-13Rα2. which serves as an HLA-A2-restricted cytotoxic T lymphocyte (CTL) epitope. The IL-13Rα2 peptide is [ka] It may comprise, consist of, or essentially be a substitution mutant variant of and wherein at least one of the amino acid residues is a residue other than that shown. In addition, the IL-13Rα2 peptide may have the following sequence: [ka] may comprise, consist of, or essentially consist of any of the sequences In a preferred embodiment, the cancer stem cell targeted cancer vaccine comprises a polypeptide comprising the polypeptide of SEQ ID NO:4. In one aspect, provided herein are peptides that correspond to survivin. It is a peptide derived from HLA-A2-restricted cytotoxic T lymphocyte (CTL) epitope. The survivin peptide acts as a [ka] or a substitution mutant variant of [ka] It may comprise a substitution mutation of, consist of, or essentially consist of, a variant or mutant of, and wherein at least one of the amino acid residues is an amino acid residue selected from the group consisting of In addition, the survivin peptide may have the following sequence: : [ka] may comprise, consist of, or essentially consist of any of the sequences In a preferred embodiment, the cancer stem cell-targeting cancer vaccine comprises the sequence In another preferred embodiment, the peptide is targeted to cancer stem cells. The cancer vaccine comprises a peptide corresponding to SEQ ID NO: 9. In another preferred embodiment, In particular, a cancer vaccine targeting cancer stem cells is a peptide corresponding to SEQ ID NO: 7 and SEQ ID NO: 9. Includes both.

[0017] Also provided herein is a method for treating cancer stem cells using any of the above IL-13Rα2 peptides. In addition, the present invention provides a method for the prophylaxis of cancer in patients. A method of administering a peptide to a patient to elicit a CTL response. Further provided herein are methods for administering the therapeutic agent to a patient under conditions sufficient to The array [ka] or a composition comprising said peptide and a physiologically acceptable carrier. Also provided herein is the use of the product as a vaccine for glioma. A method of vaccinating a patient against glioma, comprising administering to said patient a nucleic acid sequence comprising the sequence [ka] or a composition comprising said peptide and a physiologically acceptable carrier. The method includes introducing the substance into a patient under conditions sufficient for the patient to elicit a CTL response. to provide.

[0018] In another aspect, provided herein is an IL-13Rα2 peptide and one, two, In certain embodiments, the cancer vaccine comprises three or more additional cancer associated peptides. In the cancer vaccine described herein, one or more helper T cell epitopes and and / or one or more immunomodulatory agents. Under such embodiments, one or more Helper T cell epitopes and / or one or more immunomodulatory agents may be included as part of the vaccine. (e.g., in a solution, IL-13Rα2 peptide and one, two, three or more with additional brain tumor associated peptides that may be used), or separately from the vaccine (i.e., with helper T As a formulation in which the cellular epitopes and / or immune response modifiers are not part of a vaccine formulation In some embodiments, the cancer vaccines described herein may be administered. The cutin is administered as an acellular vaccine. In another embodiment, the cancer vaccine comprises: In another embodiment, the cancer vaccine is administered with an adjuvant. In a preferred embodiment, the cancer vaccine is administered in combination with an additional peptide. In another embodiment, the peptide comprising the cancer vaccine is administered in combination with an emulsifier. In another embodiment, the peptides comprising the cancer vaccine are administered together. Montanide ISA (Montanide ISA) is a component of a method of administration that involves injection with an immunomodulatory agent. Montanide ISA-51 is administered as an emulsion in some cases. It is an emulsifier that is known to also function as an adjuvant. In some cases, the cancer vaccines described herein are administered as dendritic cell vaccines.

[0019] In one embodiment, the cancer vaccine comprises an IL-13Rα2 peptide, an EphA2 peptide, and at least one In one particular embodiment, the cancer vaccine comprises at least one survivin peptide. IL-13Rα2 peptide corresponding to any one of SEQ ID NOs: 1 to 4, EphA corresponding to SEQ ID NO: 5 2 peptide, and a survivin peptide corresponding to any of SEQ ID NOs: 6 to 9. In certain preferred embodiments, the cancer vaccine comprises an IL-13Rα2 peptide corresponding to SEQ ID NO:3. , the EphA2 peptide corresponding to SEQ ID NO:5, and the survivin peptides corresponding to SEQ ID NOs:7 and 9. In some embodiments, the cancer vaccine comprises one or more of In one particular embodiment, the cancer vaccine is administered in combination with a helper T cell epitope that can The immunization inhibitor is administered together with a helper T cell epitope, where the helper T cell epitope The peptide is derived from tetanus toxoid. Cancer vaccines are [ka] In some embodiments, the cancer vaccine comprises a tetanus toxoid peptide corresponding to In one particular embodiment, the antibody is administered in combination with one or more immune response modifiers. In particular, one type of immune response modifier is a TLR3 agonist. In certain embodiments, the immune response modifier is imiquimod. In certain other embodiments, one of the immune response modifiers is GM-CSF. In some embodiments, the cancer vaccine administration method includes both imiquimod and GM-CSF. In another embodiment, the cancer vaccine is a cell-free vaccine. It is a mouse shaped cell vaccine.

[0020] In another embodiment, the cancer vaccine comprises an IL-13Rα2 peptide, an EphA2 peptide, and at least one In another embodiment, the cancer vaccine comprises at least one survivin peptide. In one particular embodiment, the cancer vaccine comprises two survivin peptides. IL-13Rα2 peptide corresponding to any one of sequence numbers 1 to 4, EphA2 peptide corresponding to SEQ ID NO:5 and at least one survivin peptide corresponding to SEQ ID NOs:6-9. In certain preferred embodiments, the cancer vaccine comprises an IL-13Rα2 peptide corresponding to SEQ ID NO:3. , an EphA2 peptide corresponding to SEQ ID NO:5, and a survivin corresponding to SEQ ID NO:7 and SEQ ID NO:9. In some embodiments, the cancer vaccine comprises one or both of a peptide. In one particular embodiment, the antibody is administered with more than one helper T cell epitope. In one embodiment, the cancer vaccine is administered with a helper T cell epitope, where the helper T cell The epitope is tetanus toxoid corresponding to SEQ ID NO: 10. In some cases, the cancer vaccine is administered in conjunction with one or more immune response modifiers. In an embodiment, the peptides comprising the cancer vaccine are emulsified by mixing with an emulsifier. In one particular embodiment, the emulsifier is administered to the patient as a medicament. 51. In some embodiments, the cancer vaccine is an acellular vaccine. In one embodiment, the cancer vaccine is a dendritic cell vaccine.

[0021] In a preferred embodiment, the immunomodulatory agent is granulocyte macrophage-specific stimulating factor (GM-CSF), also known as GM-CSF. Phage colony-stimulating factor (Leukine®; sargramostin ; molgramostim; Leucomax®). GM-CSF acts through multiple mechanisms: Enhances immune responses to tumor antigens. GM-CSF enhances the cytotoxicity of CD8+ T cells [Target Tarr, Med Oncol, 1996]. GM-CSF also acts as an anti- It also induces the migration and maturation of cells presenting antigens, including dendritic cells (DCs), and GM-CSF is important for the activation of cytotoxic T cells. GM-CSF also promotes a robust immune response. In another preferred embodiment, GM-CS biases the tumor to a Th1 phenotype that is optimal for tumor response. In another preferred embodiment, GM-CSF is administered subcutaneously in a single injection of 125 ug. In another preferred embodiment, GM-CSF is administered subcutaneously in a single injection of 100 ug. In another preferred embodiment, GM-CSF is administered in close proximity to the peptide injection. In another preferred embodiment, the peptide is administered within 3 cm of the injection. and then within 15 minutes afterwards, a GM-CSF injection is administered. These injections are given every three weeks.

[0022] In a preferred embodiment, the peptide emulsion comprises three HLA-A2 restricted peptides (each 600 μg of EphA2 (SEQ ID NO: 5), IL-13Rα2 (SEQ ID NO: 3), and survivin peptide (SEQ ID NO: An aqueous solution (800 μl) containing either or both of SEQ ID NO: 7 and SEQ ID NO: 9) and 400 μg of helper T cells 800 μl containing the cellular peptide (SEQ ID NO: 10) was diluted 1:1 (volume) with the emulsifier Montanide ISA-51. The final emulsion had a total volume of 1.6 ml. The total volume administered to the patient will be 800 μl. In this preferred embodiment, each Three hundred micrograms of peptide derived from tumor antigen and two hundred micrograms of tetanus toxoid peptide were administered subcutaneously. It is given as a single injection.

[0023] In a preferred embodiment, the method of administration of the cancer stem cell targeted cancer vaccine is delivered by subcutaneous injection. The emulsion and the separate subcutaneous injection of GM-CSF (collectively referred to herein as "subcutaneous injection") In another preferred embodiment, the cancer stem cell-targeting cancer vaccine comprises The method of administration consists of an emulsion delivered by subcutaneous injection and a separate subcutaneous injection of GM-CSF. Furthermore, the imiquimod concentration across both the emulsion injection site and the GM-CSF injection site was significantly higher than that across the GM-CSF injection site. In one preferred embodiment, topical imiquimod is administered by subcutaneous injection (or In another preferred embodiment, topical imiquimod is administered on the same day as subcutaneous injection. The vaccine is administered on the same day as the subcutaneous injections and again 72 hours later as subcutaneous injections. In a preferred embodiment, an imine applied locally beyond the site of the subcutaneous injection(s) is administered. The amount of kimodo is.

[0024] 4. definition As used herein, the terms "about" or "approximately" mean When used with a number, it refers to any number within 1, 5, or 10% of the referenced number.

[0025] As used herein, the term "medicine" refers to any of the interleukin-1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, In or in combination with a brain tumor vaccine based on the α2 peptide of the IL-13 receptor The term drug refers to any molecule, compound, and / or substance that can be used in combination with other drugs. The term includes, but is not limited to, proteins, immunoglobulins (e.g., multispecific Ig, Single chain Ig, Ig fragments, polyclonal antibodies and their fragments, monoclonal antibodies and their fragments) , peptides (e.g., peptide receptors, selectins), binding proteins, biologics, chemical Chemospecific agents, chemotoxic agents, angiogenesis inhibitors, and contains small molecule drugs.

[0026] As used herein, the term "amino acid sequence identity" refers to a pair of aligned It refers to the degree of identity or similarity, usually expressed as a percentage, between amino acid sequences that have been As used herein, "percent identity," "percentage identical," and "percent identical" refer to amino acid sequences. The terms "% identity" and "% matching" are used to indicate the maximum percentage of sequence homology. After aligning the two sequences and inserting gaps if necessary, The amino acid residue at a given position in the sequence is the same as the corresponding amino acid residue As used herein, "percentage of amino acid residues in a candidate sequence that are identical" refers to the percentage of amino acid residues in a candidate sequence that are identical. "Percentage Similarity", "Percentage Similarity", "% Similarity" and " The term "% similar" refers to aligning both sequences to reach the maximum percentage of sequence identity. After the addition and, if necessary, insertion of gaps, the corresponding amino acid residues in the peptide are Similar to the amino acid sequence at a given position in the sequence (i.e., as discussed below, It refers to the percentage of amino acid residues in a candidate sequence for which substitutions are conservative. Sequence homology, including the percentage of identity, is calculated using computer algorithms designed for this purpose. using sequence alignment techniques well known in the art, including computer algorithms. Omitted (default) parameters or software packages that include such parameters The metric is determined using the

[0027] As used herein, the term "conservative substitution" refers to a class of amino acids. It refers to the replacement of one amino acid with another amino acid of the same class. Conservative substitutions do not alter the structure or function, or both, of the peptide. The types of amino acids are hydrophobic (Met, Ala, Val, Leu, Ile), neutral hydrophilic (Cys, Ser, Thr), Acidic (Asp, Glu), basic (Asn, Gln, His, Lys, Arg), conformation disorder upters (Gly, Pro), and aromatics (Trp, Tyr, Phe).

[0028] As used herein, "imiquimod" refers to an inhibitor of the toll-like receptor 7 (TLR7) that binds to the toll-like receptor 7. Imiquimod is also known by the trade name Imiquimod. Also known as Aldara®, Zyclara® and Beselna® do.

[0029] As used herein, "GM-CSF" refers to granulocyte-macrophage colony-stimulating factor (GM-CSF). In this specification, the terms "adjuvant" and "immunomodulator" are used interchangeably. Brand and generic names for GM-CSF include Leukine®, Sargra®, These include sargramostin, molgramostim and Leucomax®.

[0030] As used herein, the term "peptide" refers to a peptide as known to those of skill in the art. It refers to a polymer of amino acids linked by amide bonds. In a preferred embodiment, The peptide binds to HLA-A2 and is 9 amino acids in length. In another preferred embodiment, the peptide binds to HLA-A2 and is 10 amino acids in length. In the method, the peptide is bound to at least one MHC class II molecule and has a 16 amino acid sequence. As used herein, the term refers to a group of amino acids linked by a covalent amide bond. The term can refer to a single peptide chain bound together by non-covalent interactions, e.g. For example, they are bound by ionic contacts, hydrogen bonds, van der Waals contacts, and hydrophobic contacts. Those skilled in the art will understand that the term can also refer to multiple peptide chains, e.g., Peptide cleavage, disulfide bond formation, glycosylation (e.g., N-linked glycosylation) Post-translational processing, such as protease cleavage, and lipid modification (e.g., S-palmitoylation) It will be appreciated that the term "amino acid sequence" as used herein includes peptides modified by a cleavage moiety.

[0031] As used herein, the terms "purified" and "isolated" refer to naturally occurring When used in reference to a peptide obtained from a source, e.g., a cell, a peptide of natural origin. Contaminants, such as soil particles, inorganic matter, chemicals, and / or cellular matter of natural origin from the environment. Materials (such as, but not limited to, cell debris, cell wall material, membranes, organelles, etc. present in cells) It refers to a peptide that is substantially free of significant amounts of nucleic acids, carbohydrates, proteins, and / or lipids. Therefore, the isolated peptides were approximately 30%, 20%, 10%, 5%, 20%, 10% and 2% (by dry weight). %, or less than 1% cellular and / or contaminating material. As used herein, the terms "purified" and "isolated" refer to a chemical compound. When used in reference to a peptide to be synthesized, the synthesis of a chemical precursor or polypeptide It refers to a peptide that is substantially free of other chemicals that contribute to its synthesis.

[0032] As used herein, the term "nucleic acid" refers to a DNA molecule (e.g., a cDNA or nucleotide analogs) and RNA molecules (e.g., mRNA) and DNA or RNA molecules made with nucleotide analogs is intended to include analogs of RNA. Nucleic acids can be single-stranded or double-stranded. Cut.

[0033] As used herein, the phrase "prophylactic vaccine" refers to a vaccine used for the purpose of preventing cancer. "Vaccine" refers to a vaccine as described herein that is used in

[0034] As used herein, the term "prophylactically effective administration method" refers to a method for treating a brain tumor or The amount, timing, frequency and dosage of one or more treatments for the prevention of the condition It refers to an effective method of administration in terms of efficacy and duration.

[0035] As used herein, the term "therapeutic vaccine" refers to a vaccine for the treatment and / or administration of a brain tumor. refers to a vaccine as described herein used for administration purposes.

[0036] As used herein, the term "therapeutically effective method of administration" refers to a method for treating brain tumors or The amount, duration, and / or duration of administration of one or more treatments for the treatment and / or management of the condition. This refers to the method of administration in terms of timing, frequency and duration.

[0037] As used herein, the term "subject" or "patient" refers to an animal (e.g., a bird). In one particular embodiment, In some embodiments, the subject is a bird. In other embodiments, the subject is a non-primate (e.g., a camel, donkey, zebra, cow, pig, horse, goat, sheep, cat, dog, rat, and mouse) and mammals, including primates (e.g., monkeys, chimpanzees, and humans). In some embodiments, the subject is a non-human animal. In another embodiment, the subject is a human. In another embodiment, the subject is a human infant. In another embodiment, the subject is a human child. In another embodiment, the subject is a human adult. In this study, the subjects were elderly humans.

[0038] As used herein, the term "human infant" refers to a human being between the age of a newborn and one year old. vinegar.

[0039] As used herein, the term "human infant" refers to a human between the ages of 1 and 3.

[0040] As used herein, the term "human child" refers to a human between the ages of 1 and 18. .

[0041] As used herein, the term "adult human" refers to a human aged 18 years or older.

[0042] As used herein, the term "elderly humans" refers to humans aged 65 and older.

[0043] As used herein, the term "brain tumor" refers to a tumor located within the cranium or central spinal canal. Brain tumors are primary tumors (i.e., tumors arising in the intracranial sphere or central spinal canal). tumors) and secondary tumors (i.e., tumors that arise from tumors originally in other organs and then spread to the intracranial sphere This refers to both tumors that have invaded the spinal canal or the central spinal canal.

[0044] As used herein, the terms "therapies" and "treatment" refer to The term "treatment" refers to the prevention or prophylaxis of brain tumors or diseases or conditions associated therewith. or any protocol(s), method(s), composition(s) that may be used in the treatment. In some embodiments, the term may refer to a compound, a pharmaceutical agent, a pharmaceutical preparation, and / or a drug. The terms "therapies" and "therapy" are understood by those skilled in the art. Biotherapeutics useful in the treatment or prevention of known brain tumors or diseases or conditions associated therewith This refers to chemotherapy, supportive care, and / or other therapies.

[0045] As used herein, the term "effective amount" refers to a dose of a brain tumor and / or one or more or enhance the prophylactic effect of other therapies to prevent the onset, recurrence, or occurrence of further symptoms. To strengthen or improve the condition, to reduce the severity or duration of brain tumors, To improve one or more symptoms, to prevent progression of brain tumors, to induce regression of brain tumors sufficient to induce a therapeutic effect of another therapy and / or to enhance or improve the therapeutic effect of another therapy. This refers to the amount of treatment that is

[0046] As used herein, in the context of administering a treatment to a subject, "in combination with" The term "prophylactic" refers to the use of more than one treatment (e.g., prophylactic and / or therapeutic). Use of the term "in combination" refers to when treatments (e.g., a first and a second treatment) are administered to a subject. The treatments are not limited to the order in which they are performed. or prior to administration of a second treatment to a subject susceptible to brain tumors (e.g., 1 minute, 5 minutes, , 15 min, 30 min, 45 min, 1 hr, 2 hr, 4 hr, 6 hr, 12 hr, 24 hr, 48 hr, 72 hr, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks prior), Simultaneously with administration of the second treatment or after administration of the second treatment (e.g., 1 min, 5 min, 15 min, 30 min, minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 after one week, two weeks, three weeks, four weeks, five weeks, six weeks, eight weeks, or twelve weeks. The treatments may be administered in a sequence and within time intervals such that the treatments can act simultaneously. In certain embodiments, the treatments are administered to a subject in a manner similar to that which they would be administered otherwise. administered to subjects in a sequence and at time intervals that provide increased benefit than if Any additional steps may be performed in any order with other additional steps. can.

[0047] As used herein, in the context of administering a treatment to a subject, "manage" refers to The terms "management," "treatment," and "management" are used to refer to the treatment of brain tumors that are not curable. However, the subject may not experience any side effects from the treatment (e.g., a prophylactic or therapeutic vaccine) or combination of treatments. In certain embodiments, the aim is to prevent the progression or worsening of the disease. For example, a subject may be administered one or more treatments (e.g., one or more of the following) to "manage" a brain tumor. or more preventive or therapeutic vaccines) are implemented.

[0048] As used herein, in the context of administering a treatment to a subject, "prevention" refers to The terms "preventing" and "prevention" refer to a treatment (e.g., prophylaxis). or combination of treatments (e.g., combination of prophylactic or therapeutic agents). recurrence, onset, and / or development of a brain tumor or symptoms thereof in a subject resulting from the administration of the This refers to the prevention or inhibition of

[0049] As used herein, the term "simultaneously" means that the means close to the same time (i.e., simultaneously may be simultaneously or (Can be two or more events occurring within a period of time before or after each other). When administered in combination with other active agents, the cancer vaccines provided herein may be administered simultaneously with other active agents. In some embodiments, the cancer vaccines and one or more of the cancer vaccines provided herein may be administered in a manner similar to that described herein. Beyond that, other drugs (e.g., helper T cell epitopes, adjuvants, and / or immunosuppressants) may be used. and a response modifier) ​​are administered to the subject at the same time, wherein the IL-13Rα2 The administration of the peptide-based vaccine and one or more other drugs may be in the same composition. In another embodiment, the cancer vaccines and one or more of the cancer vaccines provided herein are or other drugs beyond that (e.g., helper T cell epitopes, adjuvants, and / or and an immune response modifier) ​​are simultaneously administered to the subject, wherein the cancer vaccines provided herein The administration of the cupuncturist and one or more other drugs is not carried out in the same composition. In some embodiments, the drug administered simultaneously with the cancer vaccine is administered as a separate injection. In certain embodiments, the cancer vaccines provided herein and one or more Other drugs beyond these (e.g., helper T cell epitopes, adjuvants, and / or immunosuppressants) and a response modifier) ​​are administered to the subject simultaneously, wherein the simultaneous administration is at least one hour apart. , 2 hours, 3 hours, 4 hours, 5 hours, 10 hours, 12 hours, 1 day, 2 days, 3 days, 4 days, 5 days , separated by six days, one week, or two weeks.

[0050] As used herein, the term "brain tumor associated peptide" refers to any one or more The term refers to a peptide found in association with brain tumors that are HLA-A2 regulated. In some embodiments, the cytotoxic T lymphocyte (CTL) epitope acts as a The brain tumor associated peptide is a glioma associated peptide, i.e., the peptide is associated with glioma. In a preferred embodiment, the brain tumor associated peptide is a peptide that is associated with glioma cells. Exemplary brain tumor associated peptides include, but are not limited to, IL-1 These include 3Rα2 peptides, EphA2 peptides, and survivin peptides.

[0051] As used herein, the term "IL-13Rα2 peptide" refers to an IL-13Rα2 protein. The present invention refers to a peptide derived from a protein, and the peptide is capable of targeting HLA-A2 restricted cytotoxic T lymphocytes. In a specific embodiment, the IL-13Rα2 protein serves as a CTL epitope. A protein from which the IL-13Rα2 peptide is derived. In another specific embodiment, the IL-13Rα2 peptide is a human IL-13Rα2 protein. The peptide comprises any one of SEQ ID NOs: 1 to 4. In some embodiments, the IL-13Rα2 peptide The IL-13Rα2 protein is expressed in a natural (e.g., wild-type) form. Rα2 peptide, one, two, three or more amino acid mutations (e.g., Additions, substitutions, or deletions).

[0052] As used herein, the term "EphA2 peptide" refers to an EphA2 peptide derived from the EphA2 protein. The term refers to a peptide that binds to HLA-A2-restricted cytotoxic T lymphocytes (CTLs). In a specific embodiment, the EphA2 protein serves as an epitope. The protein from which the EphA2 peptide is derived is human EphA2 protein. In another specific embodiment, the EphA2 peptide comprises SEQ ID NO:5. In some embodiments, the EphA2 peptide is an EphA2 peptide that is a peptide that is a natural (e.g., wild-type) polypeptide of the EphA2 protein. As compared to EphA2 peptides present in a 3- or 4-amino acid (amino acid) form, This includes amino acid mutations (eg, additions, substitutions, or deletions).

[0053] As used herein, the term "survivin peptide" refers to a peptide that is The term refers to a peptide derived from a protein, and the peptide is an HLA-A2 restricted cytotoxic T lymphocyte antigen (T-cell antigen) In a specific embodiment, the surviving leukemia virus (LEV) serves as a cytotoxic T-cell (CTL) epitope. A protein from which the survivin peptide is derived. In another specific embodiment, the protein is human survivin protein. The survivin peptide comprises SEQ ID NOs: 6-9. The peptide is expressed as a nucleotide sequence that is specific to the survivin protein, if it exists in its native (e.g., wild-type) form. The survivin peptide may contain one, two, three or more amino acid changes compared to the original peptide. In some embodiments, the survivin peptide comprises a mutation (e.g., an addition, substitution, or deletion). In another embodiment, the survivin peptide is 10 amino acids long. It is the acid length.

[0054] As used herein, the term "acellular vaccine" includes synthetic peptides. The present invention refers to a vaccine in which the peptide is administered to a cell (e.g., a cell line) within the vaccine. The peptide is not loaded onto a cell (e.g., the peptide is in solution). In an embodiment, the peptide is emulsified in an adjuvant. In a preferred embodiment, the emulsifier is known to act as an adjuvant in some cases. The Montanide ISA 51 is

[0055] As used herein, the term "dendritic cell vaccine" refers to a peptide (singular ) or peptide(s), where the peptide(s) or peptide The (s) are loaded onto dendritic cells in the vaccine. [Brief description of the drawings]

[0056] 5. BRIEF DESCRIPTION OF THE DRAWINGS [Figure 1]FIG. 1 shows that the majority of cells in the A-172 cancer cell line express high levels of EphA2 and IL-13Rα2, but only a small proportion of these cells express CD133.

[0057] [Diagram 2] FIG. 2 depicts co-staining of CD133 and EphA2 cells of the A-172 cancer cell line, and shows that CD133+ cells of the cell line also express EphA2.

[0058] [Diagram 3] FIG. 3 depicts co-staining of CD133 and IL-13Rα2 cells of the A-172 cancer cell line, and shows that CD133+ cells of the cell line also express IL-13Rα2.

[0059] [Figure 4] FIG. 4 shows that CD133+ cells of the A-172 cancer cell line also express EphA2.

[0060] [Diagram 5] FIG. 5 shows that CD133+ cells of the A-172 cancer cell line also express IL-13Rα2.

[0061] [Figure 6] FIG. 6 shows that the majority of cells in the A-172 cancer cell line express high levels of EphA2 and IL-13Rα2, but only a small proportion of these cells express CD133.

[0062] [Figure 7] FIG. 7 shows that only a small proportion of cells in the A-172 cancer cell line express CD133.

[0063] [Figure 8] FIG. 8 shows that CD133+ cells of the A-172 cancer cell line also express EphA2 and IL-13Rα2. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0064] 6. Detailed Description Cancer stem cells are an attractive target for cancer immunotherapy. Tumor regrowth, as demonstrated by its ability to form tumors in mice and usually results in tumor formation in subsequent serial transplants in immunodeficient mice. Cancer stem cells also typically have a low cellular abundance compared to the rest of the tumor. In certain embodiments, cancer stem cells grow slowly and steadily, i.e., they are generally dormant. In addition, the cancer stem cells may comprise approximately 0.1 to 10% of the cancer cells, but not all of the cancer cells. Cancer stem cells have the following characteristics or properties: (i) the ability to initiate tumors and / or perpetuate tumor growth. (ii) (e.g., slower growth and therefore less DNA Replication-dependent errors, improved DNA repair, and / or epigenetic changes that contribute to malignancy Generally, they are more mutated than the majority of tumors (due to mutated / non-mutated alterations) (iii) may be relatively unlikely to be present in cells that have many of the characteristics of normal stem cells (e.g., Similar cell surface antigens and / or intracellular expression profiles that characterize cells, self-renewal processes, phenotype, multidrug resistance, immature phenotype, etc.) and derived from normal stem cells. (iv) being able to potentially respond to their microenvironment (e.g., cancer stem cells (v) may be a source of metastasis; (vi) capable of being slow growing or dormant (vii) capable of symmetric division; (viii) capable of symmetric division (as determined, for example, in NOD / SCID transplantation experiments); (ix) can be tumorigenic in some cases; (ii) can be relatively resistant to traditional therapies; (i.e., chemotherapy resistance), and (x) (e.g., tumor bulk and (compared to) one or more or all of the following tumor subpopulations: may have.

[0065] Provided herein is a cancer vaccine that targets both tumor bulk and cancer stem cells. As used herein, a cancer vaccine is synonymous with a cancer stem cell-targeted vaccine. The cancer vaccine formulations provided herein can be administered to cancer patients in a variety of formulations. The compounds include cancer-associated peptides, helper peptides, emulsifiers, and immune response modifiers.

[0066] In one aspect, what is presented herein is one, two, three or more In certain embodiments, the present invention provides a cancer vaccine comprising more than one cancer-associated peptide. The cancer vaccines described in or co-administered with one or more immune response modifiers. Thus, one or more helper T cell epitopes and / or one or more More than one immune response modifier may be included as part of the vaccine (e.g., one, two, three or more). in a solution containing additional cancer-associated peptides in excess of the amount of the vaccine, or (i.e., the helper T cell epitopes and / or immune response modifiers may be administered (It may be administered as a formulation that is not part of a formulation that includes the peptide.) In certain embodiments, the cancer vaccines described herein are administered as acellular vaccines. In embodiments, the cancer vaccines described herein are administered as dendritic cell vaccines. is administered.

[0067] In one embodiment, the cancer vaccine comprises an IL-13Rα2 peptide, an EphA2 peptide, and at least one In a specific embodiment, the cancer vaccine comprises at least one survivin peptide. IL-13Rα2 peptide corresponding to any one of SEQ ID NOs: 1 to 4, EphA corresponding to SEQ ID NO: 5 2 peptide, and one or more survivin peptides corresponding to SEQ ID NOs: 6-9. In another specific embodiment, the cancer vaccine comprises an IL-13Rα2 corresponding to SEQ ID NO:3. peptide, EphA2 peptide corresponding to SEQ ID NO:5, and survivin corresponding to SEQ ID NO:7. In another specific embodiment, the cancer vaccine comprises a peptide corresponding to SEQ ID NO:3. L-13Rα2 peptide, EphA2 peptide corresponding to SEQ ID NO:6, and SUL corresponding to SEQ ID NO:9 In another specific embodiment, the cancer vaccine comprises a vivin peptide. Corresponding IL-13Rα2 peptide, corresponding to SEQ ID NO:6, EphA2 peptide corresponding to SEQ ID NO:7 The survivin peptide corresponds to SEQ ID NO: 9, and other survivin peptides. In some embodiments, the cancer vaccine comprises one or more helper T cell epitopes. In a specific embodiment, the cancer vaccine is administered simultaneously with a helper T cell epitope. and administering the helper T cell epitope simultaneously with the antibody, wherein the helper T cell epitope corresponds to SEQ ID NO: 10. In some embodiments, the cancer vaccine is one or more In a specific embodiment, the immune response modifier is administered simultaneously with more than one immune response modifier. In another specific embodiment, the immune response modifier is GM-CSF. In another specific embodiment, the cancer vaccine comprises GM-CSF and imiquimod. In some embodiments, the cancer vaccine is an acellular vaccine. In one embodiment, the cancer vaccine is a dendritic cell vaccine.

[0068] 6.1 Peptides 6.1.1 IL-13Rα2 peptides IL-13Rα2 is a Th2 cytokine that induces monocytes and macrophages to produce TGFβ. It is a membrane glycoprotein that binds certain IL-13s as components of a heterodimer (e.g., Fichtner-Feigl et al., Nature Medicine 12, pp. 99-106, 2006).

[0069] As disclosed herein, IL-13Rα2 is a cancer stem cell antigen (Example 1; FIG. 2 and 8). Thus, in certain embodiments, the cancer The vaccine contains an IL-13Rα2 peptide, an HLA-A2 restricted cytotoxic T lymphocyte (CTL) epitope. Any IL-13Rα2 peptide capable of serving as a peptide may be used as described herein. In some embodiments, the vaccines described herein can be used in The IL-13Rα2 peptide used in the vaccine is any one of SEQ ID NOs: 1 to 4. In a specific embodiment, the IL-13R used in the vaccines described herein The α2 peptide comprises SEQ ID NO:3.

[0070] In some embodiments, the IL-13Rα2 peptide used in the vaccines described herein The peptides include mutant forms of SEQ ID NO:1, wherein the mutant forms of SEQ ID NO:1 include at least At least two, or at least three amino acid substitutions (e.g., conservative substitutions), This includes additions or deletions.

[0071] In some embodiments, the IL-13Rα2 peptide used in the vaccines described herein The peptide has at least 50%, 60%, 70%, 80%, or 90% identity to SEQ ID NO:1. In other embodiments, the amino acid sequences used in the vaccines described herein include The IL-13Rα2 peptide to be used has a similar sequence to SEQ ID NO:1 by at least 50% to 60%, at least 50% to 70%, at least 60% to 80%, at least 80% to 90%, at least 90% to 100%, at least 100% to 120%, at least 120% to 140%, at least 140% to 150%, at least 150% Amino acid sequences with up to 70%, 70% to 80%, 70% to 90%, or 80% to 90% identity In some embodiments, the IL-13R used in the vaccines described herein The α2 peptide has at least 50%, 60%, 70%, 80%, or 90% similarity to SEQ ID NO:1. In another embodiment, the vaccines described herein include those having an amino acid sequence similar to that of the The IL-13Rα2 peptide used in the present invention has a sequence similar to that of SEQ ID NO:1 but is at least 50% to 60%, 50% to 70%, or 80% to 90%. % to 70%, 60% to 70%, 70% to 80%, 70% to 90%, or 80% to 90% similarity It includes an amino acid sequence having the following structure:

[0072] 6.1.2 EphA2 Peptides EphA2 is a tyrosine kinase inhibitor that mediates notochord formation through its interaction with epinephrine A1. It is a receptor for phospholipase A (e.g., Naruse-Nakajima et al., Mechanism of Development (Mech. Dev., vol. 102, pp. 95-105, 2001).

[0073] As disclosed herein, EphA2 is a cancer stem cell antigen (Example 1; Figures 2 and 8). Thus, in certain embodiments, the cancer vaccines provided herein The antibody contains the EphA2 peptide as an HLA-A2 restricted cytotoxic T lymphocyte (CTL) epitope. Any functional EphA2 peptide may be used in the vaccines described herein. In some embodiments, the vaccines described herein can be used in In another embodiment, the EphA2 peptide used herein comprises SEQ ID NO:5. The EphA2 peptides used in the described vaccines are described in U.S. Pat. No. 7,297,337. is.

[0074] In some embodiments, the EphA2 peptides used in the vaccines described herein The method includes the step of mutating SEQ ID NO:5, wherein the mutant form of SEQ ID NO:5 comprises at least one of the following: one, at least two, or at least three amino acid substitutions (e.g., conservative substitutions), additions, or includes deletions.

[0075] In some embodiments, the EphA2 peptides used in the vaccines described herein The amino acid sequence is an amino acid sequence having at least 50%, 60%, 70%, 80%, or 90% identity to SEQ ID NO:5. In other embodiments, the vaccines described herein include The EphA2 peptide may have at least 50% to 60%, 50% to 70%, 60% to 70%, It includes amino acid sequences having 70% to 80%, 70% to 90%, or 80% to 90% identity. In some embodiments, the EphA2 peptides used in the vaccines described herein has at least 50%, 60%, 70%, 80%, or 90% similarity to SEQ ID NO:6. In another embodiment, the vaccines described herein include those comprising an amino acid sequence The EphA2 peptide to be used may be at least 50% to 60%, 50% to 70%, 60% to 80%, or 90% to 100% of SEQ ID NO:5. % to 70%, 70% to 80%, 70% to 90%, or 80% to 90% similarity Contains arrays.

[0076] 6.1.3 Survivin Peptides Survivin is an apoptosis inhibitor protein that is overexpressed in most human cancers. It is a protein and inhibition of its action leads to increased apoptosis (e.g., Blanc-Brude et al., Nat. Med., 8, 987-9 (see p. 94, 2002).

[0077] In some embodiments, the cancer vaccines provided herein comprise a survivin peptide. It contains surubicin, which can act as an HLA-A2 restricted cytotoxic T lymphocyte (CTL) epitope. Any of the bin peptides may be used in the vaccines described herein. In some embodiments, the vaccines described herein can be used Survivin peptides include any of the peptides corresponding to SEQ ID NOs: 6 to 9. In one embodiment, the survivin peptide used in the vaccine described herein The code comprises SEQ ID NO: 7. In other embodiments, the code used in the vaccines described herein is The survivin peptide used comprises SEQ ID NO: 9. The survivin peptide used in the vaccine described herein is represented by SEQ ID NO:7 and SEQ ID NO:8. In another embodiment, the peptides corresponding to the peptide number 9 and 10 are included in the vaccines described herein. The survivin peptides used in the present invention are described in U.S. Patent Application Publication No. 2009 / 0041732 or in US Pat. Ciesielski et al., Cancer Immunology and Immunotherapy. In the study, survivin peptidase 1 (SPR) was reported in the Journal of Clinical Immunology, Vol. 59, pp. 1211-1221, 2010. It's Chid.

[0078] In some embodiments, surbiviv is used in the vaccines described herein. The peptide includes a mutant form of SEQ ID NO:6 or SEQ ID NO:8, wherein SEQ ID NO:6 or The mutant form of SEQ ID NO:8 has at least one, at least two, or at least three amino acids. These include amino acid substitutions (eg, conservative substitutions), additions, or deletions.

[0079] In some embodiments, the survivin used in the vaccines described herein The peptide has at least 50%, 60%, 70%, 80%, or 90% identity with SEQ ID NO:6 or SEQ ID NO:8. In another embodiment, the amino acid sequence of any one of the vaccines described herein has the same identity as the vaccine The survivin peptide used in the present invention is a peptide having at least one sequence selected from the group consisting of SEQ ID NO:6 or SEQ ID NO:8 and 50% to 60%, 50% to 70%, 60% to 70%, 70% to 80%, 70% to 90%, or 80% or less In some embodiments, the amino acid sequence of the present invention is a sequence having up to 90% identity to the amino acid sequence of any one of the sequences described herein. The survivin peptide used in the vaccine is SEQ ID NO:6 or SEQ ID NO:8 and at least The amino acid sequence may have at least 50%, 60%, 70%, 80%, or 90% similarity. In an embodiment, the survivin peptides used in the vaccines described herein is SEQ ID NO: 6 or SEQ ID NO: 8 and at least 50% to 60%, 50% to 70%, 60% to 70% , 70% to 80%, 70% to 90%, or 80% to 90% similarity to the amino acid sequence .

[0080] In some embodiments, the survivin used in the vaccines described herein The peptide has at least 50%, 60%, 70%, 80%, or 90% identity with SEQ ID NO:6 or SEQ ID NO:8. In another embodiment, the amino acid sequence of any one of the vaccines described herein has the same identity as the vaccine The survivin peptide used in the present invention is a peptide having at least one sequence selected from the group consisting of SEQ ID NO:6 or SEQ ID NO:8 and 50% to 60%, 50% to 70%, 60% to 70%, 70% to 80%, 70% to 90%, or 80% or less In some embodiments, the amino acid sequence of the present invention is a sequence having up to 90% identity to the amino acid sequence of any one of the sequences described herein. The survivin peptide used in the vaccine is SEQ ID NO:6 or SEQ ID NO:8 and at least The amino acid sequence may have at least 50%, 60%, 70%, 80%, or 90% similarity. In an embodiment, the survivin peptides used in the vaccines described herein is SEQ ID NO: 6 or SEQ ID NO: 8 and at least 50% to 60%, 50% to 70%, 60% to 70% , 70% to 80%, 70% to 90%, or 80% to 90% similarity to the amino acid sequence .

[0081] 6.2 Immunomodulators and emulsifiers In some embodiments, the cancer vaccines provided herein are administered concomitantly with an immunomodulatory agent. Immunomodulatory agents are drugs that can modify the immune response of a subject. In embodiments, the immune response modifier biases the subject's immune response toward a Th1 response. In an embodiment, the immune response modifier biases the subject's immune response toward a Th2 response. As shown, immune responses that can be administered simultaneously with the cancer stem cell-targeted cancer vaccines provided herein Modulators include, but are not limited to, imiquimod (Aldara®, Zyclara®, Beselna® and GM-CSF (Leukine®, Sargramostin (sargramostin), molgramostim, and Leucomax®). In some embodiments, imiquimod and GM-CSF are administered as components of the same cancer stem cell cancer vaccine formulation. is administered.

[0082] In a preferred embodiment, the immunomodulatory agent is GM-CSF (Leukine®; Sargraham®). Also known as sargramostin; molgramostim; Leucomax® In a preferred embodiment, GM -CSF is administered subcutaneously in an amount of 125ug per injection. In another preferred embodiment In another preferred embodiment, GM-CSF is administered subcutaneously in an amount of 100 ug per injection. In another preferred embodiment, GM-CSF is administered in close proximity to the peptide injection. In another preferred embodiment, GM-CSF is administered within 3 cm of the peptide injection. The M-CSF injection is administered within 15 minutes after the peptide injection is administered. In this study, the injections are administered once every three weeks.

[0083] In a preferred embodiment, the immunomodulatory agent is imiquimod (Aldara®, Zyclara (registered trademark), and Beselna (registered trademark). In a preferred embodiment, Modo is administered locally (on the skin) in the same location as a subcutaneous injection. In one embodiment, imiquimod is administered in an amount of 250 mg in a 5% cream. In one embodiment, imiquimod is administered locally at the site where the peptide emulsion and GM-CSF are injected. In another preferred embodiment, imiquimod is administered topically on the same day as the subcutaneous injection. In another preferred embodiment, imiquimod is administered within 15 minutes prior to subcutaneous injection. In another preferred embodiment, imiquimod is administered topically on the same day and at the same time as the subcutaneous injection. and 24 hours later, topically administered. In another preferred embodiment, imiquimod is administered It is administered topically on the same day as the subcutaneous injection and every 24 hours thereafter for 5 days. In , imiquimod is administered topically every 3 weeks.

[0084] In some embodiments, the cancer vaccines provided herein are administered in combination with an adjuvant. In some embodiments, the term "adjuvant" is used as defined herein. The composition may be administered simultaneously or in the same combination as the IL-13Rα2 peptide-based vaccine. When administered in a composition, the composition enhances, promotes, and prolongs the immune response to a cancer vaccine. In some embodiments, an adjuvant is an agent that enhances, potentiates, and / or enhances a cancer It produces an immune response to the vaccine and does not cause allergies or other side effects. Bunting may be, for example, involved in the recruitment of lymphocytes, the stimulation of B and / or T cells, the stimulation of dendritic cells, and They can enhance immune responses by several mechanisms, including stimulation of macrophages. Cut.

[0085] Specific examples of adjuvants include, but are not limited to, Montanide. (Montanide) ISA-51, Montanide ISA 50V, Montanide, ISA 206, Montanide IMS 1312, VaxImmune® (CpG7909; Kohli F Pharmaceuticals (Coley Pharmaceuticals), aluminum salts (alum) (water Aluminum oxide, aluminum phosphate, and aluminum sulfate, etc.), 3 De-O-acylated molybdenum Nonophosphoryl lipid A (MPL) (see UK Patent No. 2220211), MF59 (Novartis (Novartis), AS03 (GlaxoSmithKline), AS04 (Glaxo GlaxoSmithKline), Polysorbate 80 (Tween 80; ICL Americas Inc.), imidazopyridine compounds ( See International Application PCT / US2007 / 064857, published as International Publication WO2007 / 109812; Imidazoquinoxaline compounds (International Application PCT / US2007 / 109813, published as International Publication No. WO2007 / 109813) 007 / 064858), as well as saponins such as QS21 (Kensil et al., In Vaccine Design: Subunit and Adjuvant Approaches : The Subunit and Adjuvant Approach (Powell & Newman) an, Plenum Publishing, New York, 1995); see U.S. Patent No. 5,057,540. In some embodiments, the adjuvant is Freund's adjuvant. Other adjuvants are oil-in-water emulsions (e.g., sucrose adjuvants). qualene or peanut oil), which may optionally contain an immune stimulant such as monophosphoryl lipid A. (Stoute et al., The New England Journal of Journal of Medicine (N. Engl. J. Med.), Vol. 336, pp. 86-91 (1997) ). Another adjuvant is CpG (BioWorld Today Today, November 15, 1998. Such adjuvants include MPL or 3-DMP, QS21, poly Other specific amino acids such as polymeric or monomeric amino acids such as glutamic acid or polylysine. It may be used with or without immunostimulants or other immune enhancing drugs. Different formulations of cutin may contain different adjuvants or may contain the same adjuvant. It should be understood that

[0086] 6.3 Helper T cell epitopes In some embodiments, the cancer vaccines provided herein comprise a helper T cell epitope. Helper T cell epitopes are those that are activated by the immune system to produce helper T cells. Helper T cells include agents capable of inducing a CD4+ T cell response. In some embodiments, the helper T cell epitope is presented by a class II MHC molecule. and can be recognized by the T cell receptor (TCR) of helper T cells (CD4+ T cells), thereby It activates CD4+ T cells and increases their proliferation, secretion of cytokines such as IL2, and profile. This results in the activation of the cellular antigen-presenting cells (APCs). T cells also stimulate killer T cells (also known as CD8+ T cells), thereby Prolongs and enhances T cell responses. Examples of T-helper cell epitopes include, but are not limited to, tetanus toxoid. .

[0087] 6.3.1 Tetanus toxoid A large proportion of the population is already sensitized to the tetanus toxoid (TT) protein. A well-characterized Th epitope (SEQ ID NO: 10) derived from the protein is involved in the activation of helper T cells. It is known to act as a cytoplasmic epitope.

[0088] 6.4 Peptide production and purification The peptides described herein can be synthesized using any method known in the art for peptide synthesis. It can be produced by any method, particularly by chemical synthesis. Organic chemistry, biochemistry and related fields.

[0089] 6.4.1.1 Synthetic production of peptides The peptides described herein can be prepared by conventional stepwise solution or solid phase synthesis (e.g., Chemical Approaches to the Synthesis of Peptides and Proteins Peptides and Proteins, edited by Williams et al., 1997, CR C) Publishing, Boca Raton, FL, and the references cited therein; Solid Phase Solid Phase Peptide Synthesis: A Practical Approach Atherton & Sheppard, eds., 1989, I.R. IRL, Oxford, England, and the references cited therein. (see references).

[0090] Alternatively, the peptides described herein may be synthesized using the methods described, for example, in Liu et al., 1999. 6, Tetrahedron Lett., Vol. 37, No. 7, pp. 933-936, Bacchus (Baca) et al., 1995, Journal of the American Chemical Society (J. Am. Chem. Soc., vol. 117, pp. 1881-1887; Tam et al., 1995, International Journal of Peptide Protein Research (Int. J. Peptide Protein Res.) 45, pp. 209-216; Schnolzer and Kent, 1992, Sci. Science, 256, 221-225; Liu and Tam, 1994, J. Journal of the American Chemical Society (J. Am. Chem. Soc.), Vol. 116, 10, pp. 4149-4153; Liu and Tam, 1994, Proceedings of the 1994 American Journal of Clinical Chemistry. National Academy of Sciences of the USA (Proc. Natl Acad. Sci. USA, 91, 6584-6588; Yamashiro and Li, 1988, Inter. National Journal of Peptide and Protein Research (Int. J. Peptide Pr By means of segment condensation, as described in Oligomer Res., vol. 31, pp. 322-334. Another method useful for the synthesis of the peptides described herein is by Gawa et al., 1985, Journal of the American Chemical Society (J. Am. Che m. Soc., Vol. 107, pp. 7087-7092.

[0091] If desired, disulfide bond formation is usually carried out in the presence of a mild oxidizing agent. Chemical oxidizing agents may be used, or compounds may be added to effect these bonds. can simply be exposed to atmospheric oxygen. 979, Synthesis, pp. 955-957; Stewart et al., 1984, Solid-Phase Peptide Synthesis. Solid Phase Peptide Synthesis, 2nd Edition, Pierce Chemical Company (Pierce Chemical Company, Rockford, Illinois; Ahmed et al., 19 1975, The Journal of Biological Chemistry (J. Biol. Chem.), Vol. 25 0, pp. 8477-8482; and Pennington et al., 1991 Peptides 1990, pp. 164-166. Edited by Giralt and Andreu, ESCOM, Leiden, Ontario. Various methods are known, including those described by Randa. In 1980, Kamber et al. 63, pp. 899-915. Methods carried out on solid supports are Albericio, 1985, International Journal of Peptides Int. J. Peptide Protein Res., vol. 26, pp. 92-97 No. 6,393,962, each of which is incorporated herein by reference in its entirety. do.

[0092] 6.4.1.2 Peptide purification The peptides described herein and produced using the means described are Any method known in the art for the purification of peptides, e.g., chromatographic affinity (e.g., ion exchange, affinity for specific antigens, especially after Protein A) (and sizing column chromatography), centrifugation, absorption rate differential dissolution Purification may be performed by either purification at high temperature or by other standard techniques for the purification of proteins. Additionally, the peptides may be prepared using the methods described herein or in combination to facilitate purification. The polypeptides may be fused to heterologous peptide sequences known in the art. The actual conditions used for synthesis will depend, in part, on the synthesis strategy (e.g., synthetic preparation vs. synthesis). recombinantly produced) and factors such as the net charge, hydrophobicity, and / or hydrophilicity of the peptide. The conditions will depend on the catalyst and will be apparent to one skilled in the art.

[0093] 6.5 Pharmaceutical Compositions and Routes of Administration Provided herein are pharmaceutical compositions. In some embodiments, The compositions provided are interleukin-13 receptor α2 peptide-based brain tumor vaccines. In other embodiments, the compositions provided herein include cancer vaccines and hepatitis C vaccines. The antibody may further comprise a T cell epitope, an adjuvant, and / or an immune response modifier. In some embodiments, the compositions provided herein include immune response modifiers. The pharmaceutical compositions provided are suitable for administration to animals and / or humans.

[0094] The pharmaceutical compositions provided herein (e.g., compositions comprising cancer vaccines, cancer vaccines and Compositions comprising T-helper cell epitopes, adjuvants, and / or immune response modifiers; or a composition comprising an immune response modifier) ​​that allows the composition to be administered to a subject. The object can be in any form, preferably, but not limited to, may be administered to humans, mammals, or non-human animals, such as cattle, horses, sheep, pigs, poultry, cats, etc. Animals include, for example, dogs, mice, rats, rabbits, guinea pigs, etc., and more preferably mammals. The subject is an animal, most preferably a human.

[0095] In a specific embodiment, the pharmaceutical compositions provided herein (e.g., cancer vaccines) are Compositions Comprising Cancer Vaccines and Helper T Cell Epitopes, Adjuvants, and / or Immunoglobulins The composition comprising the response modifier or the composition comprising the immune response modifier may be administered in a liquid (e.g., The compositions provided herein are in the form of an elixir, syrup, solution, emulsion, or suspension. Exemplary routes of administration of the liquid composition include, but are not limited to, parenteral, intradermal, intratumoral, intracerebral, Parenteral administration includes, but is not limited to, subcutaneous, intranodal, intravenous, intramuscular, intravenous, intravenous, intrathecal, intravenous, intravenous, intramuscular, intravenous, intrathecal, intravenous, intramuscular ...muscular, intrathecal, intramuscular, intramuscular, intramuscular, intramuscular, In particular embodiments, the composition is administered by a non- The composition for administration by injection may contain no surfactants, preservatives, wetting agents, dispersants, etc. Contains one or more of the following: dispersing agent, suspending agent, buffer, stabilizer, and isotonic agent In a specific embodiment, a pump can be used to deliver the vaccine. (e.g. Sefton, CRC Critical Reviews, CRC Crit. Ref. Biomed. Eng., 1987. 14, 201; Buchwald et al., Surgery, 1980, 88, 50 7; Saudek et al., New England Journal of Medicine (N. Engl. J. Med., 1989, 321, 574). Thus, the pump may be, but is not limited to, an insulin-like pump.

[0096] The pharmaceutical compositions provided herein (e.g., compositions comprising cancer vaccines, cancer vaccines and Compositions comprising T-helper cell epitopes, adjuvants, and / or immune response modifiers; The materials used in the preparation of the composition (or composition containing an immune response modifier) ​​are The optimal dosage of the active ingredient(s) in the pharmaceutical composition may vary. It will be apparent to one of skill in the art that the factors involved will depend on the the type of subject (e.g., human), the subject's overall health, the subject in need of such treatment, Identification of the type of brain tumor, use of the composition as part of a multi-drug regimen, and the peptide being administered The present invention includes the dosage form, method of administration, and composition employed.

[0097] The liquid compositions of the present invention may be in the form of a solution, a suspension, or other similar form. It may also include one or more of the following: Sterile diluents, such as water for injection, saline solution, preferably physiological saline, Ringer's solution, isotonic Sodium chloride, fixed oils, e.g., which can act as a solvent or suspending medium Synthetic mono- or diglycerides, polyethylene glycol, glycerin, cyclohexylglycerol, dextrin, propylene glycol, or other solvents; antimicrobial agents, e.g., benzyl alcohol; or methylparaben; antioxidants, such as ascorbic acid or sodium bisulfite chelating agents, e.g., ethylenediaminetetraacetic acid; buffering agents, e.g., acetate, citric acid Salts, or phosphates; and agents for adjusting tonicity, such as sodium chloride or dextrose. Parenteral compositions may be packaged in ampoules, disposable syringes, or containers made of glass, plastic, or The injectable compositions may be preferably sterile, or may be packaged in multiple dose vials made of other materials. It has been done.

[0098] The compositions provided herein (e.g., compositions comprising cancer vaccines, cancer vaccines and helper vaccines) are a composition comprising a per-T cell epitope, an adjuvant, and / or an immune response modifier; or (compositions containing immune response modifiers) include pharma- ceutical acceptable carriers or vehicles. As used herein, the term "pharmaceutical acceptable" means , animals, and more specifically, humans, approved by federal or state regulatory agencies for use. approved by the United States Pharmacopoeia or listed in the United States Pharmacopoeia or other generally recognized pharmacopoeias The term "carrier" means a diluent, adjuvant, excipient, or vehicle. Refers to the vehicle with which the pharmaceutical composition is administered. Saline solution as well as aqueous Dextrose and glycerol solutions are employed as liquid carriers, particularly for injectable solutions. Suitable excipients include starch, glucose, lactose, sucrose, gelatin, malt, Rice, wheat flour, chalk, silica gel, sodium stearate, glycerol monostearate acrylate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol Examples of suitable pharmaceutical carriers include ethanol, ethanol, and the like. "Remington's Pharmaceutical Sciences" by E.W. Martin The formulation should suit the mode of administration.

[0099] In one embodiment, the compositions provided herein (e.g., compositions comprising a cancer vaccine) are , cancer vaccines and helper T cell epitopes, adjuvants, and / or immune response modifiers - Patents.com The composition comprising the substance or the composition comprising the immune response modifier may be used to treat animals, particularly humans, with Pharmaceutical compositions suitable for oral administration are formulated in accordance with routine procedures. The ingredients in the composition may be administered separately or mixed together in unit dosage form, e.g., The drug is dried and freeze-dried in a sealed container such as an ampoule or sachet indicating the amount of active drug. The compositions described herein are provided as a dry powder or as a water-free concentrate. is administered by injection, the ingredients may be mixed prior to administration if necessary. An ampule of sterile water for injection or saline may be provided.

[0100] The compositions provided herein, including, for example, cancer vaccines, Compositions, cancer vaccines and helper T cell epitopes, adjuvants, and / or immune responses Compositions comprising a modulator or compositions comprising an immune response modulator include, but are not limited to, Further preventive and therapeutic agents, antiemetics, hematopoietic colony stimulating factors, adjuvant therapy, anti- and selected from the group consisting of antibody / antibody fragment-based drugs, antidepressants, and analgesics. The active agent may comprise:

[0101] The pharmaceutical compositions provided herein (e.g., compositions comprising cancer vaccines, cancer vaccines and Compositions comprising T-helper cell epitopes, adjuvants, and / or immune response modifiers; or compositions containing immune response modifiers) are prepared using methods well known in the pharmaceutical art. For example, compositions intended to be administered by injection may be formulated to form a solution. In addition, the peptides of the vaccines described herein can be combined with water and / or other liquid components. To facilitate the formation of a homogeneous solution or suspension, a surfactant may be added. may be added.

[0102] The pharmaceutical compositions described herein may be included in a container, pack, or device together with instructions for administration. The device may be enclosed in a dispenser.

[0103] 6.6 Preventive and therapeutic uses In one aspect, provided herein is a cancer vaccine as described herein. and administering to a subject in need thereof an effective amount of and / or a method of managing it.

[0104] In another aspect, provided herein is a method for treating a patient (e.g., a human patient) comprising administering to said patient a therapeutically effective amount of A method for preventing, treating, and / or managing brain tumors, the method comprising administering a prophylactically effective administering to the patient a dosing regimen effective for the treatment or therapy, the dosing regimen comprising administering to the patient: Administering the cancer vaccine described herein or the pharmaceutical composition described herein wherein the patient has been diagnosed with a brain tumor.

[0105] In another aspect, provided herein is a method for treating a patient (e.g., a human patient) comprising administering to said patient a therapeutically effective amount of A method for preventing, treating, and / or managing brain tumors, the method comprising administering a prophylactically effective administering to the patient a dosing regimen effective for the treatment or therapy, the dosing regimen comprising administering to the patient: Administering the cancer vaccine described herein or the pharmaceutical composition described herein wherein the patient has a recurrence of the brain tumor.

[0106] In another aspect, provided herein is a method for treating a patient (e.g., a human patient) comprising administering to said patient a therapeutically effective amount of A method for preventing, treating, and / or managing brain tumors, the method comprising administering a prophylactically effective administering to the patient a dosing regimen effective for the treatment or therapy, the dosing regimen comprising administering to the patient: Administering the cancer vaccine described herein or the pharmaceutical composition described herein wherein the patient is receiving a brain tumor that does not include a vaccine as described herein. Tumor treatment has failed or is failing.

[0107] In another aspect, provided herein is a method for treating a patient (e.g., a human patient) comprising administering to said patient a therapeutically effective amount of A method for preventing, treating, and / or managing brain tumors, the method comprising administering a prophylactically effective administering to the patient a dosing regimen effective for the treatment or therapy, the dosing regimen comprising administering to the patient: Administering the cancer vaccine described herein or the pharmaceutical composition described herein wherein the patient is in remission from the brain tumor.

[0108] In another aspect, provided herein is a method for treating a patient (e.g., a human patient) comprising administering to said patient a therapeutically effective amount of A method for preventing, treating, and / or managing brain tumors, the method comprising administering a prophylactically effective administering to the patient a dosing regimen effective for the treatment or therapy, the dosing regimen comprising administering to the patient: Administering the cancer vaccine described herein or the pharmaceutical composition described herein wherein the patient is receiving a brain tumor that does not include a vaccine as described herein. In one embodiment of this aspect, the patient is refractory to tumor treatment as described herein. have undergone or are undergoing brain tumor treatment not including the vaccine being considered. In one embodiment, the patient has previously received a medicament for the prevention, treatment, and / or management of a brain tumor. , have not undergone any brain tumor treatment that does not involve the vaccines described herein.

[0109] In another aspect, provided herein is a method for treating a patient (e.g., a human patient) comprising administering to said patient a therapeutically effective amount of A method for preventing, treating, and / or managing brain tumors, the method comprising administering a prophylactically effective administering to the patient a dosing regimen effective for the treatment or therapy, the dosing regimen comprising administering to the patient: Administering the cancer vaccine described herein or the pharmaceutical composition described herein In some embodiments, the patient is undergoing other brain tumor treatments. Conventional brain tumor treatments include, for example, chemotherapy, radiation therapy, surgical therapy, small molecule therapy, and the like. , biotherapy, antibody therapy, hormone therapy, immunotherapy, anti-angiogenic therapy, or any combination thereof. In some embodiments, previous treatments have failed in the patient. In some embodiments, the method is effective in treating the cancer comprising administering the cancer vaccine described herein. The dosing regimen is administered to a patient immediately after the patient has received a previous treatment. In some embodiments, the patient is not informed of the outcome of previous treatments before the cancer vaccine is administered. In one embodiment, the prior chemotherapy may be temolodimide. In one embodiment, the previous treatment is radiation therapy. For this, the traditional treatment is a combination of temozolomide and radiation therapy. In a preferred embodiment, temozolomide in combination with radiation therapy. The method is carried out using the method of Stupp. In some embodiments, the combination treatment is surgery. In some embodiments, the patient is treated with temozolomide prior to treatment. Undergoing Surgery In some embodiments, the patient undergoes surgery prior to the start of radiation therapy. In each of these embodiments describing the use of combination therapy, the cancer vaccine is It may be administered before, during or after treatment of the patient with the associated therapy.

[0110] In some embodiments, the cancer vaccines described herein are useful for preventing, treating, or preventing brain tumors. In other embodiments, the compounds described herein are administered as monotherapy for the treatment and / or management of a variety of conditions. Provided herein is a method for administering to a subject in need thereof a cancer vaccine as described herein, and Other than the cancer vaccines described in the specification, any cancer vaccines for brain tumors or one or more brain tumors. Currently in use, has been used, or is believed to be useful in the prevention, treatment, and / or management of the condition and one or more drugs known to be or that may be useful. The drugs of the combination therapy may be administered sequentially or simultaneously. In the present invention, the combination therapy is described as having an additive or synergistic effect. In combination with a cancer vaccine, the prophylactic or therapeutic effects of the cancer vaccine described herein may be enhanced. In some embodiments, the combination therapy comprises a combination of This may be performed before, during or after administration of the composition.

[0111] In another aspect, provided herein is an effective amount of a cancer therapeutic agent described herein. Inducing an immune response in a subject suffering from brain tumor, comprising administering a vaccine In some embodiments, the cancer vaccines described herein or The immune response induced in a subject by the composition described herein is capable of inhibiting the development of brain tumors in the subject. In some embodiments, the methods described herein are effective in preventing, treating, and / or managing or a composition as described herein. The induced immune response is effective to reduce symptoms of the brain tumor in the subject.

[0112] The doctor will perform a neurological examination, imaging tests (e.g., computed tomography (CT), magnetic resonance imaging (MRI) Magnetic resonance imaging (MRI), ultrasound, X-ray imaging, and positron emission tomography (PET) readings ); and conventional brain tumor screening, including, but not limited to, biopsy (e.g., stereotactic biopsy). Any of the screening methods can be used to diagnose a patient.

[0113] 6.6.1 Dosage and frequency of administration The compounds described herein are believed to be effective in the treatment, prevention, and / or management of brain tumors. The composition (e.g., a composition comprising a cancer vaccine, a cancer vaccine and a helper T cell epitope) Compositions containing the peptides, adjuvants, and / or immune response modifiers or immune response modifiers The amount of the composition (or compositions) to be administered may vary depending on the condition of the brain tumor, the location of the tumor, and the type of tumor to which the composition or compositions are to be administered. Such use may depend on the patient, the route of administration, and / or the type of brain tumor. The amount can be determined by standard clinical techniques and according to the judgment of the practitioner.

[0114] For example, an effective dose may vary depending on the means of administration, the target site, and the physiological condition of the patient (age, weight, and health). whether the patient is a human or animal; other medicines or and whether the treatment is prophylactic or therapeutic. Usually, the patient is a human, but the patient may be a non-human mammal, including a transgenic mammal. Treatment dosages are optimally titrated to optimize safety and efficacy. do.

[0115] In some embodiments, in vitro assays are used to help identify optimal dose ranges. The effective dose is determined based on the results of in vitro or animal model test systems. It can be extrapolated from the response curve.

[0116] In certain embodiments, the cancer vaccine is an acellular vaccine, wherein the acellular vaccine The present invention relates to a method for the treatment of brain tumors comprising administering to a subject an IL-13Rα2 peptide and one, two, three or more additional brain tumor-associated In some embodiments, for example, the acellular cancer vaccine comprises a peptide per dose. or approximately 25, 50, 75, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 550, 600, 650, 700, 750, or 800 μg of each brain tumor-associated peptide In another embodiment, for example, the acellular cancer vaccine contains about 2 5 to 50, 25 to 75, 25 to 100, 50 to 100, 50 to 150, 50 to 200, 100 to 150, 100 to to 200, 100 to 250, 100 to 300, 150 to 200, 150 to 250, 150 to 300, 200 to 250, 2 50 to 300, 250 to 350, 250 to 400, 300 to 350, 300 to 400, 300 to 450, 300 to 50 0, 350 to 400, 350 to 450, 400 to 500, 400 to 600, 500 to 600, 500 to 700, 600 to In other embodiments, the composition comprises up to 700, 600 to 800, or 700 to 800 μg of each brain tumor associated peptide. For example, the acellular cancer vaccine is administered at a dose of about 5 μg to 100 mg, or less than 15 μg per kg of patient. ~50mg, 15μg~25mg, 15μg~10mg, 15μg~5mg, 15μg~1mg, 15μg~100μg , 15μg to 75μg, 5μg to 50μg, 10μg to 50μg, 15μg to 45μg, 20μg to 40μg , or 25-35 μg of each brain tumor associated peptide.

[0117] In one embodiment, the acellular cancer vaccine is administered simultaneously with the helper T cell epitope. In some embodiments, by way of example, the acellular cancer vaccine is administered at a concentration of about 25, 50, 75, 10 0, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 50 In another embodiment, the antibody is administered simultaneously with 0, 550, or 600 μg of a helper T cell epitope. For example, the acellular cancer vaccine may be about 25 to 50, 25 to 75, 25 to 100, 50 to 100 , 50 to 150, 50 to 200, 100 to 150, 100 to 200, 100 to 250, 100 to 300, 150 to 2 00, 150 to 250, 150 to 300, 200 to 250, 250 to 300, 250 to 350, 250 to 400, 300 350 to 350, 300 to 400, 300 to 450, 300 to 500, 350 to 400, 350 to 450, 400 to 500 , 400-600, or 500-600 μg of a helper T cell epitope.

[0118] In certain embodiments, the acellular cancer vaccine is administered simultaneously with an immune response modifier. In some embodiments, by way of example, the acellular cancer vaccine comprises about 100, 200, 300, 400, 50 0, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, or 1800 In another embodiment, the immune response modifier is administered simultaneously with 0.1 μg of the immune response modifier, e.g., The cystic cancer vaccine is about 100 to 300, 200 to 400, 400 to 800, 600 to 800, 800 to 1000, 8 00 to 1200, 1000 to 1200, 1000 to 1400, 1200 to 1400, 1200 to 1600, 1400 to 1600 , 1400 to 1800, or 1600 to 1800 μg of an immune response modifier. In an embodiment, for example, the acellular cancer vaccine is administered at a dose of about 1, 5, 10, 15, 2, 3, 4, 5, 6, 7, 8, 9 ... 0, 25, 30, 35, 40, 45, 50, 55, or 60 μg of an immune response modifier are administered simultaneously. In one embodiment, by way of example, the acellular cancer vaccine is administered at a dose of about 1 to 5, 1 or 2 mg / kg of patient. to 10, 5 to 10, 5 to 15, 10 to 15, 10 to 20, 15 to 20, 15 to 25, 15 to 30, 20 to 25, 20 to 30, 20 to 35, 25 to 30, 25 to 35, 25 to 40, 30 to 35, 30 to 40, 35 to Immune response of 40, 35-45, 40-45, 40-50, 45-50, 50-55, or 50-60 μg It is administered simultaneously with the modulating agent.

[0119] In some embodiments, the acellular cancer vaccine is administered simultaneously with an adjuvant. In one embodiment, the composition comprising the cell-free IL-13Rα2 peptide-based vaccine comprises 0 It is mixed with an adjuvant in a ratio of .5:1, 1:0.5, 1:1, 1:2, 1:3, 2:1, or 3:1.

[0120] In one embodiment, the cancer vaccine is a dendritic cell-based vaccine, The dendritic cell-based vaccine consists of dendritic cells loaded with IL-13Rα2 peptides. and dendritic cells loaded with one, two, three or more brain tumor associated peptides. In some embodiments, by way of example, the dendritic cell-based cancer vaccine comprises Or about 10 3 , 5×10 3 , 10 4 , 5×10 4 , 10 5 , 5×10 5 , 10 6 , 5×10 6 , 10 7 , 3×10 7 , 5×10 7 , 7×107 , 10 8 , 5×10 8 , 1×10 9 , 5×10 9 , 1×10 10 , 5×10 10 , 1×10 11 , 5×10 11 , or 10 12 These include dendritic cells carrying brain tumor-associated peptide(s). In one embodiment, for example, the dendritic cell-based cancer vaccine comprises , about 10 3 〜10 4 , 10 3 〜10 5 , 10 4 〜10 5 , 10 4 〜10 6 , 10 5 〜10 6 , 10 5 ~ 10 7 , 10 6 〜10 7 , 10 6 〜10 8 , 10 7 〜10 8 , 10 7 〜10 9 , 10 8 〜10 9 , 10 9 〜10 10 , 10 10 〜10 11 , or 10 11 〜10 12 List of brain tumor-associated peptides (multiple possible) These include dendritic cells.

[0121] In one embodiment, the dendritic cell-based cancer vaccine comprises a helper T cell epitope. In some embodiments, for example, a dendritic cell-based Cancer vaccines are available at approximately 25, 50, 75, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 550, or 600 μg of helper T cell epitopes In another embodiment, by way of example, a dendritic cell-based cancer vaccine is administered. The range is about 25 to 50, 25 to 75, 25 to 100, 50 to 100, 50 to 150, 50 to 200, 100 to 1 50, 100 to 200, 100 to 250, 100 to 300, 150 to 200, 150 to 250, 150 to 300, 200 250 to 250, 250 to 300, 250 to 350, 250 to 400, 300 to 350, 300 to 400, 300 to 450 , 300 to 500, 350 to 400, 350 to 450, 400 to 500, 400 to 600, or 500 to 600 μg is administered simultaneously with a helper T cell epitope.

[0122] In a preferred embodiment, the helper T cell epitope is a tetanus toxoid peptide. The peptide is SEQ ID NO:10 and is administered in a single dose.

[0123] In one embodiment, the dendritic cell-based cancer vaccine comprises a dendritic cell-based cancer vaccine that is administered as an immune response modifier. In some embodiments, for example, a dendritic cell-based cancer vaccine is administered. Chin is about 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1 In another embodiment, the immune response modifier is administered simultaneously with 400, 1500, 1600, 1700, or 1800 μg of the immune response modifier. In an embodiment, by way of example, the dendritic cell-based cancer vaccine comprises about 100 to 300, 200 400 to 400, 400 to 800, 600 to 800, 800 to 1000, 800 to 1200, 1000 to 1200, 1000 to up to 1400, 1200 to 1400, 1200 to 1600, 1400 to 1600, 1400 to 1800, or 1600 to 1800 In another embodiment, the antibody is administered simultaneously with 1 μg of an immune response modifier, e.g., dendritic Cancer vaccines based on blastocytic cells are available at approximately 1, 5, 10, 15, 20, 25, 30, 35, 40, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 210, 220, 2 In another embodiment, the immune response modifier is administered simultaneously with 0, 45, 50, 55, or 60 μg of the immune response modifier. For example, a dendritic cell-based cancer vaccine can be administered at a dose of approximately 1 to 5, 1 or 2 mg / kg of patient. to 10, 5 to 10, 5 to 15, 10 to 15, 10 to 20, 15 to 20, 15 to 25, 15 to 30, 20 to 25, 20 to 30, 20 to 35, 25 to 30, 25 to 35, 25 to 40, 30 to 35, 30 to 40, 35 to Immune response of 40, 35-45, 40-45, 40-50, 45-50, 50-55, or 50-60 μg It is administered simultaneously with the modulating agent.

[0124] In one embodiment, the dendritic cell-based cancer vaccine is administered in combination with an adjuvant. In some embodiments, a dendritic cell-based IL-13Rα2 peptide-based The composition containing the subject vaccine may be 0.5:1, 1:0.5, 1:1, 1:2, 1:3, 2:1, or 3:1 It is mixed with the adjuvant at 200.degree.

[0125] In certain embodiments, the compositions described herein (e.g., including cancer vaccines) are Compositions, cancer vaccines and helper T cell epitopes, adjuvants, and / or immune responses The composition comprising the modulator or the immune response modifier may be administered once as a single dose. In some embodiments, the compositions described herein (e.g., For example, a composition comprising a cancer vaccine, a cancer vaccine and a helper T cell epitope, an adjuvant and / or a composition comprising an immune response modifier, or a composition comprising an immune response modifier , administered in multiple doses (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more than 10 doses) wherein the administration is for at least 1, 2, 3, 4, 5, 6, 7, 8, 9 days. In a specific embodiment, the cancer vaccine may be administered in increments of 10, 15, or 30 days. The stimulant is administered intranodally or subcutaneously, and the immune response modifier is administered intramuscularly.

[0126] In some embodiments, the compositions described herein are administered to a subject who has a cancer stem cell-targeted cancer vaccine. When the composition includes cutin, the composition may be administered over a 21 week period, with administrations at weeks 0, 3, In one embodiment, the treatment is performed at weeks 6, 9, 12, 15, 18, and 21. The compositions, including acellular cancer stem cell targeted cancer vaccines, contain helper T cell epitopes, azidopa, In a specific embodiment, the antibody is administered simultaneously with the adjuvant, and / or the immune response modifier. The compositions described herein, including acellular cancer stem cell targeted cancer vaccines, were shown to be effective in treating cancer insufficiency over a 21 week period. The doses were administered at weeks 0, 3, 6, 9, 12, 15, 18, and 19. The administration is performed at week 21, and the composition is administered simultaneously with an immune response modifier, wherein the immune response modifier The decorative substance is administered on each administration day of the acellular cancer stem cell targeting cancer vaccine and In another specific embodiment, the acellular cancer stem cell targeting cancer The compositions described herein, including vaccines, are administered over a 21 week period, The tests were conducted in weeks 0, 3, 6, 9, 12, 15, 18, and 21. The composition is administered simultaneously with an immune response modifier, wherein the immunomodulatory agent inhibits the proliferation and proliferation of acellular cancer stem cells. A cell-targeted cancer vaccine is administered on each administration day of the peptide. The cancer stem cell-targeting cancer vaccine is administered subcutaneously, and the immunomodulatory drug is administered subcutaneously. In a specific embodiment, the acellular cancer stem cell targeted cancer vaccine is administered subcutaneously and Some immunomodulators are administered subcutaneously and others are administered topically.

[0127] In some embodiments, the compositions described herein are dendritic cell-based. In the case of a cancer stem cell-targeted cancer vaccine comprising a composition comprising a composition for administering a cancer stem cell-targeted cancer vaccine to a patient, the composition may be administered over a period of six weeks, and administration may include administering In one embodiment, the acellular cancer stem cell transplantation is performed at weeks 0, 2, 4, and 6. The compositions, including targeted cancer vaccines, may comprise a helper T cell epitope, an adjuvant, and / or In a specific embodiment, the dendritic cell-based The compositions described herein, including a cancer stem cell targeted cancer vaccine, and the administration occurs at weeks 0, 2, 4, and 6, and the composition and administering simultaneously with an immune response modifier, wherein the immune response modifier is a dendritic cell-based The vaccine will be administered twice weekly, beginning on the first day of administration of the cancer stem cell-targeted cancer vaccine. In a specific embodiment, the dendritic cell-based cancer stem cell targeted cancer vaccine is administered intranodal. and the immune response modifier is administered intramuscularly.

[0128] In some embodiments, the compositions described herein are dendritic cell-based. In the case of a cancer stem cell-targeted cancer vaccine comprising a composition comprising a composition for administering a cancer stem cell-targeted cancer vaccine to a patient, the composition may be administered for 26 weeks, and administration may include administering , Week 0, Week 2, Week 4, Week 6, Week 10, Week 14, Week 18, Week 22, and Week 26 In one embodiment, the vaccine comprises a cell-free IL-13Rα2 peptide-based vaccine. The composition may comprise a T helper cell epitope, an adjuvant, and / or an immune response modifier. In a specific embodiment, the dendritic cell-based cancer stem cell-targeted cancer vaccine is administered at the same time. The compositions described herein comprising cutin are administered for 26 weeks, the administration comprising: It will be conducted in weeks 0, 2, 4, 6, 10, 14, 18, 22, and 26. and the composition is administered simultaneously with an immune response modifier, wherein the immune response modifier The study was conducted over a 1-week period beginning on the first day of administration of a dendritic cell-based cancer stem cell-targeting cancer vaccine. In a specific embodiment, the dendritic cell-based cancer stem cell targeting Cancer vaccines are administered intranodally and immune response modifiers are administered intramuscularly.

[0129] 6.6.2 Brain tumors The cancer vaccines described herein are useful in the prevention, treatment, and / or management of brain tumors. Any type of brain tumor can be treated according to the methods described herein. and may be treated with the cancer vaccines described herein. Not considered to be a cause of death, but may be a cause of death in gliomas (astrocytomas (e.g., pilocytic astrocytoma, diffuse astrocytoma) glioma, anaplastic astrocytoma, glioblastoma, oligodendroglioma, brainstem glioma, non-brainstem glioma , ependymomas, and mixed tumors containing two or more glial cell types), acoustic neuroma, Cranial pharyngiomas, meningiomas, medulloblastomas, primary central nervous system lymphomas, and Includes tumors of the pineal gland (eg, pineal astrocytoma and pineal parenchymal tumors) and pituitary gland. Gliomas are further classified as recurrent malignant gliomas, high-risk WHO grade II astrocytomas, and oligodendroglioma. Astrocytoma, recurrent WHO grade II glioma, newly diagnosed malignant or intrinsic brainstem glioma The study included recurrent unresectable low-grade gliomas, incompletely resected non-brainstem gliomas, and recurrent unresectable low-grade gliomas. According to the methods described herein, the cancer vaccines described herein can be administered. An additional type of brain tumor that may be treated with thrombin is adult low-grade invasive supratentorial astrocytoma. / oligodendroglioma, adult low-grade invasive supratentorial astrocytoma, adult low-grade invasive supratentorial astrocytoma Dendroglioma, adult low-grade invasive supratentorial astrocytoma / oligodendroglioma (pilocytic astrocytoma) adult low-grade invasive supratentorial astrocytoma (excluding pilocytic astrocytoma), adult Human low-grade invasive supratentorial oligodendroglioma (excluding pilocytic astrocytoma), adult intracranial ependymal tumor adult intracranial anaplastic ependymoma, adult intracranial anaplastic ependymoma (excluding subependymoma and myxopapillary tumor), adult intracranial anaplastic ependymoma, Differentiated glioma, anaplastic glioblastoma, pilocytic astrocytoma, subependymoma, myxopapillary, 1no Up to 3 limited metastatic lesions (intraparenchymal), more than 3 metastatic lesions (intraparenchymal), leptomeningeal metastasis These include metastases (neoplastic meningitis), primary CNS lymphoma, metastatic spinal tumor, or meningioma.

[0130] In one embodiment, the method described herein is followed by the method described herein. A brain tumor that may be treated with the cancer vaccines described herein is a glioma. and administering the cancer vaccines described herein according to the methods described herein. In another specific embodiment, the brain tumor that can be treated with the method is a recurrent malignant glioma. and, in accordance with the methods described herein, the cancer vaccines described herein. Brain tumors that may be treated are recurrent WHO grade II gliomas. In accordance with the methods described herein, Brain tumors that can be treated with chin include newly diagnosed malignant or intrinsic brain stem gliomas. In a specific embodiment of the present invention, the method of the present invention is carried out according to the methods described herein. Brain tumors that may be treated with the described cancer vaccines include incompletely resected non-brainstem gliomas. In another specific embodiment, according to the methods described herein, Brain tumors that may be treated with the cancer vaccines described herein include recurrent, unresectable, low-grade In one embodiment, the patient is diagnosed with recurrent malignant glioma, recurrent glioma. Cytoma, undifferentiated astrocytoma, undifferentiated oligodendroglioma, or undifferentiated mixed oligoastrocytoma In another specific embodiment, the patient is an adult with newly diagnosed high-risk or low-risk malignant tumor. In another specific embodiment, the patient is an adult with newly diagnosed high-grade glioma. In another specific embodiment, the patient is an adult with high-risk low-grade astrocytoma. The patient is an adult with a newly diagnosed high-risk low-grade oligoastrocytoma. In a specific embodiment, the patient is an adult with recurrent high-risk low-grade astrocytoma. In another specific embodiment, the patient has recurrent high-risk low-grade oligoastrocytoma. In another specific embodiment, the patient is an adult with recurrent high-risk low-grade In another specific embodiment, the patient is an adult with oligodendroglioma. In another specific embodiment, the patient is a child with endogenous malignant glioma. In another specific embodiment, the patient is a child with brain stem glioma. In another specific embodiment, the patient is a child with a non-brainstem high-grade glioma that has been treated with chemotherapy. In this study, patients were children with recurrent unresectable low-grade gliomas. In embodiments, the patient is a child with newly diagnosed diffuse intrinsic pontine glioma. In a specific embodiment of the present invention, the patient has any high-grade glioma affecting the brain stem, and Children treated with RT or without chemotherapy during RT. In embodiments, the patient is a patient with newly diagnosed non-brainstem hypertension treated with RT in conjunction with chemotherapy. In another specific embodiment, the patient is a child with high-grade glioma. Children with newly diagnosed non-brainstem high-grade gliomas treated with RT without In other specific embodiments, the patient has recurrent non-brainstem high-grade myeloma that has relapsed after treatment. Children with gliomas.

[0131] In another embodiment, the method described herein is performed according to the method described herein. A brain tumor that may be treated with the cancer vaccine is astrocytoma. In accordance with the methods described herein, Brain tumors that can be treated with chin include high-risk WHO grade II astrocytomas. In an embodiment, the method described herein is followed by the method described herein. A type of brain tumor that may be treated with a cancer vaccine is oligoastrocytoma.

[0132] 6.6.3 Patient population In some cases, the cancer vaccines or compositions described herein may be used to treat naive controls. In one embodiment, the present invention can be administered to subjects who are not brain tumor-bearing, i.e., subjects who do not have brain tumors. The cancer vaccine or composition described herein is intended to be used in naive subjects at risk for developing brain tumors. It is administered to elephants.

[0133] In certain embodiments, the cancer vaccine or composition described herein is for treating brain tumors. In some embodiments, the method is administered to a patient diagnosed with The cancer vaccine or composition may be administered to brain tumor patients before symptoms appear or become severe. In a preferred embodiment, the brain tumor is a glioma.

[0134] In certain embodiments, the cancer vaccine or composition described herein is for treating brain tumors. The subject may be a patient in need of treatment, prevention, and / or management of You may or may not have previously been treated for cancer, or you may be in remission. Such patients may have had a relapse or have previously failed treatment. In addition, the subject may have abnormal cytogenetics. The cancer stem cell-targeted cancer vaccines and compositions may be used as any line of brain tumor therapy, e.g. For example, it may be used as a first-line, second-line, or third-line brain tumor therapy. In one embodiment, a subject may be given a vaccine or pharmaceutical composition described herein. Or the subject to whom it is being given is or has been receiving other brain tumor therapy. In such a manner, the subject may be or may not be given the vaccine or pharmaceutical composition described herein. Subjects included in the study did not receive or were not receiving other brain tumor therapies.

[0135] In a specific embodiment, the subject undergoes, but is not limited to, a neurological examination; an imaging procedure; (e.g., computed tomography (CT), magnetic resonance imaging (MRI), ultrasound examination) CT, X-ray imaging, fluid-attenuated inversion recovery (FLAIR) sequences, T2-weighted imaging, and and positron emission tomography (PET) scans; and biopsies (e.g., sterotactic biopsies). Brain tumors are diagnosed using techniques known to those of skill in the art, including by immunohistochemistry, immunohistochemistry, and cytopathology. Tumor response was assessed by McDonald criteria or Response Assessment in Neuro-Oncology (RANO) criteria. Tumor size or response to treatment can be assessed using diffusion-weighted and perfusion-weighted imaging. Dynamic contrast-enhanced T1 permeability imaging, Dynamic susceptibility imaging, Diffusion tensor imaging, and magnetic resonance spectroscopy, anatomical MRI T2-weighted images, and fluid-attenuated inversion recovery (FLAIR) T2-weighted images. and gadolinium-enhanced T1-weighted imaging. These imaging techniques can be used to assess tumor cellularity, white matter infiltration, and hypoxia. Used to assess metabolic abnormalities, including vascular disease and necrosis, neocapillary blood volume, or permeability 18F-fluoromisonidazole PET and 3'-deoxy-3'-18F-fluorothymidine PE Positron emission tomography (PET) techniques such as T may also be used to image tumor response. do.

[0136] In one embodiment, the cancer vaccine or composition described herein is for treating brain tumors. It may be administered to subjects undergoing or who have undergone radiation therapy to treat them. In such a manner, the cancer vaccine or composition described herein may be used to treat brain tumors. In another embodiment, the present invention provides a method for treating a subject's rheumatoid arthritis, the method comprising administering the present invention to the subject simultaneously with or after radiation therapy. The cancer vaccines or compositions described herein may be administered in combination with radiation therapy to treat brain tumors. Administered to a subject prior to, and in some embodiments during and / or after, radiation therapy. In some preferred embodiments, radiation therapy is fractionated external beam radiation therapy, including but not limited to fractionated external beam radiation therapy. Stereotactic external beam radiation therapy, whole brain radiation therapy, stereotactic radiosurgery, or craniospinal radiation therapy It is radiation therapy.

[0137] In one embodiment, the cancer vaccine or composition described herein is for treating brain tumors. The compound is administered to a subject undergoing or who has undergone chemotherapy to treat the subject. In one embodiment, the cancer vaccine or composition described herein is used to treat brain tumors, In another embodiment, the method of the present invention is administered to a subject simultaneously with or after chemotherapy. The cancer vaccines or compositions described may be administered prior to chemotherapy and for the treatment of brain tumors. In some embodiments, the compound is administered to the subject during and / or after chemotherapy. In a preferred embodiment of the present invention, chemotherapy is Rosourea, platinum-based regimens, etoposide, cisplatin, bevacizumab (Avastin (registered trademark), irinotecan, cyclophosphamide, BCNU (carmustine), capecitabine, high-dose methotrexate, topotecan, high-dose azotoxin ARA-C, hydroxyurea, α-interferon, somatostatin Analogs, intra-CSF chemotherapy (liposomal cytarabine, methotrexate The drugs used are rituximab (Rituxan®), cytarabine, thiotepa, or rituximab.

[0138] In one embodiment, the cancer vaccine or composition described herein is for treating brain tumors. Two or more treatments, including chemotherapy, radiation therapy, or surgery, have failed to treat the disease. In a preferred embodiment, the brain tumor is For example, patients may have failed both chemotherapy and surgery or may have undergone both. Alternatively, patients may have received both radiation therapy and surgery. In addition, patients may have received both chemotherapy and radiation therapy. In some preferred embodiments, the patient may have failed The concomitant therapy received or has received is resection and temozolomide (Temodar® ))(150-200mg / m 2 ) 5 / 28 schedule, resection and BCNU (BCNU) ) wafers (Gliadel®), bevacizumab (Avastin®) and chemotherapy , combination PCV (CCNU) (lomostin) and rocarbazine and vincristine), high-dose methotrexate and vincristine, pro Carbazidine, cytalibine, or rituximab, high-dose chemotherapy with stem cell rescue, or rituximab (Rituxan®) and temozolomide (Temodar®) ).

[0139] In one embodiment, the cancer vaccine or composition described herein is for treating brain tumors. The drug is administered to a subject undergoing or who has undergone surgery to remove the tumor. In the present invention, the cancer vaccine or composition described herein is a method for eliminating brain tumors. In another embodiment, the method of the present invention is administered to a subject simultaneously with or after surgery. The cancer vaccines or compositions described may be administered prior to surgery to remove a brain tumor and at In some embodiments, it is administered to the subject during and / or after surgery.

[0140] In certain embodiments, the cancer vaccines or compositions described herein are administered in combination with other therapies. such as chemotherapy, radiation therapy, hormone therapy, surgery, small molecule therapy, anti-angiogenic therapy, and and / or as an alternative to biological therapy, including immunotherapy, wherein the The other therapies may be more toxic, i.e., not acceptable or tolerable to the subject. are known or may prove to have undesirable side effects.

[0141] In a specific embodiment, the cancer vaccine or composition described herein is administered by radiation. The subject is administered the same or similar therapeutic agent to subjects who will be undergoing, are undergoing, or have undergone radiation therapy. In addition to undergoing surgery, patients were also treated with chemotherapy, hormone therapy, small molecule therapy, and anti-inflammatory drugs. Those who have undergone angiogenic therapy and / or biological therapy, including immunotherapy.

[0142] In other embodiments, the cancer vaccine or composition described herein comprises a hormonal will be receiving, is receiving, or has received chemotherapy and / or biotherapy, including immunotherapy These subjects are not only those who have undergone surgery, but also those who have undergone chemical chemotherapy, small molecule therapy, antiangiogenic therapy, and / or radiation therapy.

[0143] In certain embodiments, the cancer vaccine or composition described herein comprises one or more In one embodiment, the present invention is administered to a subject who is refractory to more than one therapy. A cancer is refractory to a given therapy if at least a significant portion of the cancer cells remain unkilled. It also means that cell division is not inhibited. Whether the cancer cells are refractory or not Determination of the antibody titer can be performed using any method known in the art for assaying the effectiveness of a therapy against cancer cells. By either method, the art-accepted “refractory” In various embodiments, the term may be used in vivo or in vitro. In the case where the amount of cancer cells is not sufficiently reduced or increases, the cancer becomes intractable. It is.

[0144] In some embodiments, the cancer vaccine or composition described herein is for treating brain tumors. In a specific embodiment, the subject is in remission from detectable The patient does not have a brain tumor that is detectable by any of the methods described herein (e.g., MRI). ) or is not detectable using conventional methods known to those of skill in the art.

[0145] In one embodiment, the cancer vaccine or composition described herein is for treating gliomas. In a specific embodiment, the method is administered to a subject diagnosed with The cancer vaccine or composition may be used to treat astrocytoma (e.g., pilocytic astrocytoma, diffuse astrocytoma, In another specific embodiment, the method is administered to a subject diagnosed with gliomas (such as gliomas with glioma tumors, ... and anaplastic astrocytoma). In accordance with the present invention, the cancer vaccine or composition described herein is In another specific embodiment, the cancer vaccine described herein is administered to an elephant. Alternatively, the composition is administered to a subject diagnosed with oligodendroglioma. Therefore, the cancer vaccine or composition described herein can be administered to a subject diagnosed with brain stem glioma. In another specific embodiment, the cancer vaccine or In another specific embodiment, the composition is administered to a subject diagnosed with ependymoma. The cancer vaccines or compositions described herein may be used to treat mixed tumors containing two or more glial cell types. The therapeutic agent is administered to a subject diagnosed with a tumor.

[0146] In a specific embodiment, the cancer vaccine or composition described herein is In another specific embodiment, the method of the present invention is administered to a subject diagnosed with malignant glioma. The cancer vaccine or composition described in the document is effective in treating patients diagnosed with high-risk WHO grade II astrocytoma. In another specific embodiment, the method comprises administering to a subject having a cancer as described herein. The vaccine or composition is administered to a subject diagnosed with oligoastrocytoma. In an embodiment, the cancer vaccine or composition described herein is administered to a patient suffering from recurrent WHO grade I cancer. In another specific embodiment, the method of the present invention is administered to a subject diagnosed with type II glioma. The cancer vaccine or composition described in In another specific embodiment, the method is administered to a subject diagnosed with a tumor. The cancer vaccine or composition is administered to a subject diagnosed with incompletely resected non-brainstem glioma. In another specific embodiment, the cancer vaccine or The composition is administered to a subject diagnosed with recurrent unresectable low-grade glioma.

[0147] In a specific embodiment, the cancer vaccine or composition described herein is administered to a patient suffering from hearing loss. In another specific embodiment, the method is administered to a subject diagnosed with schwannoma. The cancer vaccine or composition is administered to a subject diagnosed with craniopharyngioma. In a specific embodiment, the cancer vaccine or composition described herein is administered to a patient suffering from meningioma. In another specific embodiment, the method described herein is administered to a subject who has been diagnosed with The cancer vaccine or composition is administered to a subject diagnosed with medulloblastoma. In such a manner, the cancer vaccine or composition described herein may be used to treat primary central nervous system lymphoma. In another specific embodiment, the method is administered to a subject diagnosed with a pancreatic cancer. The cancer vaccine or composition may be used to treat tumors of the pineal gland (e.g., pineal astrocytoma or pineal gland tumor). In another specific embodiment, the subject is administered the medicament described herein. The described cancer vaccines or compositions are administered to a subject diagnosed with a pituitary tumor.

[0148] In one embodiment, a cancer vaccine or composition described herein is administered. The subject is an adult human. In one embodiment, the cancer vaccine described herein Alternatively, the subject to which the composition is administered is an elderly human. The subjects to which the described cancer vaccines or compositions are administered are human children. In such a manner, the subject to which the cancer vaccine or composition described herein is administered is a human. In one embodiment, the cancer vaccine or composition described herein is The subject to be administered is a human infant.

[0149] In one embodiment, a cancer vaccine or composition described herein is administered. The subject is HLA-A2 positive, for example as determined by flow cytometry.

[0150] In one embodiment, a cancer vaccine or composition described herein is administered. Subjects will have a Karnofsky Scale (KPS) score of greater than 60. KPS is used to determine randomization of chemotherapy. It is used as a stratification and selection variable in randomized trials and has a range of 0 to 100. Patients with a score above 60 are unable to work, are able to live at home, and are unable to receive a variety of Take care of most of the patient's personal needs with as much assistance as necessary Patients with a score above 70 are able to maintain daily life with some effort and are able to Patients who score above 80 are unable to carry out daily activities. Able to do all the above and exhibit only minor signs and symptoms of the disease. A number of patients are normal, have no health complaints, and show no signs or symptoms of the disease. stomach.

[0151] In one embodiment, a cancer vaccine or composition described herein is administered. The target is approximately 1000 / mm 3 , 1500 / mm 3 , 2000 / mm 3 , 2500 / mm 3 , 3000 / mm 3 , or 3500 / mm 3 Of, if The width is about 1000 / mm 3 ~1500 / mm 3 , 1000 / mm 3 ~2000 / mm3 , 1500 / mm 3 ~2500 / mm 3 , 1500 / mm 3 ~3000 / mm 3 , 2000 / mm 3 ~3500 / mm 3 , or 2500 / mm 3 ~3500 / mm 3 has a white blood cell count of In a specific embodiment, a cancer vaccine or composition described herein is administered. The target is 2500 / mm 3 Have a white blood cell count of 0.01 or higher.

[0152] In one embodiment, a cancer vaccine or composition described herein is administered. The target is approximately 100 / mm 3 , 200 / mm 3 , 300 / mm 3 , 400 / mm 3 , 500 / mm 3 , or 600 / mm 3 of or about 100 / mm 3 ~400 / mm 3 , 200 / mm 3 ~400 / mm 3 , 300 / mm 3 ~500 / mm 3 , 300 / mm 3 ~600 / mm 3 , 400 / mm 3 ~500 / mm 3 , or 400 / mm 3 ~600 / mm 3 Specific embodiments In the present invention, the subject to which the cancer vaccine or composition described herein is administered has a cancer incidence rate of 400 / mm 3 Have lymphocyte counts of 0.1 or higher.

[0153] In one embodiment, a cancer vaccine or composition described herein is administered. The target is approximately 25,000 / mm 3 , 50,000 / mm 3 , 75,000 / mm 3 , 100,000 / mm 3 , 200,000 / mm 3 , or 300, 000 / mm 3 or about 25,000 / mm 3 ~100,000 / mm 3 , 50,000 / mm 3 ~100,000 / mm 3 , 75,00 0 / mm 3 ~100,000 / mm 3 , 100,000 / mm 3 ~200,000 / mm 3 , 100,000 / mm 3 ~300,000 / mm 3 ,also is 200,000 / mm 3 ~300,000 / mm 3 In a specific embodiment, the patient has a platelet count of The subjects to whom the cancer vaccine or composition described in the document is administered have a cell count of 100,000 / mm 3 More than 1000 blood It has a number of plates.

[0154] In one embodiment, a cancer vaccine or composition described herein is administered. The subject is expected to have a blood glucose level of about 5 g / dL, 10 g / dL, 15 g / dL, or 20 g / dL, or between about 5 and 10 g / dL, 5 and 15 g / dL. In specific embodiments, the patient has a hemoglobin count of 10-20 g / dL, 10-15 g / dL, or 10-20 g / dL. In the present invention, a subject to be administered a cancer vaccine or composition described herein has a blood glucose level of 10 g / dL or higher. has a hemoglobin count of

[0155] In one embodiment, a cancer vaccine or composition described herein is administered. Subjects were randomly assigned to receive AST, ALT, GGT, LDH, and erythrocyte sedimentation (ES) tests within 1, 1.5, 2, 2.5, or 3 times the upper limit of normal. In a specific embodiment, the method described herein has a phosphodiesterase (GPA) level of 1 or more. Subjects receiving the described cancer vaccines or compositions have AST levels within 2.5 times the upper limit of normal. , ALT, GGT, LDH, and alkaline phosphatase levels.

[0156] In one embodiment, a cancer vaccine or composition described herein is administered. The subject is expected to have a blood glucose level of about 1 mg / dL, 1.5 mg / dL, 2 mg / dL, 2.5 mg / dL, or 3 mg / dL, or between about 1.5 and 2.5 Total bilirubin in mg / dL, 1.5-3 mg / dL, 2-2.5 mg / dL, or 2-3 mg / dL In a specific embodiment, the cancer vaccine or composition described herein has The subjects to be treated have a total bilirubin of 2 mg / dL or greater.

[0157] In one embodiment, a cancer vaccine or composition described herein is administered. Subjects were randomly assigned to receive a serum creatinine level within 0.5, 1, 1.5, 2, 2.5, or 3 times the upper limit of normal. In a specific embodiment, the cancer vaccine or The subject to whom the composition is administered has a serum creatinine level within 1.5 times the upper limit of normal. do.

[0158] In one embodiment, a cancer vaccine or composition described herein is administered. Subjects were randomly assigned to receive coagulation test protocols within 0.5, 1, 1.5, 2, 2.5, or 3 times the upper limit of normal. In one embodiment, the thromboplastin time (PT) and the partial thromboplastin time (PTT) are In this case, the subject to whom the cancer vaccine or composition described herein is administered is within the normal range. Coagulation tests Prothrombin time (PT) and partial thromboplastin time (PTT) were performed within 24 hours. do.

[0159] 6.6.4 Combination therapy In certain embodiments, the methods described herein for preventing, treating, and / or managing brain tumors are provided herein. The methods provided herein provide prophylactic and / or therapeutic administration of a medicament for the treatment of a patient (e.g., a human patient) in need thereof. and / or administering to the patient a therapeutically effective method, the method comprising administering to the patient a therapeutically effective administering the cancer vaccine or composition described herein and one or more additional treatments, The additional treatment is not a cancer vaccine or a composition described herein. The cancer vaccine or composition described in and the additional treatment may be administered separately, simultaneously, or sequentially. The combination therapy may act additively or synergistically.

[0160] The combination therapy may be administered to a subject in the same pharmaceutical composition. Alternatively, the combination therapy may be administered in separate The pharmaceutical compositions may be administered simultaneously to a subject. The combination therapy may be administered by the same or different routes of administration. Thus, it can be performed on a subject.

[0161] Useful or useful in the prevention, treatment, and / or management of cancer (e.g., brain cancer). Any therapy (e.g., therapeutic or prophylactic agent) that has been or is currently being used in In the methods described herein, a cancer vaccine or composition described herein may be combined with Therapies may be used in combination, including but not limited to peptides, polypeptides, antibodies, conjugates, These include antibodies, nucleic acid molecules, small molecules, mimetics, synthetic drugs, inorganic molecules, and organic molecules. Non-limiting examples of the therapeutic agent include chemotherapy, radiation therapy, hormone therapy, surgery, small molecule therapy, anti-inflammatory drugs, and the like. Angiogenic therapy, differentiation therapy, epigenetic therapy, radioimmunotherapy, targeted therapy, and / or In one embodiment, the prophylactic and / or therapeutic agents of the present invention include biological therapies, including immunotherapies. A therapeutically effective method involves implementing a combination of treatments.

[0162] In one embodiment, the prior chemotherapy is temolozimide. In one embodiment, the prior therapy is radiation therapy. is a combination of temozolomide and radiation therapy. The combination of chemotherapy and radiation therapy is performed using the method of Stupp. In one embodiment, temozolomide, Avastin® (bevacizumab) and radiation therapy In another embodiment, the prior treatment is surgery. In some embodiments, the patient undergoes surgery prior to initiation of the combination therapy. The patient undergoes surgery prior to treatment with temozolomide. Surgery is performed prior to the initiation of radiation therapy. Each of these embodiments describing the use of combination therapy In the present invention, a cancer vaccine is administered prior to, during, or after treatment of a patient with a combination therapy. In a preferred embodiment, the patient may be administered a cancer stem cell targeted vaccine prior to administration. In a preferred embodiment, the patient has failed Avastin® (bevacizumab) therapy. In this study, patients were randomly assigned to receive Avastin (bevacizumab) prior to administration of the cancer stem cell-targeting vaccine. ) therapy and during treatment with a cancer stem cell-targeting vaccine, ) (bevacizumab).

[0163] Cancer Treatments That May be Used in Combination with the Cancer Vaccines or Compositions Described Herein Examples of methods include, but are not limited to: acivicin; aclarubicin; acodazole hydrochloride; acloni adrenaline; adzelesin; aldesleukin; altretamine; ambomycin; methacetamide Thoron;Aminoglutethimide;Amsacrine;Anastrozole;Anthracyclines; Anthramycin; Asparaginase; Asperlin; Azacitidine (Vidaza ));Azetepa;Azotomycin;Batimastat;Benzodepa;Bicalutamide;Bicalutamide hydrochloride Santren; bisphosphonates (e.g., pamidronate (A) Aredria), sodium clondronate (Bone Bonefos), zoledronic acid (Zometa), alendronate (Fosa) Fosamax), etidronate, ibandronate, cimadronate, risedronate bromate, and tiludromate; bizelesin; bleomycin sulfate; brequinar na Thorium; Bropirimine; Busulfan; Cactinomycin; Calsterone; Caracemide ;Carbetimer;Carboplatin;Carmustine;Carubicin hydrochloride;Carzelesin;Sede Fingol;Chlorambucil;Cilolemycin;Cisplatin;Cladribine;Mesir Crescentitol acid; Cyclophosphamide; Cytarabine (Ara-C); Dacalcium phosphate Vadim; Dactinomycin; Daunorubicin hydrochloride; Decitabine (Dacogen) ;Demethylating agents, dexormaplatin; dexaguanine; dexaguanine mesylate; diazico docetaxel; doxorubicin; doxorubicin hydrochloride; droloxifene; citric acid Droloxifene; Dromostanolone propionate; Duazomycin; Edatrexate EphA2 inhibitor; Elsamitrucin; Enloplatin; Enpro Mate; Epipropizin; Epirubicin hydrochloride; Elbrozole; Esorubicin chloride; Es Tramustine;Estramustine phosphate sodium;Etanidazole;Etoposide;Li Etoposide hydrochloride; Etoprine; Fadrozole hydrochloride; Fazarabine; Fenretinide; Fen Loxuridine;Fludarabine phosphate;Fluorouracil;Furocitabine;Fosquidone ;Fostriecin sodium;Gemcitabine;Histone deacetylase inhibitors (HDAC s) Gemcitabine hydrochloride; Hydroxyurea; Idarubicin hydrochloride; Ifosfamide; Ilmophor Syn; Imatinib mesylate (Gleevec, Glivec); Interleukin II (including recombinant interleukin II, or rIL2), interferon α-2a; interferon α-2b; interferon α-n1; interferon α-n3; interferon Interferon beta-Ia; Interferon gamma-Ib; Iproplatin; Irinotecan hydrochloride; Acetic acid Lanreotide; Lenalidomide (Revlimid); Letrozole; Leuproacetate Lido;Liarozole hydrochloride;Lometrexol sodium;Lomustine;Losoxan hydrochloride thoron; masoprocol; maytansine; mechlorethamine hydrochloride; anti-CD2 antibodies (e.g., Prizmab (MedImmune, Inc.; incorporated herein by reference in its entirety). International Publication WO 02 / 098370); megestrol acetate; melengestrol acetate; Melphalan; Menogaril; Mercaptopurine; Methotrexate; Methotrexate sodium; metoprine; meturedepa; mitindomide; mitocalcin; mitochromin; mi Togilin; Mitomarcin; Mitomycin; Mitosper; Mitotane; Mitoxantrone hydrochloride ;Mycophenolic acid;Nocodazole;Nogalamycin;Ormaplatin;Oxaliplatin paclitaxel; pegaspargase; periomycin; pentamsutidine peplomycin sulfate; perfosfamide; pipobroman; piposulfan; pyrrolo Xantrone; Plicamycin; Promestane; Porfimer sodium; Porphyro mycin; prednimustine; procarbazine hydrochloride; puromycin; puromycin hydrochloride Isin; Pyrazofurin; Ribopurin; Rogletimide; Safingol; Safingol hydrochloride le;semustine;simtrazene;sparfosate sodium;sparsomycin;hydrochloride Spirogermanium; Spiromustine; Spiroplatin; Streptonigrin; Strep Tozocin;Sulofenur;Tallysomycin;Tecogalan sodium;Tegafur;Hydroxytryptamine Teloxantrone; Temoporfin; Teniposide; Teroxylon; Testolactone; Thia Miprine; Thioguanine; Thiotepa; Tiazofurin; Tirapazamine; Toremifecitrate Trexetron acetate; Triciribine phosphate; Trimetrexate; Trimethoprim glucuronide Trexate; Triptorelin; Tubrozole hydrochloride; Uracil mustard; Uredep; Vapreotide; Verteporfin; Vinblastine sulfate; Vincristine sulfate; Vindesine Vindesine sulfate; Vinepidine sulfate; Vinglycinate sulfate; Vinylurosine sulfate; Alcohol Vinorelbine sulphate; Vinlocidine sulfate; Vinzolidine sulfate; Vorozole; Zeniplatin; Includes zinostatin; zorubicin hydrochloride.

[0164] Cancer Treatments That May be Used in Combination with the Cancer Vaccines or Compositions Described Herein Other examples of methods include, but are not limited to: 20-epi-1,25 dihydroxyvitamin D3; 5-ethynyluracil; Sil;Abiraterone;Aclarubicin;Acylfulvene;Adecypenol;Adozelesin ;Aldesleukin;ALL-TK antagonist;Altretamine;Ambamustine;Amide oxal; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; Anastrozole;Andrographolide;Angiogenesis inhibitor;Antagonist D;Antagonist Nist G; Antarelix; Anti-dorsal morphogenetic protein-1; Anti-androgen, Prostate cancer ;Antineoplastons;Antisense oligonucleotides;Gly aphidicolin synthase;apoptotic gene regulator;apoptotic regulator;ap Arginine deaminase;Asulaculin;Atamestane;A Trimustine; Axinastatin 1; Axinastatin 2; Axinastatin 3; Azaacet Lon; Azatoxin; Azatyrosine; Baccatin III derivatives; Balanol; Batimastat BCR / ABL antagonist; Benzochlorin; Benzoylstaurosporine; β-lactam beta-arretin derivatives; betaclamycin B; betulinic acid; bFGF inhibitors; bicalutamide ;Bisantrene;Bisaziridinylspermine;Bisnafide;Bistraten A;Bizere Syn;Brephlate;Bropirimine;Budotitanium;Buthionine sulfoximine;Cal Sipotriol; Calphostin C; Camptothecin derivatives; Canarypox IL-2; Capecitabine Carboxamido-amino-triazole;Carboxamidotriazole;CaRest M3 ;CARN 700;Cartilage derived inhibitor;Carzelesin;Casein kinase inhibitor (ICOS);Cas Tanospermine; Cecropin B; Cetrorelix; Chlorlns; Chloroquinone Xaline sulfonamide; Cicaprost; cis-porphyrin; Cladribine; Clomiphene Clotrimazole; Collismycin A; Collismycin B; Combretastatin A4; Combretastatin analogues; Conagenin; Clambesidin 816; Crisnatol; Cryptophycin 8; Cryptophycin A derivative; Curacin A; Cyclopentatetrachino cycloplatin; cytarabine octylphosphate; cytolytic factor; cytosine Statins; Dacliximab; Decitabine; Dehydrodidemnin B; Deslorelin; Dexamethasone Methasone; dexphosphamide; dexrazoxane; dexverapamil; diaziquone; di Demnin B;Didox;Diethylnorspermine;Dihydro-5-azacytidine;Dihydro Taxol, Dioxamycin; Diphenylspiromustine; Docetaxel; Docosanoate ol; dolasetron; doxifluridine; droloxifene; dronabinol; duocalin Lumycin SA; Ebselen; Ecomustine; Edelfosine; Edrecolomab; Eflornix Chin; Elemene; Emiteful; Epirubicin; Epristeride; Estramustine-like Body; Estrogen agonist; Estrogen antagonist; Etanidazole; Phosphorus etoposide;exemestane;fadrozole;fazarabine;fenretinide;fi Rugrastim; Finasteride; Flavopiridol; Freselastine; Fluasterone; Fludarabine; Fluorodaunorhysine hydrochloride; Forfenimex; Formestane; Host Liesin; Fotemustine; Gadolinium texaphyrin; Gallium nitrate; Galocitabine ;Ganirelix;Gelatinase inhibitor;Gemcitabine;Glutathione inhibitor;HMG CoA reduction Protozoan enzyme inhibitors (e.g., atorvastatin, cerivastatin, fluvastatin, lescor Lupitor, Lupitor, Lovastatin, Rosuvastatin, and Simvastatin); Hepsulfa Heregulin; Hexamethylene bisacetamide; Hypericin; Ibandronic acid; I Darubicin; Idoxifene; Idramanton; Ilmofosine; Ilomastat; Imidacloprid Zoacridone; Imiquimod; Immunostimulant peptides; Insulin-like growth factor-1 receptor inhibitors ;Interferon agonist;Interferon;Interleukin;Iobengua iododoxorubicin; ipomeanol, 4-iropract; irsogladine; isobacter isohomohalichondrin B; itasetron; Suplakinolide; Kahalalide F; Lamellarin-N triacetate; Lanreotide; Leinamycin; Lenograstim; Lentinan sulfate; Leptolstatin; Letrozole; Leukemia inhibitory factor ;Leukocyte alpha interferon;Leuprolide + estrogen + progesterone;Leupro Relin; Levamisole; LFA-3TIP (Biogen, Cambridge ), Massachusetts (MA); International Publication No. WO 93 / 0686 and U.S. Patent No. 6,162,432; Arozole; Linear polyamine analogues; Lipophilic disaccharide peptides; Lipophilic platinum compounds; Lysoc Phosphatidylcholine 7; Lobaplatin; Lombricin; Lometrexol; Lonidamine; Rosoxa Intolone; lovastatin; loxoribine; raltotecan; lutetium texaphyrin; Lysophilin; lytic peptide; maytansine; mannostatin A; mari Mastat; Masoprocol; Maspin; Matrilysin inhibitors; Matrix metallo Proteinase inhibitors; Menogaril; Melbaron; Metellin; Methioninase; Metoc Lopramide;MIF inhibitors;Mifepristone;Miltefosine;Milimostim;Mismatch Double-stranded RNA with; Mitoguazone; Mitolactol; Mitomycin analogue; Mitonafy fibroblast growth factor-saporin;mitoxantrone;mof Arotene; Molgramostim; Monoclonal antibody, Human chorionic gonadotropin; Monoclonal antibody Sulfolyl lipid A + Mycobacterium cell wall sk; Mopidamol; Multidrug resistance gene inhibitor; Multiple Tumor Suppressor Gene 1-Based Therapy; Mustard Anticancer Agent; Mycaperoxide B; Myco Bacterial cell wall extracts;myriaporone;N-acetyldinaline;N-substituted benzamides; Nafarelin; Nagressip; Naloxone + Pentazocine; Napavine; Naphterpine; Na Rutograstim; Nedaplatin; Nemorubicin; Neridronic acid; Neutral endopeptidase ;Nilutamide;Nisamycin;Nitric oxide regulators;Nitric oxide antioxidants;Nitrulline;O6 -Benzylguanine;Octreotide;Oxenon;Oligonucleotides;Onaprist Ondansetron; Ondansetron; Oracin; Oral cytokine inducer; Oral mapratin; oxalic acid; oxaunomycin; paclitaxel; pa Clitaxel analogues; Paclitaxel derivatives; Palauamine; Palmitoyl rhizoxin; Pamidronic acid; Panaxytriol; Panomiphen; Parabactin; Pazeliptin; Pegasus Spargase; Perdecin; Sodium pentosan polysulfate; Pentostatin; Pentro zole; perflubron; perphosphamide; perillyl alcohol; phenazinomycin Phenyl acetate;Phisphatase inhibitors;Picibanil;Pilocarpine hydrochloride;Pirarubicin piritrexim; plasminogen activator inhibitor; plasminogen activator inhibitor Gold complexes;Platinum compounds;Platinum-triamine complexes;Porfimer sodium;Porphyromonas Isin;Prednisone;Propyl bis-acridone;Prostaglandin J2;Protea Inhibitors of proteolytic enzymes;Protein A-based immunomodulators;Protein kinase C inhibitors;Protein kinase C inhibitors tein kinase C inhibitors, microalgae;protein tyrosine phosphatase inhibitors; Purine nucleoside phosphorylase inhibitors; Purpurin; Pyrazoloacridine; Pyri Doxylated hemoglobin-polyoxyethylene conjugate; raf antagonist; Raltitre Xed; Ramosetron; Ras farnesyl protein transferase inhibitor; Ra s inhibitor;ras-GAP inhibitor;demethylated retinoid;rhenium Re 186 etidronate; zoxin; ribozyme; RII retinamide; rogletimide; rohitukine; Murtid; Rocinimex; Rubiginone B1; Ruboxil; Safingol; Saintopin ;SarCNU;Sarcophytol A;Sargramostim;Sdi 1 mimetic;Semustine;Aging-derived inhibitor 1;sense oligonucleotide;signal transduction inhibitor;signal transduction regulator ;Single-chain antigen-binding protein;Sizofiran;Sobuzoxane;Sodium borocaptate ;Sodium phenylacetate;Sorberol;Somatomedin binding protein;Sonermin; Sparfosic acid; Spicamycin D; Spiromustine; Splenopentin; Spongista squalamine;stem cell inhibitor;stem cell division inhibitor;stypiamide;stromelisin Sulfinosine; Superactive vasoactive intestinal peptide antagonist; Sladiz TA;Suramin;Swainsonine;Synthetic glycosaminoglycan;Talimustine;5-fluoro Uracil; leucovorin; tamoxifen methiodide; tauromustine; tazarotene; Tecogalan sodium; Tegafur; Tellurapyrylium; Telomerase inhibitors; Temopo Rufin;Temozolomide;Teniposide;Tetrachlorodecaoxide;Tetrazomine;Tali Blastin; Thiocoraline; Thrombopoietin; Thrombopoietin Mimetic drugs; Thymalfasin; Thymopoietin receptor agonist; Thymotrin; Thyroid stimulator Hormones;Ethyl etiopurpurin tin;Tirapazamine;Titanocene dichloride;Topsenti toremifene; totipotent stem cell factor; translation inhibitors; tretinoin; triacetylglucosamine Lysine;Triciribine;Trimetrexate;Triptorelin;Tropisetron;Turos Tyrosine kinase inhibitors; Tyrphostins; UBC inhibitors; Ubenimex; Urogenital Sinus-derived growth inhibitor; Urokinase receptor antagonist; Vapreotide; Variolin B ;Vector-based, red blood cell gene therapy;Thalidomide;Veraresol;Veramine;Belgins ;Verteporfin;Vinorelbine;Vinxartine;VITAXIN (trademark) (November 14, 2002) "Integrin αvβ3 antagonists in combination with other preventive or therapeutic agents," Methods of preventing or treating inflammatory or autoimmune diseases by administering venting or Treating Inflammatory or Autoimmune Disorders by Administering Integr in αvβ3 Antagonists in Combination With Other Prophylactic or Therapeutic Agen See U.S. Patent Publication US 2002 / 0168360 A1 entitled "Polymer-Based Polymeric Polymers for Use With Fluorescent Light-Emitting Diodes"); Includes: zaprost; zaprost; zeniplatin; zilascorb; and zinostatin stimalamer. do.

[0165] In some embodiments, in combination with a cancer vaccine or composition described herein. The therapy or the therapies used in combination with the vaccine are immunomodulatory agents. The term "electrode" may also be referred to as a "transporter" and the two terms are used interchangeably herein. Non-limiting examples of immunomodulatory agents that may be used in combination with the cancer vaccines or compositions described herein include Illustrative examples include cytokines, peptidomimetics, and antibodies (e.g., human, humanized, chimeric, , monoclonal, polyclonal, antigen binding site (Fv), single chain antibody (ScFv), Fab or F(ab)2 fragments, or epitope-binding fragments), nucleic acid molecules (e.g. (e.g., antisense nucleic acid molecules and triple helices), small molecules, organic compounds, and inorganic compounds. In particular, immunomodulatory agents include, but are not limited to, methotrexate, leflunomide, Cyclophosphamide, Cytoxan, Immuran, Cyclosporine A, Minoxine Clin, azathioprine, antibiotics (e.g., FK506 (tacrolimus)), methylprednisolone Nisolone (MP), corticosteroids, steroids, mycophenolate mofetil, rapamycin Sirolimus, mizoribine, deoxyspergualin, brequinar, maloprost nitriloamines (e.g., leflunamide), T cell receptor modulators, cytokine receptor modulators, and modulators Other examples of immunomodulatory agents include those described in, for example, US Pat. See U.S. Publication No. 2005 / 0002934 A1, paragraphs 259-275, which is incorporated herein by reference. In one embodiment, the immunomodulatory agent is a chemotherapeutic agent. In some embodiments, the immunomodulatory agent is an immunomodulatory agent other than a chemotherapeutic agent. Thus, the treatment(s) used in accordance with the present invention are not immunomodulatory. In another preferred embodiment, the immunomodulatory agent is GM-CSF. In another preferred embodiment, both GM-CSF and imiquimod are administered to the immune system. Used as a regulating agent.

[0166] In some embodiments, in combination with a cancer vaccine or composition described herein. The treatment(s) used in combination are anti-angiogenic agents. Non-limiting examples of angiogenesis inhibitors that may be used in combination with the vaccine or composition include protein Proteins, polypeptides, peptides, conjugates, antibodies (e.g., human, humanized, chimeric, monoclonal, monoclonal, polyclonal, antigen binding site (Fv), single chain antibody (ScFv), Fab fragment, F(ab) 2 fragments, and antigen-binding fragments thereof), e.g., antibodies that specifically bind to TNF-α, nucleic acid molecules, molecules (e.g., antisense molecules or triple helices), organic molecules, inorganic molecules, and angiogenesis Other examples of angiogenesis inhibitors include small molecules that reduce or inhibit U.S. Publication No. 2005 / 0002934 A1, paragraphs 277-28, which are incorporated herein by reference. 2. In a preferred embodiment, the antiangiogenic therapy is bevacizumab. (Avastin®). In another embodiment, the therapeutic agent used in accordance with the present invention is The treatment(s) is not an angiogenesis inhibitor.

[0167] In some embodiments, in combination with a cancer vaccine or composition described herein. The treatment(s) used in conjunction with the cancer vaccines described herein are anti-inflammatory agents. Non-limiting examples of anti-inflammatory agents that may be used in combination with the composition include those known to those of skill in the art that are effective in treating inflammation. The anti-inflammatory agent includes any anti-inflammatory agent, including agents useful in the treatment of chronic inflammation and chronic diseases. Typical examples are nonsteroidal anti-inflammatory drugs (NSAIDs), steroidal anti-inflammatory drugs, and anticholinergic drugs. Medications (e.g., atropine sulfate, atropine methyl nitrate, and ipratropium bromide (ATRO VENT®), β2-agonists (e.g., abuterol (VENTOLIN®), (trademark) and PROVENTIL (trademark), bitolterol (TORNALATE (trademark)), levalbuterol (XOPONEX™), metaproterenol (ALUPENT™), pirbuterol (MAXAI R™), terbutlaine (BRETHAIRE™ and BRETHINE™ )), albuterol (PROVENTIL®, REPETABS®, and VOLMAX®), Formoterol (FORADIL AEROLIZER®), and salmeterol (SEREVENT®) ) and SEREVENT DISKUS™), and methylxanthines (e.g., theophylline (UNIPHYL™, THEO-DUR™, SLO-BID™, and TEHO-42™) Examples of NSAIDs include, but are not limited to, aspirin, ibuprofen, and celecoxib. (CELEBREX®), diclofenac (VOLTAREN®), etodolac (LODINE®), (trademark), fenoprofen (NALFON®), indomethacin (INDOCIN®), Ketoralac (TORADOL™), Oxaprozin (DAYPRO™), Nabumentone (RELAFEN®), sulindac (CLINORIL®), Tolmentin (TOLECTIN™), rofecoxib (VIOXX™), Proxen (ALEVE™, NAPROSYN™), Ketoprofen (ACTRON™) Such NSAIDs include cyclooxygenase, ... By inhibiting cyclooxgenase enzymes (e.g., COX-1 and / or COX-2) Examples of steroidal anti-inflammatory drugs include, but are not limited to, glucocorticoids, dexamethasone, Methasone (DECADRON™), corticosteroids (e.g., methylprednisolone ( MEDROL(TM), cortisone, hydrocortisone, prednisone (PREDNISONE(TM) ) and DELTASONE®), prednisolone (PRELONE® and PEDIAPRED® ), triamcinolone, azulfidine, and inhibitors of eicosanoids (e.g., protease inhibitors). Other examples of anti-inflammatory agents include staglandins, thromboxanes, and leukotrienes. See, e.g., U.S. Publication No. 005 / 0002934 A1, paragraph 29, which is incorporated by reference in its entirety. In another embodiment, the treatment (s) used in accordance with the present invention can be found in is not an anti-inflammatory agent.

[0168] In one embodiment, in combination with a cancer vaccine or composition described herein. The treatment(s) used include alkylating agents, nitrosoureas, antimetabolites, and amines. tracycline, a topoisomerase II inhibitor, or a mitotic inhibitor. include, but are not limited to, busulfan, cisplatin, carboplatin, cholorombucil ( holormbucil, cyclophosphamide, ifosfamide, decarbazine, These include mechlorethamine, melphalan, and temozolomide. Nitrosoureas are not limited. Anti-metabolites include, but are not limited to, carmustine (BCNU) and lomustine (CCNU). including but not limited to 5-fluorouracil, capecitabine, methotrexate, gemcitabine Anthracyclines include, but are not limited to, Daunorubicin, Doxorubicin, Epirubicin, Idarubicin, and Mitoxantrone Topoisomerase II inhibitors include, but are not limited to, topotecan, irinotecan , etopiside (VP-16), and teniposide. Mitotic inhibitors include, but are not limited to, taxanes (paclitaxel, docetaxel), and Contains vinca alkaloids (vinblastine, vincristine, and vinorelbine) do.

[0169] Currently available cancer treatments, as well as their dosages, routes of administration, and recommended uses, are described in detail in this publication. As known in the art and described in the Physician's Desk Reference (60th ed., 2006), In accordance with the present invention, the dosage and administration of chemotherapy agents are described in the literature. The dosing frequency is described above.

[0170] 6.6.5 Biological Assays The cancer vaccines and compositions described herein are useful in treating and preventing brain tumors. The ability to perform or manage a task may be tested.

[0171] 6.6.5.1 In vivo assays The cancer vaccines and compositions described herein should be tested in appropriate cultures prior to use in humans. The present invention can be tested in animal model systems. Such animal model systems include, but are not limited to, rats, mice, and the like. Any animal system known in the art may be used, including mice, chickens, cows, monkeys, pigs, dogs, rabbits, etc. Some features of the means may be varied; some features may be limited. However, sequential administration of vaccine components, such as vaccine components administered separately, is not possible. whether the vaccine components are administered individually or as a mixture, and the frequency of administration of the vaccine components. .

[0172] Animal models of cancer may be used to evaluate the efficacy and safety of the cancer vaccines or compositions described herein. The present invention may be used to evaluate the efficacy of the combination therapies described herein. Examples of models include, but are not limited to, IL-13Rα2 expressing brain tumor cell lines or IL-13Rα2 expressing These models include xenograft studies using primary human tumor cells expressing Thus, mice were immunized to induce a T cell response specific for IL-13Rα2, which It is then evaluated for its ability to inhibit tumor growth. To test the ability of IL-13Rα2-specific T cell responses to inhibit the growth of pre-existing tumors, To achieve this, tumor xenografts are performed prior to immunization. To assess the ability of the immune response to prevent the development of IL-13Rα2-specific T cell responses, , is induced prior to injection of tumor cells.

[0173] 6.6.5.2 Cytotoxicity Assays The toxicity and / or efficacy of the cancer vaccines and compositions described herein may be determined, for example, by: LD 50 (the dose at which 50% of the population is lethal) and ED 50 (For use in treating 50% of the population) Measured by standard pharmaceutical procedures in cell cultures or experimental animals to determine the amount of The dose ratio between toxic and therapeutic effects is the therapeutic index, and it is called the LD 50 / ED 50 Treatment methods that exhibit large therapeutic indices are preferred. Therapeutic methods shown to be effective may be used, but with minimal expected damage to non-infected cells. In order to reduce side effects, the tissues in which such drugs act must be Care should be taken to design a delivery system that is oriented to the location of the

[0174] 6.7 Products Also included herein are finished, packaged and labeled pharmaceutical products. The product is packed in a suitable vessel or container, such as a sealed glass vial or other container. The pharmaceutical agent may be, for example, a unit dosage form, as described herein. The compositions may contain components of the cancer vaccines described in.

[0175] In a specific embodiment, the unit dose form is a parenteral, intravenous, intramuscular, intranasal , cutaneous, or subcutaneous delivery. Accordingly, each delivery route is encompassed herein. The solution is preferably sterile and is suitable for

[0176] As with any drug product, packaging materials and containers are designed to protect the In addition, the pharmaceutical compositions provided herein are designed to protect the stability of pharmaceuticals. Advise the physician, laboratory assistant, or patient on appropriate methods of preventing or treating the brain tumor in question. In other words, the product contains instructions for use, monitoring, and other informational material. or suggest a dosing regimen, including but not limited to, how to administer the drug, and other information. The instructions for use are included.

[0177] Specifically, provided herein are boxes, bottles, tubes, vials, containers, sprays, packaging materials such as inhalers, inhalers, infusion (iv) bags, envelopes, and the like; and said packaging materials At least one of the vaccines or pharmaceutical compositions described herein contained within 2. An article of manufacture comprising a unit dosage form, wherein the vaccine or pharmaceutical composition described herein is The pharmaceutical composition comprises a cancer vaccine as described herein, and the packaging material comprises By administering the specific dosages and using the specific administration methods described in the specification, The IL-13Rα2 peptide-based vaccines described herein are intended to be used in the treatment of brain tumors or indicates that the compound may be used to prevent, manage, and / or treat one or more of the conditions The instructions for use are included. EXAMPLES

[0178] 7. Working Example The following examples further illustrate the invention but, of course, are by no means intended to be limiting. This disclosure should not be construed as limiting the scope of the present invention.

[0179] 7.1 Example 1 This example demonstrates that EphA2 and IL-13Rα2 are cancer stem cell antigens.

[0180] 7.1.1 Materials and Methods Flow cytometry was performed on the brain tumor cell line A-172 to detect Eph expression in these cancer cells. The expression of IL-13Rα2 and IL-13Rα2 was evaluated. The experimental protocol included the following steps.

[0181] A-172 cells were thawed and seeded into 10 cm culture dishes under sterile conditions using aseptic technique. -172 cells were grown in MEM containing 10% FBS. Both cell lines were maintained in humidified air with 5% CO2. Grown at 37° C. The A-172 cells were passaged 1:5 every 3 days.

[0182] On the day of the experiment, cells were washed once with 1x PBS and incubated with 2 ml of 0.25% trypsin-EDTA for 3 min at 37°C. The cells were then gently removed from the tissue culture plate with gentle agitation. The cells were then detached and diluted with 10 ml of DMEM. The cells were then placed in a 50 ml conical tube and centrifuged at 350 × g. The cells were centrifuged at 4°C for 5 min. The supernatant was aspirated and the cells were resuspended in 10 ml of DMEM. The cells were mixed with an equal volume of trypan blue, and the mixture was carefully placed in a hemocytometer for counting. , cell volume is 5 x 10 6 The concentration was adjusted to 1 ml with DMEM.

[0183] 20 Flow Cytometry Tubes Fisher Scientific Scientific) was prepared and 100 μl of cells (5 × 10 5 Cell / Chi tubes) (10 tubes containing A-172 cells).

[0184] 20 μl of Fc blocking reagent was added to each tube and the tubes were incubated at room temperature for 10 minutes. Incubated.

[0185] As shown in Table 1 below, 10 μl of each antibody was added to the indicated working concentration shown in Table 2 below. The tubes were gently agitated for 4 min. The plate was incubated at 4°C for 30 minutes. Table 1: A-172 cells [Table 1] Table 2: [Table 2]

[0186] After incubation, the cells were centrifuged at 300 × g for 1 min in a refrigerated tabletop microcentrifuge. The supernatant was removed and the cells were washed three times with ice-cold FACS buffer. The cells were resuspended in 100 μl of FACS buffer and 10 μl of secondary antibody was added to the appropriate tube. The tube was incubated for 30 minutes at 4°C in the dark with gentle agitation. did.

[0187] After incubation, centrifuge the cells at 300 x g for 1 minute in a refrigerated tabletop microcentrifuge. The supernatant was removed and the cells were washed three times with ice-cold FACS buffer. The cells were resuspended in 200 μl of FACS buffer and analyzed by FACS Calibur. Flow cytometer (FACSCalibur) (BD Biosciences) were analyzed by a tomometer.

[0188] 7.1.2 Results In brain tumors, brain tumor stem cells can be identified using the marker CD133, i.e. Brain tumor stem cells are known to express the CD133 antigen (see, e.g., Singh et al., See Nature 2004, vol. 432:396-401, the disclosure of which is incorporated herein by reference. (The entirety of which is incorporated herein by reference.) Cancer stem cells of the brain tumor cell line A-172 express CD1 33 (e.g., Qiang et al., 2009, Cancer Letters). Letters 271:13-21, the disclosure of which is incorporated herein by reference in its entirety. (Incorporated herein).

[0189] As shown in FIG. 1, all cells of the A-172 line were positive for EphA2 and IL-13Rα2. However, a small proportion of such cells were also positive for CD133. The + cell subpopulation represents a cancer stem cell subpopulation of the A-172 cell line, and the expression of CD133 on A-172 cells The same expression pattern was observed in subsequent duplicate experiments (see Figures 6 and 7).

[0190] As shown in FIG. 2, the CD133+ population was also positive for EphA2 expression, and thus, 2 is present on the cancer stem cell population derived from the A-172 cell line, thus demonstrating that EphA2 is an anti-cancer stem cell This fact was confirmed in subsequent duplicated experiments (see Figure 8). ). Furthermore, as shown in FIG. 4, EphA2 is more highly expressed on CD133+ cells compared to CD133− cells. was expressed at a level

[0191] Similarly, as shown in Figure 2, the CD133+ population of the A-172 cell line also exhibited IL-13Rα2 expression. The results showed that IL-13Rα2 was present on the cancer stem cell population derived from the A-172 cell line. Thus, IL-13Rα2 is a cancer stem cell antigen. This was confirmed by duplicated experiments (see FIG. 8). Furthermore, as shown in FIG. 5, IL-13Rα2 was expressed by CD1 It was expressed to higher levels on CD133+ cells compared with CD33− cells.

[0192] 7.1.3 Conclusion These data suggest that EphA2 is a cancer stem antigen and therefore a promising therapeutic approach for cancers such as brain cancer. This indicates that the present invention can be used in the field of Sequence Listing: [Table 3]

[0193] Equivalent: The present invention is not to be limited in scope by the specific embodiments described herein. Indeed, various modifications of the invention in addition to those described may be made in accordance with the teachings of the above. Such modifications will be apparent to those skilled in the art from the description. are intended to be within the scope.

[0194] Various publications, patents, and patent applications are cited herein, the disclosures of which are incorporated herein by reference in their entirety. is incorporated herein by reference in its entirety.

Claims

1. 1. A pharmaceutical composition for treating a brain tumor in a subject in need thereof, comprising: (i) a pharmaceutical composition comprising an IL-13Rα2 peptide having an amino acid sequence selected from SEQ ID NOs: 1-4, an EphA2 peptide having the amino acid sequence of SEQ ID NO: 5, a survivin peptide having the amino acid sequence of SEQ ID NO: 9, and a tetanus toxoid peptide having the amino acid sequence of SEQ ID NO: 10, wherein the composition is formulated as an emulsion; and (ii) one or more T cell receptor modulators; the pharmaceutical composition does not contain a peptide consisting of SEQ ID NO:7 and is not used to be co-administered with a peptide consisting of SEQ ID NO:7; and The pharmaceutical composition is adapted to be co-administered with bevacizumab. The pharmaceutical composition.

2. 2. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is emulsified with Montanide ISA-51.

3. 3. The pharmaceutical composition of claim 1 or 2, wherein the pharmaceutical composition is administered subcutaneously to the subject and the one or more T cell receptor modulators are administered intravenously, subcutaneously, or intramuscularly to the subject.

4. 4. The pharmaceutical composition of any one of claims 1 to 3, wherein the one or more T cell receptor modulators are selected from peptides, polypeptides, proteins, fusion proteins, and / or antibodies that immunospecifically bind to a T cell receptor, a ligand of a T cell receptor, or a fragment thereof.

5. 5. The pharmaceutical composition of any one of claims 1 to 4, wherein the one or more T cell receptor modulators are selected from an anti-CD4 antibody, an anti-CD3 antibody, an anti-CD5 antibody, an anti-CD7 antibody, an anti-CD8 antibody, an anti-CD40 ligand monoclonal antibody, an anti-CD52 antibody, an anti-CD2 antibody, an anti-CD11a antibody, an anti-B7 antibody, a CTLA4-immunoglobulin, LFA-3TIP, and combinations thereof.

6. The pharmaceutical composition of any one of claims 1 to 5, wherein the subject is in remission, in a relapse, and / or has experienced the failure of at least one previous treatment.

7. The pharmaceutical composition according to any one of claims 1 to 6, wherein said pharmaceutical composition is adapted to be co-administered with at least one additional cancer treatment.

8. 8. The pharmaceutical composition of claim 7, wherein the at least one additional cancer treatment is radiation therapy, chemotherapy, or surgery.

9. The pharmaceutical composition of any one of claims 1 to 8, wherein the IL-13Rα2 peptide comprises SEQ ID NO:

3.

10. The pharmaceutical composition according to any one of claims 1 to 9, wherein said pharmaceutical composition is adapted to be co-administered with one or more additional immunomodulatory agents.

11. 11. The pharmaceutical composition of claim 10, wherein the one or more additional immunomodulatory agents are selected from a nucleic acid molecule, a Toll-like receptor (TLR) agonist, and / or an immune response modifier that biases the subject's immune response toward a Th1 or Th2 response.

12. The pharmaceutical composition of claim 11, wherein the TLR agonist is a TLR3 agonist.

13. 13. The pharmaceutical composition of any one of claims 1 to 12, wherein the brain tumor is a glioma, astrocytoma, glioblastoma, oligodendroglioma, brain stem glioma, ependymoma, or a mixed tumor comprising two or more glial cell types.

14. The pharmaceutical composition according to any one of claims 1 to 12, wherein the brain tumor is an acoustic neuroma, a craniopharyngeal tumor, a meningioma, or a medulloblastoma.

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