Combination therapy with neoantigen vaccine

Abstract

The present invention relates to neoplasia vaccine or immunogenic composition administered in combination with other agents, such as checkpoint blockade inhibitors for the treatment or prevention of neoplasia in a subject.

1 - 47 . (canceled) 
     
     
         48 . A method of treating a neoplasia in a subject in need thereof comprising:
 (A) administering a cell therapy, wherein the cell therapy comprises 
 (1) antigen presenting cells (APCs) comprising:
 (i) one or more polypeptides comprising at least two peptide sequences calculated by an HLA peptide binding analysis using a program implemented on a computer system to have a binding affinity to a protein encoded by an HLA allele of the subject with an IC50 of less than 500 nM, or 
 (ii) one or more polynucleotides encoding the at least two peptide sequences; or 
 
 (2) T cells stimulated with APCs comprising (i) or (ii); 
 wherein the at least two peptide sequences are encoded by a plurality of cancer specific nucleic acid sequences that are identified as being specific to cancer cells of the subject; 
 wherein the plurality of cancer specific nucleic acid sequences that are identified as being specific to cancer cells of the subject encodes two or more different peptide sequences of two or more different proteins that are expressed by the cancer cells; 
 wherein two or more different peptide sequences of two or more different proteins comprise a cancer-specific amino acid mutation that is not present in non-cancer cells from the subject, and 
   (B) administering at least one checkpoint inhibitor, wherein the at least one checkpoint inhibitor is nivolumab or pembrolizumab.   
     
     
         49 . The method of  claim 48 , wherein the at least two peptide sequences comprises at least three, at least four or at least five peptides sequences. 
     
     
         50 . The method of  claim 48 , wherein the at least two peptide sequences ranges from 5 to 50 amino acids in length. 
     
     
         51 . The method of  claim 48 , wherein
 (i) the subject is suffering from a neoplasia selected from the group consisting of: Non-Hodgkin’s Lymphoma (NHL), clear cell Renal Cell Carcinoma (ccRCC), melanoma, sarcoma, leukemia or a cancer of the bladder, colon, brain, breast, head and neck, endometrium, lung, ovary, pancreas or prostate,;   (ii) the subject has no detectable neoplasia but is at high risk for disease recurrence; or   (iii) the subject has previously undergone autologous hematopoietic stem cell transplant (AHSCT).   
     
     
         52 . The method of  claim 48 , wherein the neoplasia is metastatic. 
     
     
         53 . The method of  claim 48 , wherein
 (i) administration of the checkpoint inhibitor is initiated before initiation of administration of the cell therapy,   (ii) administration of the checkpoint inhibitor is withheld during the week prior to administration of the cell therapy, or is withheld during administration of the cell therapy;   (iii) administration of the checkpoint inhibitor is initiated after initiation of administration of the cell therapy;   (iv) administration of the checkpoint inhibitor is initiated simultaneously with the initiation of administration of the cell therapy, or   (iv) administration of the immune checkpoint inhibitor is initiated following tumor resection.   
     
     
         54 . The method of  claim 48 , wherein
 (i) administration of the checkpoint inhibitor continues every 2-8 or more weeks after the first administration of the checkpoint inhibitor, p   (ii) administration of the checkpoint inhibitor continues every 2, 3 or 4, 6 or 8 weeks after the first administration of the checkpoint inhibitor;   (iii) administration of the checkpoint inhibitor is initiated following tumor resection;   (iv) administration of the cell therapy is initiated 1-15 weeks after tumor resection; or   (v) administration of the cell therapy is initiated 4-12 weeks after tumor resection.   
     
     
         55 . The method of  claim 48 , wherein the cell therapy is administered intravenously. 
     
     
         56 . The method of  claim 48 , further comprising administration of one or more additional agents, wherein the one or more additional agents
 (i) are selected from the group consisting of: chemotherapeutic agents, anti-angiogenesis agents and agents that reduce immune-suppression;   (ii) are one or more anti-glucocorticoid induced tumor necrosis factor family receptor(GITR) agonistic antibodies or   (iii) is an anti-CTLA-4 antibody.   
     
     
         57 . The method of  claim 48 , wherein the cell therapy comprises APCs comprising (i) or (ii), and the APCs are from the subject. 
     
     
         58 . The method of  claim 48 , wherein the cell therapy comprises T cells stimulated with APCs comprising (i) or (ii), and the T cells are from the subject. 
     
     
         59 . The method of  claim 48 , wherein the cell therapy comprises the T cells and a pharmaceutically acceptable carrier or excipient. 
     
     
         60 . The method of  claim 48 , wherein the cell therapy comprises APCs comprising (i) or (ii), and the APCs are not from the subject. 
     
     
         61 . The method of  claim 48 , wherein the cell therapy comprises T cells stimulated with APCs comprising (i) or (ii), and the T cells are not from the subject. 
     
     
         62 . The method of  claim 48 , wherein the bladder cancer is bladder carcinoma. 
     
     
         63 . The method of  claim 48 , wherein the bladder cancer is a cancer of the renal pelvis or ureter. 
     
     
         64 . The method of  claim 48 , wherein the melanoma is metastatic melanoma. 
     
     
         65 . The method of  claim 48 , wherein the subject has not been treated previously and has metastatic melanoma. 
     
     
         66 . The method of  claim 48 , wherein the at least two peptide sequences ranges from 15 to 35 amino acids in length. 
     
     
         67 . The method of  claim 48 , wherein one or more polypeptides comprising at least two peptide sequences calculated by an HLA peptide binding analysis using a program implemented on a computer system to have a binding affinity to a protein encoded by an HLA allele of the subject with an IC50 of less than 150 nM. 
     
     
         68 . The method of  claim 48 , wherein the at least two peptide sequences are identified by
 a. whole genome or whole exome nucleic acid sequencing of a nucleic acid sample of the subject’s tumor and of a non-tumor sample of the subject; and   b. identifying at least 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 of non-silent tumor mutations, wherein the mutations are present in the genome of cancer cells of the subject but not in normal tissue from the subject, wherein the non-silent mutations are determined by analysis of the sequences obtained by the whole genome or whole exome nucleic acid sequencing.   
     
     
         69 . The method of  claim 48 , wherein the at least one checkpoint inhibitor is administer prior to administering the cell therapy. 
     
     
         70 . The method of  claim 48 , wherein the subject is not immuno-compromised by a previous cancer-directed therapy. 
     
     
         71 . The method of  claim 48 , wherein the at least one checkpoint inhibitor is administered intravenously.