Arenavirus particles as cancer vaccines

Abstract

The present application relates generally to genetically modified arenaviruses that are suitable vaccines against neoplastic diseases, such as cancer. The arenaviruses described herein may be suitable for vaccines and/or treatment of neoplastic diseases and/or for the use in immunotherapies. In particular, provided herein are methods and compositions for treating a neoplastic disease by administering a genetically modified arenavirus in combination with an immune checkpoint inhibitor, wherein the arenavirus has been engineered to include a nucleotide sequence encoding a tumor antigen, tumor associated antigen or antigenic fragment thereof.

1 . A method for treating a neoplastic disease in a subject comprising, administering to a subject in need thereof an arenavirus particle and an immune checkpoint inhibitor, wherein said arenavirus particle is engineered to contain an arenavirus genomic segment comprising:
 (i) a nucleotide sequence encoding a tumor antigen, tumor associated antigen or an antigenic fragment thereof; and   (ii) at least one arenavirus open reading frame (“ORF”) in a position other than the wild-type position of said ORF, wherein said ORF encodes the glycoprotein (“GP”), the nucleoprotein (“NP”), the matrix protein Z (“Z protein”) or the RNA dependent RNA polymerase L (“L protein”) of said arenavirus particle.   
     
     
         2 . The method of  claim 1 , wherein said tumor antigen or tumor associated antigen is selected from the group consisting of oncogenic viral antigens, cancer-testis antigens, oncofetal antigens, tissue differentiation antigens, mutant protein antigens, neoantigens, Adipophilin, AIM-2, ALDH1AI, BCLX (L), BING-4, CALCA, CD45, CPSF, cyclin D1, DKKI, ENAH (hMcna), Ga733 (EpCAM), EphA3, EZH2, FGF5, glypican-3, G250/MN/CAIX, HER-2/neu, IDO1, IGF2B3, IL13Ralpha2, Intestinal carboxyl esterase, alpha-foetoprotein, Kallikrein 4, KIF20A, Lengsin, M-CSF, MCSP, mdm-2, Meloe, MMP-2, MMP-7, MUC1, MUC5AC, p53 (non-mutant), PAX5, PBF, PRAME, PSMA, RAGE, RAGE-1, RGS5, RhoC, RNF43, RU2AS, secernin 1, SOX1O, STEAP1 (six-transmembrane epithelial antigen of the prostate 1), survivinn, Telomerase, VEGF, WT1, EGF-R, CEA, CD20, CD33, CD52, glycoprotein 100 (GP100 or gp 100 protein), MELANA/MART1, MART2, NY-ESO-1, p53, MAGE A1, MAGE A3, MAGE-4, MAGE-5, MAGE-6, CDK4, alpha-actinin-4, ARTC1, BCR-ABL, BCR-ABL fusion protein (b3a2), B-RAF, CASP-5, CASP-8, beta-catenin, Cdc27, CDK4, CDKN2A, CLPP, COA-1, dek-can fusion protein, EFTUD2, Elongation factor 2, ETV6-AML, ETV6-AML1 fusion protein, FLT3-ITD, FN1, GPNMB, LDLR-fucosyltransferaseAS fusion protein, NFYC, OGT, OS-9, pml-RARalpha fusion protein, PRDX5, PTPRK, H-ras, K-ras (V-Ki-ras2 Kirsten rat sarcoma viral oncogene), N-ras, RBAF600, SIRT2, SNRPD1, SSX, SSX2, SYT-SSX1 or -SSX2 fusion protein, TGF-betaRII, Triosephosphate isomerase, ormdm-2, LMP2, HPV E6/E7, EGFRvIII (epidermal growth factor variant III), Idiotype, GD2, ganglioside G2), Ras-mutant, p53 (mutant), Proteinase3 (PR1), Tyrosinase, PSA, hTERT, Sarcoma translocation breakpoints, EphA2, prostatic acid phosphatase PAP, neo-PAP, ML-IAP, AFP, ERG (TMPRSS2 ETS Fusion gene), NA17, PAX3, ALK, Androgen Receptor, Cyclin B1, Polysialic acid, MYCN, TRP2, TRP2-Int2, GD3, Fucosyl GM1, Mesothelin, PSCA, sLe(a), cyp1B1, PLAC1, GM3, BORIS, Tn, GLoboH, NY-BR-1, SART3, STn, Carbonic Anhydrase IX, OY-TES1, Sperm protein 17, LCK, high molecular weight melanoma-associated antigen (HMWMAA), AKAP-4, SSX2, XAGE 1, B7H3, Legumain, Tie 2, Page4, VEGFR2, MAD-CT-1, FAP, PDGFR-beta, MAD-CT-2, For-related antigen 1, TRP1, CA-125, CA19-9, Calretinin, Epithelial membrane antigen (EMA), Epithelial tumor antigen (ETA), CD19, CD34, CD99, CD117, Chromogranin, Cytokeratin, Desmin, Glial fibrillary acidic protein (GFAP), gross cystic disease fluid protein (GCDFP-15), HMB-45 antigen, Myo-D1, muscle-specific actin (MSA), neurofilament, neuron-specific enolase (NSE), placental alkaline phosphatase, synaptophysis, thyroglobulin, thyroid transcription factor-1, dimeric form of the pyruvate kinase isoenzyme type M2 (tumor M2-PK), BAGE BAGE-1, CAGE, CTAGE, FATE, GAGE, GAGE-1, GAGE-2, GAGE-3, GAGE-4, GAGE-5, GAGE-6, GAGE-7, HCA661, HOM-TES-85, MAGEA, MAGEB, MAGEC, NA88, NY-SAR-35, SPANXB1, SPA17, SSX, SYCP1, TPTE, Carbohydrate/ganglioside GM2 (oncofetal antigen-immunogenic-1 OFA-I-1), GM3, CA 15-3 (CA 27.29\BCAA), CA 195, CA 242, CA 50, CAM 43, CEA, EBNA, EF2, Epstein-Barr virus antigen, HLA-A2, HLA-A11, HSP70-2, KIAAO205, MUM-1, MUM-2, MUM-3, Myosin class I, GnTV, Herv-K-mel, LAGE-1, LAGE-2, (sperm protein) SP17, SCP-1, P15(58), Hom/Mel-40, E2A-PRL, H4-RET, IGH-IGK, MYL-RAR, TSP-180, P185erbB2, p180erbB-3, c-met, nm-23H1, TAG-72, TAG-72-4, CA-72-4, CAM 17.1, NuMa, 13-catenin, P16, TAGE, CT7, 43-9F, 5T4, 791Tgp72, 13HCG, BCA225, BTAA, CD68\KP1, CO-029, HTgp-175, M344, MG7-Ag, MOV18, NB\70K, NY-CO-1, RCAS1, SDCCAG16, TA-90, TAAL6, TLP, TPS, CD22, CD27, CD30, CD70, prostein, TARP (T cell receptor gamma alternate reading frame protein), Trp-p8, integrin αvβ3 (CD61), galactin, or Ral-B, CD123, CLL-1, CD38, CS-1, CD138, and ROR1. 
     
     
         3 . The method of  claim 1 , wherein said nucleotide sequence encodes two, three, four, five, six, seven, eight, nine, ten or more tumor antigens or tumor associated antigens or antigenic fragments thereof. 
     
     
         4 . The method of  claim 1 , wherein said immune checkpoint inhibitor inhibits, decreases or interferes with the activity of a negative checkpoint regulator is selected from the group consisting of Cytotoxic T-lymphocyte antigen-4 (CTLA-4), CD80, CD86, Programmed cell death 1 (PD-1), Programmed cell death ligand 1 (PD-L1), Programmed cell death ligand 2 (PD-L2), Lymphocyte activation gene-3 (LAG-3; also known as CD223), Galectin-3, B and T lymphocyte attenuator (BTLA), T-cell membrane protein 3 (TIM3), Galectin-9 (GAL9), B7-H1, B7-H3, B7-H4, T-Cell immunoreceptor with Ig and ITIM domains (TIGIT/Vstm3/WUCAM/VSIG9), V-domain Ig suppressor of T-Cell activation (VISTA), Glucocorticoid-induced tumor necrosis factor receptor-related (GITR) protein, Herpes Virus Entry Mediator (HVEM), OX40, CD27, CD28, CD137. CGEN-15001T, CGEN-15022, CGEN-15027, CGEN-15049, CGEN-15052, and CGEN-15092. 
     
     
         5 . The method of  claim 1 , to wherein said subject is suffering from, is susceptible to, or is at risk for a neoplastic disease selected from the group consisting of acute lymphoblastic leukemia; acute lymphoblastic lymphoma; acute lymphocytic leukaemia; acute myelogenous leukemia; acute myeloid leukemia (adult/childhood); adrenocortical carcinoma; AIDS-related cancers; AIDS-related lymphoma; anal cancer; appendix cancer; astrocytomas; atypical teratoid/rhabdoid tumor; basal-cell carcinoma; bile duct cancer, extrahepatic (cholangiocarcinoma); bladder cancer; bone osteosarcoma/malignant fibrous histiocytoma; brain cancer (adult/childhood); brain tumor, cerebellar astrocytoma (adult/childhood); brain tumor, cerebral astrocytoma/malignant glioma brain tumor; brain tumor, ependymoma; brain tumor, medulloblastoma; brain tumor, supratentorial primitive neuroectodermal tumors; brain tumor, visual pathway and hypothalamic glioma; brainstem glioma; breast cancer; bronchial adenomas/carcinoids; bronchial tumor; Burkitt lymphoma; cancer of childhood; carcinoid gastrointestinal tumor; carcinoid tumor; carcinoma of adult, unknown primary site; carcinoma of unknown primary; central nervous system embryonal tumor; central nervous system lymphoma, primary; cervical cancer; childhood adrenocortical carcinoma; childhood cancers; childhood cerebral astrocytoma; chordoma, childhood; chronic lymphocytic leukemia; chronic myelogenous leukemia; chronic myeloid leukemia; chronic myeloproliferative disorders; colon cancer; colorectal cancer; craniopharyngioma; cutaneous T-cell lymphoma; desmoplastic small round cell tumor; emphysema; endometrial cancer; ependymoblastoma; ependymoma; esophageal cancer; ewing's sarcoma in the Ewing family of tumors; extracranial germ cell tumor; extragonadal germ cell tumor; extrahepatic bile duct cancer; gallbladder cancer; gastric (stomach) cancer; gastric carcinoid; gastrointestinal carcinoid tumor; gastrointestinal stromal tumor; germ cell tumor: extracranial, extragonadal, or ovarian gestational trophoblastic tumor; gestational trophoblastic tumor, unknown primary site; glioma; glioma of the brain stem; glioma, childhood visual pathway and hypothalamic; hairy cell leukemia; head and neck cancer; heart cancer; hepatocellular (liver) cancer; hodgkin lymphoma; hypopharyngeal cancer; hypothalamic and visual pathway glioma; intraocular melanoma; islet cell carcinoma (endocrine pancreas); Kaposi Sarcoma; kidney cancer (renal cell cancer); langerhans cell histiocytosis; laryngeal cancer; lip and oral cavity cancer; liposarcoma; liver cancer (primary); lung cancer, non-small cell; lung cancer, small cell; lymphoma, primary central nervous system; macroglobulinemia, Waldenström; male breast cancer; malignant fibrous histiocytoma of bone/osteosarcoma; medulloblastoma; medulloepithelioma; melanoma; melanoma, intraocular (eye); merkel cell cancer; merkel cell skin carcinoma; mesothelioma; mesothelioma, adult malignant; metastatic squamous neck cancer with occult primary; mouth cancer; multiple endocrine neoplasia syndrome; multiple myeloma/plasma cell neoplasm; mycosis fungoides, myelodysplastic syndromes; myelodysplastic/myeloproliferative diseases; myelogenous leukemia, chronic; myeloid leukemia, adult acute; myeloid leukemia, childhood acute; myeloma, multiple (cancer of the bone-marrow); myeloproliferative disorders, chronic; nasal cavity and paranasal sinus cancer; nasopharyngeal carcinoma; neuroblastoma, non-small cell lung cancer; non-hodgkin lymphoma; oligodendroglioma; oral cancer; oral cavity cancer; oropharyngeal cancer; osteosarcoma/malignant fibrous histiocytoma of bone; ovarian cancer; ovarian epithelial cancer (surface epithelial-stromal tumor); ovarian germ cell tumor; ovarian low malignant potential tumor; pancreatic cancer; pancreatic cancer, islet cell; papillomatosis; paranasal sinus and nasal cavity cancer; parathyroid cancer; penile cancer; pharyngeal cancer; pheochromocytoma; pineal astrocytoma; pineal germinoma; pineal parenchymal tumors of intermediate differentiation; pineoblastoma and supratentorial primitive neuroectodermal tumors; pituitary tumor; pituitary adenoma; plasma cell neoplasia/multiple myeloma; pleuropulmonary blastoma; primary central nervous system lymphoma; prostate cancer; rectal cancer; renal cell carcinoma (kidney cancer); renal pelvis and ureter, transitional cell cancer; respiratory tract carcinoma involving the NUT gene on chromosome 15; retinoblastoma; rhabdomyosarcoma, childhood; salivary gland cancer; sarcoma, Ewing family of tumors; Sézary syndrome; skin cancer (melanoma); skin cancer (non-melanoma); small cell lung cancer; small intestine cancer soft tissue sarcoma; soft tissue sarcoma; spinal cord tumor; squamous cell carcinoma; squamous neck cancer with occult primary, metastatic; stomach (gastric) cancer; supratentorial primitive neuroectodermal tumor; T-cell lymphoma, cutaneous (Mycosis Fungoides and Sézary syndrome); testicular cancer; throat cancer; thymoma; thymoma and thymic carcinoma; thyroid cancer; thyroid cancer, childhood; transitional cell cancer of the renal pelvis and ureter; urethral cancer; uterine cancer, endometrial; uterine sarcoma; vaginal cancer; vulvar cancer; and Wilms Tumor. 
     
     
         6 . The method of  claim 1 , wherein said arenavirus particle and said immune checkpoint inhibitor are co-administered simultaneously. 
     
     
         7 . The method of  claim 1 , wherein said arenavirus particle is administered:
 (i) prior to administration of said immune checkpoint inhibitor; or   (ii) after administration of said immune checkpoint inhibitor.   
     
     
         8 . (canceled) 
     
     
         9 . The method of  claim 7 , wherein the interval between administration of said arenavirus particle and said immune checkpoint inhibitor is about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 1 week, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 13 days, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, or more. 
     
     
         10 . The method of  claim 1 , wherein said arenavirus particle and said immune checkpoint inhibitor are administered in a therapeutically effective amount. 
     
     
         11 . The method of  claim 1 , wherein said method comprises administering to said subject a first arenavirus particle, and administering to said subject, after a period of time, a second arenavirus particle. 
     
     
         12 . The method of  claim 11 , wherein said first arenavirus particle and said second particle are derived from different arenavirus species and/or comprise nucleotide sequences encoding different tumor antigen, tumor associated antigens or antigenic fragments thereof. 
     
     
         13 . The method of  claim 1 , wherein said arenavirus genomic segment is selected from the group consisting of:
 (i) an S segment, wherein the ORF encoding the NP is under control of an arenavirus 5′ untranslated region (“UTR”);   (ii) an S segment, wherein the ORF encoding the Z protein is under control of an arenavirus 5′ UTR;   (iii) an S segment, wherein the ORF encoding the L protein is under control of an arenavirus 5′ UTR;   (iv) an S segment, wherein the ORF encoding the GP is under control of an arenavirus 3′ UTR;   (v) an S segment, wherein the ORF encoding the L protein is under control of an arenavirus 3′ UTR;   (vi) an S segment, wherein the ORF encoding the Z protein is under control of an arenavirus 3′ UTR;   (vii) an L segment, wherein the ORF encoding the GP is under control of an arenavirus 5′ UTR;   (viii) an L segment, wherein the ORF encoding the NP is under control of an arenavirus 5′ UTR;   (ix) an L segment, wherein the ORF encoding the L protein is under control of an arenavirus 5′ UTR;   (x) an L segment, wherein the ORF encoding the GP is under control of an arenavirus 3′ UTR;   (xi) an L segment, wherein the ORF encoding the NP is under control of an arenavirus 3′ UTR; and   (xii) an L segment, wherein the ORF encoding the Z protein is under control of an arenavirus 3′ UTR,   wherein said arenavirus 3′ UTR is the 3′ UTR of the arenavirus S segment or the arenavirus L segment, and wherein said arenavirus 5′ UTR is the 5′ UTR of the arenavirus S segment or the arenavirus L segment.   
     
     
         14 . (canceled) 
     
     
         15 . The method of  claim 1 , wherein said arenavirus particle comprises a second arenavirus genomic segment so that said arenavirus particle comprises an S segment and an L segment. 
     
     
         16 . The method of  claim 15 , wherein said arenavirus particle is attenuated, infectious, and replication-competent. 
     
     
         17 - 25 . (canceled) 
     
     
         26 . The method of  claim 1 , wherein the arenavirus particle is a tri-segmented arenavirus particle comprising either one L segment and two S segments. 
     
     
         27 - 29 . (canceled) 
     
     
         30 . The method of  claim 26 , wherein propagation of said tri-segmented arenavirus particle does not result in a replication-competent bi-segmented viral particle after 70 days of persistent infection in mice lacking type I interferon receptor, type II interferon receptor and recombination activating gene 1 (RAG1) and having been infected with 10 4  PFU of said tri-segmented arenavirus particle. 
     
     
         31 . The method of  claim 26 , wherein inter-segmental recombination of two S segments, uniting two arenavirus ORFs on only one instead of two separate segments, abrogates viral promoter activity. 
     
     
         32 .- 33 . (canceled) 
     
     
         34 . The method of  claim 26 , wherein the two S segments comprise: (i) one or two nucleotide sequences each encoding a tumor antigen, tumor associated antigen or an antigenic fragment thereof; or (ii) one or two duplicated arenavirus ORFs; or (iii) one nucleotide sequence encoding a tumor antigen, tumor associated antigen or an antigenic fragment thereof and one duplicated arenavirus ORF. 
     
     
         35 - 37 . (canceled) 
     
     
         38 . The method of  claim 1 , wherein said arenavirus particle is derived from lymphocytic choriomeningitis virus (“LCMV”). 
     
     
         39 . (canceled) 
     
     
         40 . The method of  claim 38 , wherein said LCMV is MP strain, WE strain, Armstrong strain, or Armstrong Clone 13 strain. 
     
     
         41 .- 42 . (canceled) 
     
     
         43 . The method of  claim 1 , wherein the growth or infectivity of said arenavirus particle is not affected by said nucleotide sequence encoding a tumor antigen, tumor associated antigen or an antigenic fragment thereof. 
     
     
         44 . A pharmaceutical composition comprising an arenavirus particle, an immune checkpoint inhibitor and a pharmaceutically acceptable carrier, wherein said arenavirus particle is engineered to contain an arenavirus genomic segment comprising:
 (i) a nucleotide sequence encoding a tumor antigen, tumor associated antigen or an antigenic fragment thereof; and   (ii) at least one arenavirus open reading frame (“ORF”) in a position other than the wild-type position of said ORF, wherein said ORF encodes the glycoprotein (“GP”), the nucleoprotein (“NP”), the matrix protein Z (“Z protein”) or the RNA dependent RNA polymerase L (“L protein”) of said arenavirus particle, and   wherein said immune checkpoint inhibitor inhibits, decreases or interferes with the activity of a negative checkpoint regulator.   
     
     
         45 - 79 . (canceled) 
     
     
         80 . A kit comprising one or more containers and instructions for use, wherein said one or more containers comprise said pharmaceutical composition of  claim 44 . 
     
     
         81 . A kit comprising two or more containers and instructions for use, wherein one of said containers comprises an arenavirus particle and another of said containers comprises an immune checkpoint inhibitor, wherein said arenavirus particle is engineered to contain an arenavirus genomic segment comprising:
 a. a nucleotide sequence encoding a tumor antigen, tumor associated antigen or an antigenic fragment thereof; and   b. at least one arenavirus open reading frame (“ORF”) in a position other than the wild-type position of said ORF, wherein said ORF encodes the glycoprotein (“GP”), the nucleoprotein (“NP”), the matrix protein Z (“Z protein”) or the RNA dependent RNA polymerase L (“L protein”) of said arenavirus particle, and   wherein said immune checkpoint inhibitor inhibits, decreases or interferes with the activity of a negative checkpoint regulator.   
     
     
         82 - 116 . (canceled) 
     
     
         117 . The method of  claim 1 , wherein said immune checkpoint inhibitor inhibits, decreases or interferes with the activity of a negative checkpoint regulator. 
     
     
         118 . The method of  claim 1 , wherein said immune checkpoint inhibitor is an antibody that binds to or inhibits activity of Programmed cell death 1 (PD1). 
     
     
         119 . The method of  claim 1 , wherein said immune checkpoint inhibitor is an antibody that binds to or inhibits activity of Programmed cell death ligand 1 (PD-L1), Cytotoxic T-lymphocyte antigen-4 (CTLA4), T-cell membrane protein 3 (TIM-3), Lymphocyte activation gene-3 (LAG-3), or T-Cell immunoreceptor with Ig and ITIM domains (TIGIT). 
     
     
         120 . The method of  claim 1 , wherein said arenavirus particle encodes a neoantigen. 
     
     
         121 . (canceled) 
     
     
         122 . The method of  claim 1 , wherein said arenavirus particle encodes a melanoma antigen. 
     
     
         123 - 125 . (canceled) 
     
     
         126 . The method of  claim 120 , wherein said subject is suffering from colon cancer. 
     
     
         127 . The method of  claim 122 , wherein said subject is suffering from melanoma. 
     
     
         128 . The method of  claim 120 , wherein said immune checkpoint inhibitor is an antibody that binds to or inhibits activity of Programmed cell death 1 (PD 1). 
     
     
         129 . (canceled)