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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 ac

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.

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1. A method of identifying subject-specific peptides and preparing a subject-specific immunogenic composition comprising said subject-specific peptides that upon administration presents said subject-specific peptides to the subject's immune system, wherein the subject has a tumor and said subject-sp

1. A method of identifying subject-specific peptides and preparing a subject-specific immunogenic composition comprising said subject-specific peptides that upon administration presents said subject-specific peptides to the subject's immune system, wherein the subject has a tumor and said subject-specific peptides are specific to the subject and the subject's tumor, said method comprising: sequencing nucleic acid sample of the subject's tumor and of a non-tumor sample of the subject,identifying 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 sequences comprising tumor-specific non-silent mutations not present in the non-tumor sample;producing 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 subject-specific peptides encoded by said 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 sequences comprising tumor-specific non-silent mutations non present in the non-tumor samplemeasuring binding of said produced subject-specific peptides to a HLA protein of said subject,wherein each of said subject-specific peptides has a different tumor neo-epitope that is an epitope specific to the tumor of the subject, from the neo-epitopes identified in tumor specific mutations,wherein each neo-epitope is an expression product of a tumor-specific non-silent mutation not present in the non-tumor sample and each neo-epitope binds to a HLA protein of the subject,wherein said subject-specific peptides have a point mutation and bind to HLA proteins of the subject with an IC50 less than 500 nM;formulating said subject-specific immunogenic composition for administration to the subject so that upon administration said 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 subject-specific peptides are presented to the subject's immune system,wherein said immunogenic composition comprises:said 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 subject-specific peptides, comprising:(1) a peptide that has a non-synonymous mutation leading to different amino acids in comparison with a protein of the non-tumor sample; or(2) a peptide having a read-through mutation in which a stop codon is modified or deleted, leading to translation of a longer protein in comparison with a protein of the non-tumor sample with a novel tumor-specific sequence at the C-terminus; or(3) a peptide that has a splice site mutation that leads to the inclusion of an intron in the mature mRNA and thus has a unique tumor-specific protein sequence; or(4) a peptide representing a chromosomal rearrangement that has Given rise to a chimeric protein with tumor-specific sequences at the junction of two proteins of the non-tumor sample and thus represents a gene fusion;or (5) a peptide representing in comparison with a protein of the non-tumor sample a frameshift mutation or deletion that leads to a new open reading frame and a novel tumor-specific protein sequence. 2. The method of claim 1, wherein the subject-specific immunogenic composition comprises a subject-specific peptide about 8 to 50 amino acids in length. 3. The method of claim 1, wherein the subject-specific immunogenic composition comprises a subject-specific peptide greater than 15 amino acids in length. 4. The method of claim 1, wherein the subject-specific immunogenic composition comprises a subject-specific peptide about 24-40 amino acids in length. 5. The method of claim 1, wherein the subject-specific immunogenic composition comprises a subject-specific peptide that activates anti-tumor CM T cells. 6. The method of claim 1, wherein the subject-specific immunogenic composition comprises a subject-specific peptide that binds to the HLA protein of the subject with an IC50 less than 250 nM. 7. The method of claim 1, wherein the subject-specific immunogenic composition comprises a subject-specific peptide that binds to the HLA protein of the subject with an IC50 less than 100 nM. 8. The method of claim 1, wherein the subject-specific immunogenic composition comprises a subject-specific peptide that binds to the HLA protein of the subject with an IC50 less than ˜50 nM. 9. The method of any one of claims 1 to 8, wherein the measuring of binding of the subject-specific peptides to the HLA protein comprises measuring binding of the subject-specific peptides to a class I HLA protein of the subject. 10. The method of claim 1, wherein the formulating comprises preparing the composition for administering in conjunction with at least one adjuvant. 11. The method of claim 1, wherein the formulating comprises preparing the composition for administering in conjunction with at least one adjuvant, wherein the adjuvant is administered separately. 12. The method of claim 1, wherein the formulating comprises preparing the composition for administering in conjunction with at least one adjuvant, wherein preparing comprises including the adjuvant in the subject-specific immunogenic composition. 13. The method of claim 1, wherein the formulating comprises preparing the composition for administering in conjunction with at least one carrier, wherein preparing comprises including the carrier in the subject-specific immunogenic composition. 14. The method of claim 1, wherein the formulating comprises preparing the composition for administering in conjunction with another anti-cancer therapeutic agent. 15. The method of claim 1, wherein the formulating comprises preparing the composition for administering in conjunction with an anti-immunosuppressive/immunostimulatory agent. 16. The method of claim 1, wherein the formulating comprises preparing the composition for administering in conjunction with an anti-immunosuppressive/immunostimulatory agent that provides CTLA4 PD-1 or PD-L 1 blockade. 17. The method of claim 1, wherein the formulating comprises preparing the composition for administering in conjunction with an anti-immunosuppressive/immunostimulatory agent comprising an anti-CTLA4 antibody or an anti-PD 1 antibody or an anti-Pb-L 1 antibody. 18. The method of any one of claims 15-17, wherein the formulating comprises preparing the composition for administering in conjunction with at least one adjuvant. 19. The method of any one of claims 15-17, wherein the formulating comprises preparing the composition for administering in conjunction with at least one adjuvant, wherein the adjuvant is administered separately. 20. The method of any one of claims 15-17, wherein the formulating comprises preparing the composition for administering in conjunction with at least one adjuvant, wherein preparing comprises including the adjuvant in the subject-specific immunogenic composition. 21. The method of claim 18, wherein the formulating comprises preparing the composition for administering in conjunction with at least one carrier, wherein the preparing comprises including the carrier in the subject-specific immunogenic composition. 22. The method of claim 19, wherein the formulating comprises preparing the composition for administering in conjunction with at least one carrier, wherein the preparing comprises including the carrier in the subject-specific immunogenic composition. 23. The method of claim 20, wherein the formulating comprises preparing the composition for administering in conjunction with at least one carrier, wherein the preparing comprises including the carrier in the subject-specific immunogenic composition. 24. The method of any one of claims 15-17, wherein the formulating comprises preparing the composition for administering in conjunction with another anti-cancer therapeutic agent. 25. The method of claim 18, wherein formulating comprises preparing the composition for administering in conjunction with another anti-cancer therapeutic agent. 26. The method of claim 19, wherein the formulating comprises preparing the composition for administering in conjunction with another anti-cancer therapeutic agent. 27. The method of claim 20, wherein the formulating comprises preparing the composition for administering in conjunction with another anti-cancer therapeutic agent. 28. The method of claim 21, wherein the formulating comprises preparing the composition for administering in conjunction with another anti-cancer therapeutic agent. 29. The method of claim 22, wherein the formulating comprises preparing the composition for administering in conjunction with another anti-cancer therapeutic agent. 30. The method of claim 23, wherein the formulating comprises preparing the composition for administering in conjunction with another anti-cancer therapeutic agent. 31. The method of claim 1, wherein the formulating comprises including an expression product of an identified new open reading frame. 32. The method of claim 1, wherein the formulating comprises including an expression product of an identified point mutation and binds to the HLA protein of the subject with an IC50 less than 500 nM. 33. The method of claim 1 wherein the measuring of binding of the subject-specific peptides to the HLA protein comprises in vitro testing of peptide binding to HLA protein. 34. The method of claim 1, wherein the selecting identifying subject specific sequences or formulating comprises determining expression levels of at least one subject-specific peptide in cancerous tissue of the subject and including in the subject specific-composition the subject specific-peptide when expressed in a relatively high amount in the cancerous tissue of the subject. 35. The method of claim 1, wherein the formulating comprises preparing the composition for presenting to the subject's immune system a subject-specific peptide by expression thereof in vivo by a vector. 36. The method of claim 1, wherein the formulating comprises preparing the composition for presenting to the subject's immune system a subject-specific peptide by expression thereof in vivo by a nucleic acid molecule vector. 37. The method of claim 1, wherein the formulating comprises preparing the composition for presenting to the subject's immune system a subject-specific peptide by expression thereof in vivo by a viral vector. 38. The method of claim 1, wherein the formulating comprises preparing the composition for presenting to the subject's immune system a subject-specific peptide by administration thereof through the immunogenic composition comprising the subject-specific peptide. 39. The method of claim 1, wherein the presenting to the subject's immune system comprises a subject-specific peptide eliciting a T-cell. 40. The method of claim 39, further comprising isolating the T-cell from the subject. 41. The method of claim 40, further comprising expanding the isolated T-cell. 42. The method of claim 1, wherein the tumor is a solid tumor. 43. The method of claim 1, wherein the tumor is a hematological tumor. 44. The method of claim 1, wherein the tumor is a breast tumor, an ovarian tumor, a prostate tumor, a lung tumor, a kidney tumor, a gastric tumor, a colon tumor, a testicular tumor, a head and neck tumor, a pancreatic tumor, a brain tumor, a melanoma, a lymphoma or a leukemia. 45. The method of claim 1, wherein the tumor is a melanoma. 46. The method of claim 1, wherein the tumor is a leukemia.