VIRUS VECTORS EXPRESSING MULTIPLE EPITOPES OF TUMOR ASSOCIATED ANTIGENS FOR INDUCING ANTITUMOR IMMUNITYProvided are polynucleotides and viral vectors, particularly, alphavirus vectors such as Sindbis viral vectors, which encode multiple, e.g., two or more, epitopes of at least one tumor associated antigen in which each epitope is separated by a processing or enzyme cleavage site. The multiple epitopes of the two or more tumor associated antigens encoded by the described polynucleotides and viral vectors may be the same or different. Methods of treating mammalian subjects having a cancer or tumor expressing the tumor associated antigen epitopes are provided, in which the viral vectors encoding the multiple epitopes, as well as other immunostimulatory or immunomodulatory components, generate an anti-cancer or anti-tumor immune response in which high levels of effector T cells increase the survivability of tumored mammalian subjects and result in epitope spreading, thus providing a further enhancement of the immune response.A polynucleotide encoding an alphavirus protein, or a fragment thereof, and two or more epitopes of one or more tumor associated antigens, wherein each epitope is separated by an enzyme cleavage site. 2. The polynucleotide according to claim 1, wherein the alphavirus protein, or a fragment thereof, is a Sindbis virus protein, or a fragment thereof. 3. The polynucleotide according to claim 1 or claim 2, wherein the two or more epitopes comprise 5-30 amino acids. 4. The polynucleotide according to any one of claims 1-3, wherein the tumor associated antigen is expressed on the surface of a cancer or tumor cell or is expressed in the cytosol of the cancer or tumor cell. 5. The polynucleotide according to any one of claims 1-4, wherein the two or more epitopes comprise an amino acid sequence of a tumor associated antigen listed in any one of Tables 1-28. 6. The polynucleotide according to claim 4, wherein the two or more epitopes are of one or more tumor associated antigens selected from kallikrein 4, papillomavirus binding factor (PBF), preferentially expressed antigen of melanoma (PRAME), Wilms’ tumor-1 (WT1), Hydroxysteroid Dehydrogenase Like 1 (HSDL1), mesothelin, cancer testis antigen (NY-ESO-1), carcinoembryonic antigen (CEA), p53, human epidermal growth factor receptor 2/neuro receptor tyrosine kinase (Her2/Neu), carcinoma-associated epithelial cell adhesion molecule (EpCAM), ovarian and uterine carcinoma antigen (CA125), folate receptor α, sperm protein 17, tumor- associated differentially expressed gene-12 (TADG-12), mucin-16 (MUC-16), L1 cell adhesion molecule (L1CAM), mannan-MUC-1, Human endogenous retrovirus K (HERV-K-MEL), Kita- kyushu lung cancer antigen-1 (KK-LC-1), human cancer/testis antigen (KM-HN-1), cancer testis antigen (LAGE-1), melanoma antigen-A1 (MAGE-A1), Sperm surface zona pellucida binding protein (Sp17), Synovial Sarcoma, X Breakpoint 4 (SSX-4), Transient axonal glycoprotein-1 (TAG-1), Transient axonal glycoprotein-2 (TAG-2), Enabled Homolog (ENAH), mammoglobin- A, NY-BR-1, Breast Cancer Antigen, (BAGE-1), B melanoma antigen, melanoma antigen-A1 (MAGE-A1), melanoma antigen-A2 (MAGE-A2), mucin k, synovial sarcoma, X breakpoint 2 (SSX-2), Taxol-resistance-associated gene-3 (TRAG-3), Avian Myelocytomatosis Viral Oncogene (c-myc), cyclin B1, mucin 1 (MUC1), p62, survivin, lymphocyte common antigen (CD45), Dickkopf WNT Signaling Pathway Inhibitor 1 (DKK1), telomerase, Kirsten rat sarcoma viral oncogene homolog (K-ras), G250, intestinal carboxyl esterase, alpha-fetoprotein, Macrophage Colony-Stimulating Factor (M-CSF), Prostate-specific membrane antigen (PSMA), caspase 5 (CASP-5), Cytochrome C Oxidase Assembly Factor 1 Homolog (COA-1), O-linked β- N-acetylglucosamine transferase (OGT), Osteosarcoma Amplified 9, Endoplasmic Reticulum Lectin (OS-9), Transforming Growth Factor Beta Receptor 2 (TGF-betaRII), murine leukemia glycoprotein 70 (gp70), Calcitonin Related Polypeptide Alpha (CALCA), Programmed cell death 1 ligand 1 (CD274), Mouse Double Minute 2Homolog (mdm-2), alpha-actinin-4, elongation factor 2, Malic Enzyme 1 (ME1), Nuclear Transcription Factor Y Subunit C (NFYC), G Antigen 1,3 (GAGE-1,3), melanoma antigen-A6 (MAGE-A6), cancer testis antigen XAGE-1b, six transmembrane epithelial antigen of the prostate 1 (STEAP1), PAP, prostate specific antigen (PSA), Fibroblast Growth Factor 5 (FGF5), heat shock protein hsp70-2, melanoma antigen-A9 (MAGE-A9), Arg-specific ADP-ribosyltransferase family C (ARTC1), B-Raf Proto-Oncogene (B-RAF), Serine/Threonine Kinase, beta-catenin, Cell Division Cycle 27 homolog (Cdc27), cyclin dependent kinase 4 (CDK4), cyclin dependent kinase 12 (CDK12), Cyclin Dependent Kinase Inhibitor 2A (CDKN2A), Casein Kinase 1 Alpha 1 (CSNK1A1), Fibronectin 1 (FN1), Growth Arrest Specific 7 (GAS7), Glycoprotein nonmetastatic melanoma protein B (GPNMB), HAUS Augmin Like Complex Subunit 3 (HAUS3), LDLR-fucosyltransferase, Melanoma Antigen Recognized By T-Cells 2 (MART2), myostatin (MSTN), Melanoma Associated Antigen (Mutated) 1 (MUM-1-2-3), Poly(A) polymerase gamma (neo-PAP), myosin class I, Protein phosphatase 1 regulatory subunit 3B (PPP1R3B), Peroxiredoxin-5 (PRDX5), Receptor-type tyrosine-protein phosphatase kappa (PTPRK), Transforming protein N-Ras (N-ras), retinoblastoma-associated factor 600 (RBAF600), sirtuin-2 (SIRT2), SNRPD1, triosephosphate isomerase, Ocular Albinism Type 1 Protein (OA1), member RAS oncogene family (RAB38), Tyrosinase related protein 1-2 (TRP-1-2), Melanoma Antigen Gp75 (gp75), tyrosinase, Melan-A (MART-1), Glycoprotein 100 melanoma antigen (gp100), N-acetylglucosaminyltransferase V gene (GnTVf), Lymphocyte Antigen 6 Complex Locus K (LY6K), melanoma antigen-A10 (MAGE-A10), melanoma antigen-A12 (MAGE-A12), melanoma antigen-C2 (MAGE-C2), melanoma antigen NA88-A, Taxol-resistant-associated protein 3 (TRAG-3), BDZ binding kinase (pbk), caspase 8 (CASP-8), sarcoma antigen 1 (SAGE), Breakpoint Cluster Region-Abelson oncogene (BCR-ABL), fusion protein...
항종양 면역을 유도하기 위한 종양 관련 항원의 다중 에피토프를 발현하는 바이러스 벡터본 발명은 하나 이상의 종양 관련 항원의 다중, 예를 들어 2개 이상의 에피토프로서 각각이 프로세싱 또는 효소 절단 부위에 의해 분리된 에피토프를 코딩하는 폴리펩티드, 바이러스 벡터, 특히 신드비스 바이러스 벡터와 같은 알파바이러스 벡터를 제공한다. 기재된 폴리뉴클레오티드 및 바이러스 벡터에 의해 코딩되는 둘 이상의 종양 관련 항원의 다중 에피토프는 동일하거나 상이할 수 있다. 종양 관련 항원 에피토프를 발현하는 암 또는 종양을 가진 포유류 대상체를 치료하는 방법으로서, 다중 에피토프뿐 아니라 다른 면역자극 또는 면역조절 성분을 코딩하는 바이러스 벡터는, 높은 수준의 이펙터 T 세포는 종양보유 포유류 대상체의 생존 가능성을 증가시키고 에피토프 확산을 일으켜 면역 반응을 더욱 향상시키는, 항암 또는 항종양 면역 반응을 생성하는 것인 방법을 제공한다.알파바이러스 단백질 또는 이의 단편, 및 하나 이상의 종양 관련 항원의 2개 이상의 에피토프를 코딩하는 폴리뉴클레오티드로서, 각각의 에피토프는 효소 절단 부위에 의해 분리되는 것인 폴리뉴클레오티드.