Compositions and methods of identifying tumor specific neoantigens

Abstract

The present invention related to immunotherapeutic peptides and their use in immunotherapy, in particular the immunotherapy of cancer. Specifically, the invention provides a method of identifying tumor specific neoantigens that alone or in combination with other tumor-associated peptides serve as active pharmaceutical ingredients of vaccine compositions which stimulate anti-tumor responses.

What is claimed: 
     
         1 . A method of treating cancer in a subject in need thereof comprising administering to the subject (a) a personal pharmaceutical composition comprising:
 a therapeutic amount of a plurality of cancer neoantigen peptides or one or more polynucleotides encoding the plurality of cancer neoantigen peptides,
 wherein each of the cancer neoantigen peptides or a portion thereof binds to a protein encoded by an HLA allele expressed by the subject and is encoded by at least one expressed gene of the subject's cancer cells, and 
 wherein at least one of the cancer neoantigen peptides or a portion thereof comprises one or more mutations that are not present in a normal tissue of the subject; and 
   (b) an anti-immunosuppressive agent or immunostimulatory agent;   wherein (a) and (b) are administered simultaneously or sequentially.   
     
     
         2 . The method of  claim 1 , wherein the anti-immunosuppressive agent or immunostimulatory agent is an anti-CTLA agent, an anti-PD-1 agent, an anti-PD-L1 agent or a combination thereof. 
     
     
         3 . The method of  claim 1 , wherein the cancer is a solid tumor. 
     
     
         4 . The method of  claim 1 , wherein the cancer is melanoma, lung cancer, or bladder cancer. 
     
     
         5 . The method of  claim 1 , wherein at least one of the one or more mutations is:
 (A) a point mutation and the cancer neoantigen peptide binds to the protein encoded by an HLA allele expressed by the subject with an IC 50  less than 500 nM and a greater affinity than a corresponding wild-type peptide,   (B) a splice-site mutation,   (C) a frameshift mutation,   (D) a read-through mutation, or   (E) a gene-fusion mutation.   
     
     
         6 . The method of  claim 1 , wherein each cancer neoantigen peptide has a length of from 8 to 50 naturally occurring amino acids. 
     
     
         7 . The method of  claim 1 , wherein at least one of the cancer neoantigen peptides has a length of at least 10 naturally occurring amino acids. 
     
     
         8 . The method of  claim 1 , wherein an immune response is elicited in the subject. 
     
     
         9 . The method of  claim 1 , wherein administering comprises intravenous injection, sub-cutaneous injection, intradermal injection, intraperitoneal injection, or intramuscular injection. 
     
     
         10 . The method of  claim 1 , wherein the personal pharmaceutical composition comprises a plurality of cancer neoantigen peptides and each of the cancer neoantigen peptides is present in the composition at an amount of from 50 μg to 1.5 mg. 
     
     
         11 . The method of  claim 1 , wherein a first cancer neoantigen peptide of the plurality binds to a protein encoded by a first HLA allele expressed by the subject and a second cancer neoantigen peptide of the plurality binds to a protein encoded by a second HLA allele expressed by the subject, wherein the first and second HLA alleles expressed by the subject are different HLA alleles. 
     
     
         12 . The method of  claim 1 , wherein the personal pharmaceutical composition further comprises an immuno-effective amount of an adjuvant. 
     
     
         13 . The method of  claim 1 , wherein the plurality of cancer neoantigen peptides comprises at least 4 cancer neoantigen peptides. 
     
     
         14 . The method of  claim 1 , wherein the plurality of cancer neoantigen peptides comprises at least 8 cancer neoantigen peptides. 
     
     
         15 . The method of  claim 1 , wherein at least one of the cancer neoantigen peptides is linked to a peptide epitope that induces a helper T cell response, or wherein the one or more polynucleotides comprises a sequence encoding a peptide epitope that induces a helper T cell response that is operatively linked to a sequence encoding at least one of the plurality of cancer neoantigen peptides. 
     
     
         16 . The method of  claim 1 , wherein the personal pharmaceutical composition comprises a plurality of cancer neoantigen peptides, wherein at least one of the cancer neoantigen peptides is a synthetic peptide. 
     
     
         17 . The method of  claim 1 , wherein the personal pharmaceutical composition comprises one or more polynucleotides encoding the plurality of cancer neoantigen peptides, wherein the one or more polynucleotides are DNA or mRNA. 
     
     
         18 . The method of  claim 1 , wherein at least one of the cancer neoantigen peptides binds to the protein encoded by the HLA allele expressed by the subject with an IC 50  of less than 250 nM. 
     
     
         19 . The method of  claim 1 , wherein at least one of the cancer neoantigen peptides binds to the protein encoded by the HLA allele expressed by the subject with an IC 50  of less than 100 nM 
     
     
         20 . A kit, comprising
 (a) a first component comprising a plurality of cancer neoantigen peptides or one or more polynucleotides encoding the plurality of cancer neoantigen peptides,
 wherein each of the cancer neoantigen peptides or a portion thereof binds to a protein encoded by an HLA allele expressed by the subject and 
   is encoded by at least one expressed gene of the subject's cancer cells; and
 wherein at least one of the cancer neoantigen peptides or a portion thereof comprises one or more mutations that are not present in a normal tissue of the subject; and 
   (b) a second component comprising an anti-immunosuppressive agent or immunostimulatory agent.   
     
     
         21 . A combination therapy comprising
 (a) a plurality of cancer neoantigen peptides or one or more polynucleotides encoding the plurality of cancer neoantigen peptides,
 wherein each of the cancer neoantigen peptides or a portion thereof binds to a protein encoded by an HLA allele expressed by the subject; and 
   is encoded by at least one expressed gene of the subject's cancer cells; and
 wherein at least one of the cancer neoantigen peptides or a portion thereof comprises one or more mutations that are not present in a normal tissue of the subject; and 
   (b) an anti-immunosuppressive agent or immunostimulatoryagent.