received by the International Bureau on 27 July 2016.

We claim:

1. A composition comprising an immunogenic agent that is or comprises a neoepitope recognizable by a human patient's immune system as non-self, wherein the patient is suffering from cancer characterized by one or more tumors expressing the neoepitope.

2. The composition of claim 1, wherein, the neoepitope shares a consensus sequence with an infectious agent.

3. The composition of claim 1, wherein the neoepitope is or comprises a nonamer neoepitope.

4. The composition of claim 1, wherein the neoepitope shows increased binding affinity to MHC class I molecules or improved recognition by cytotoxic T cells.

5. The composition of claim 1, wherein the neoepitope has greater binding affinity to a major histocompatibility complex (MHC) molecule compared to a corresponding wildtype epitope that is not a neoepitope specifically associated with the one or more tumors.

6. The composition of claim 1, wherein the immunogenic agent is or comprises a peptide.

7. The composition of claim 1 or claim 6, wherein the immunogenic agent has a length appropriate for MHC presentation. 105

8 The composition of claim 7, wherein the length is that appropriate for presentation by

MHC Class I.

9. The composition of claim 8, wherein the length is that of 8- 1 1 amino acids.

10. The composition of claim 7, wherein the length is that appropriate for presentation by MHC Class II.

1 1. The composition of claim 1, wherein the neoepitope has an amino acid sequence selected from those set forth in Figure 21.

12. The composition of claim 1, wherein the cancer is or comprises a cancer selected from the group comprising: carcinoma, sarcoma, myeloma, leukemia, or lymphoma.

13. The composition of claim 12, wherein the cancer is selected from a group comprising: lung carcinoma, melanoma, renal carcinoma, bladder carcinoma, small cell carcinoma, and head and neck cancer.

14. The composition of claim 13, wherein the cancer is or comprises lung carcinoma.

15. A composition comprising a nucleic acid whose sequence comprises coding sequence for a neoepitope recognizable by a human patient's immune system as non-self, wherein the patient is suffering from cancer characterized by one or more tumors expressing the neoepitope. 106

16. The composition of claim 15, wherein, the neoepitope shares a consensus sequence with an infectious agent.

17. The composition of claim 15, wherein the neoepitope is or comprises a nonamer neoepitope.

18. The composition of claim 15, wherein the neoepitope shows increased binding affinity to MHC class I molecules or improved recognition by cytotoxic T cells.

19. The composition of claim 15, wherein the neoepitope has greater binding affinity to a major histocompatibility complex (MHC) molecule compared to a corresponding wildtype epitope that is not a neoepitope specifically associated with the one or more tumors.

20. The composition of claim 15, wherein the neoepitope has a length appropriate for MHC presentation.

21. The composition of claim 20, wherein the length is that appropriate for presentation by MHC Class I.

22. The composition of claim 21, wherein the length is that of 8- 11 amino acids.

23. The composition of claim 20, wherein the length is that appropriate for presentation by MHC Class II. 107

24. The composition of claim 15, wherein the neoepitope has an amino acid sequence selected from those set forth in Figure 21.

25. The composition of claim 15, wherein the cancer is or comprises a cancer selected from the group comprising: carcinoma, sarcoma, myeloma, leukemia, or lymphoma.

26. The composition of claim 25, wherein the cancer is selected from a group comprising: lung carcinoma, melanoma, renal carcinoma, bladder carcinoma, small cell carcinoma, and head and neck cancer.

27. The composition of claim 15, wherein the cancer is or comprises lung carcinoma.

28. A composition comprising a nucleic acid that hybridizes with a nucleic acid encoding a neoepitope recognizable by a human patient's immune system as non-self, wherein the patient is suffering from cancer characterized by one or more tumors expressing the neoepitope.

29. The composition of claim 15 or claim 28, wherein the nucleic acid is capable of detecting the neoepitope, or expression thereof, at the nucleic acid level.

30. The composition of claim 28, wherein, the neoepitope shares a consensus sequence with an infectious agent.

31. The composition of claim 28, wherein the neoepitope is or comprises a nonamer neoepitope. 108

32. The composition of claim 28, wherein the neoepitope shows increased binding affinity to MHC class I molecules or improved recognition by cytotoxic T cells.

33. The composition of claim 28, wherein the neoepitope has greater binding affinity to a major histocompatibility complex (MHC) molecule compared to a corresponding otherwise identical epitope that is not a neoepitope specifically associated with the one or more tumors.

34. The composition of claim 28, wherein the neoepitope has a length appropriate for MHC presentation.

35. The composition of claim 28, wherein the length is that appropriate for presentation by MHC Class I.

36. The composition of claim 35, wherein the length is that of 8-11 amino acids.

37. The composition of claim 28, wherein the length is that appropriate for presentation by MHC Class II.

38. The composition of claim 28, wherein the neoepitope has an amino acid sequence selected from those set forth in Figure 21.

39. The composition of claim 28, wherein the cancer is or comprises a cancer selected from the group comprising: carcinoma, sarcoma, myeloma, leukemia, or lymphoma. 109

40. The composition of claim 39, wherein the cancer is selected from a group comprising: lung carcinoma, melanoma, renal carcinoma, bladder carcinoma, small cell carcinoma, and head and neck cancer.

41. The composition of claim 28, wherein the cancer is or comprises lung carcinoma.

42. A composition comprising an agent that specifically detects a neoepitope recognizable by a human patient's immune system as non-self, wherein the patient is suffering from cancer characterized by one or more tumors expressing the neoepitope.

43. The composition of claim 42, wherein the agent specifically detects the neoepitope at the protein level.

44. The composition of claim 42, wherein the agent specifically detects the neoepitope at the nucleic acid level.

45. The composition of claim 42, wherein, the neoepitope shares a consensus sequence with an infectious agent.

46. The composition of claim 42, wherein the neoepitope is or comprises a nonamer neoepitope.

47. The composition of claim 42, wherein the neoepitope shows increased binding affinity to MHC class I molecules or improved recognition by cytotoxic T cells. 110

48. The composition of claim 42, wherein the neoepitope has greater binding affinity to a major histocompatibility complex (MHC) molecule compared to a corresponding otherwise identical epitope that is not a neoepitope specifically associated with the one or more tumors.

49. The composition of claim 42, wherein the neoepitope has a length appropriate for MHC presentation.

50. The composition of claim 49, wherein the length is that appropriate for presentation by MHC Class I.

51. The composition of claim 50, wherein the length is that of 8- 11 amino acids.

52. The composition of claim 49, wherein the length is that appropriate for presentation by MHC Class II.

53. The composition of claim 42, wherein the neoepitope has an amino acid sequence selected from those set forth in Figure 21.

54. The composition of claim 42, wherein the cancer is or comprises a cancer selected from the group comprising: carcinoma, sarcoma, myeloma, leukemia, or lymphoma.

55. The composition of claim 54, wherein the cancer is selected from a group comprising: lung carcinoma, melanoma, renal carcinoma, bladder carcinoma, small cell carcinoma, and head and neck cancer. 111

56. The composition of claim 42, wherein the cancer is or comprises lung carcinoma.

57. A method of treating cancer comprising steps of: administering to a subject determined to have cancer characterized by a tumor expressing one or more nonamer neoepitopes a therapy that enhances neoantigen-specific effector T-cell response.

58. The method of claim 57, wherein the subject is receiving or will receive therapy with an immune checkpoint modulator.

59. The method of claim 57, wherein the subject has established tumors.

60. The method of claim 57, wherein the cancer is or comprises a cancer selected from the group comprising: carcinoma, sarcoma, myeloma, leukemia, or lymphoma.

61. The method of claim 60, wherein the cancer is selected from a group comprising: lung carcinoma, melanoma, renal carcinoma, bladder carcinoma, small cell carcinoma, and head and neck cancer.

62. The method of claim 57, wherein the cancer is or comprises lung carcinoma.

63. The method of claim 57, wherein the therapy is or comprises an immune checkpoint modulator. 112

64. A method comprising steps of: detecting a marker of high mutations in a cancer sample from a subject; and identifying the subject as a candidate for treatment with an immune checkpoint modulator.

65. The method of claim 64, wherein the step of detecting comprises sequencing one or more exomes from the cancer sample.

66. The method of claim 64, wherein the number of mutations identifies the subject as a candidate for treatment with an immune checkpoint modulator.

67. The method of claim 66, wherein a high number of mutations identifies the subject as a candidate for treatment with an immune checkpoint modulator.

68. The method of claim 67, wherein a high number of nonsynonymous mutations identifies the subject as a candidate for treatment with an immune checkpoint modulator.

69. The method of claim 64, wherein the ratio of transition mutations to transversion mutations identifies the subject as a candidate for treatment with an immune checkpoint modulator.

70. The method of claim 69, wherein the ratio comprises the molecular smoking signature.

71. The method of claim 64, wherein the somatic mutation comprises a neoepitope recognized by a T cell.

72. The method of claim 71, wherein the number of neoepitopes identifies the subject as a candidate for treatment with an immune checkpoint modulator.

73. The method of claim 64 wherein the neoepitopes identifies the subject as a candidate for treatment with an immune checkpoint modulator.

74. The method of claim 73, wherein the neoepitopes are associated with high mutation rate.

75. The method of claim 74, wherein high mutations are present in genes encoding proteins involved in DNA repair.

76. The method of claim 74, wherein high mutations are present in genes encoding proteins involved in cell signal transduction.

77. The method of claim 64, wherein the neoepitope has greater binding affinity to a major histocompatibility complex (MHC) molecule compared to a corresponding epitope that does not have a mutation.

78. The method of claim 64,wherein the somatic mutation comprises a neoepitope comprising a nonamer that is not expressed in the same cell type that does not have a somatic mutation.

79. The method of claim 78, wherein the neoepitope shares a consensus sequence with an infectious agent.

80. The method of claim 64, wherein the cancer is or comprises a cancer selected from the group comprising: carcinoma, sarcoma, myeloma, leukemia, or lymphoma.

81. The method of claim 80, wherein the cancer is selected from a group comprising: lung carcinoma, melanoma, renal carcinoma, bladder carcinoma, small cell carcinoma, and head and neck cancer.

82. The method of claim 64, wherein the immune checkpoint modulator interacts with cytotoxic T-lymphocyte antigen 4 (CTLA4), programmed death 1 (PD-1) or its ligands, lymphocyte activation gene-3 (LAG3), B7 homolog 3 (B7-H3), B7 homolog 4 (B7-H4), indoleamine (2,3)-dioxygenase (IDO), adenosine A2a receptor, neuritin, B- and T- lymphocyte attenuator (BTLA), killer immunoglobulin-like receptors (KIR), T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3), inducible T cell costimulator (ICOS), CD27, CD28, CD40, CD137, or combinations thereof.

83. The method of claim 64, wherein the immune checkpoint modulator is an antibody agent.

84. The method of claim 83, wherein the antibody agent is or comprises a monoclonal antibody or antigen binding fragment thereof.

85. The method of claim 84, wherein the antibody is pembrolizumab. 115

86. The method of claim 64,wherein the subject has not previously been treated with a cancer therapeutic.

87. The method of claim 64, wherein the subject has not previously been treated with a cancer immunotherapeutic.

88. The method of claim 85, further comprising a step of administering pembrolizumab to the subject.

89. A method comprising steps of: detecting a low number of mutations in a cancer sample from a subject; and identifying the subject as a poor candidate for treatment with an immune checkpoint modulator.

90. A method comprising steps of: determining a subject has a cancer comprising a marker of high mutations, wherein the mutations comprises a neoepitope comprising a nonamer, and selecting for the subject a cancer treatment comprising an immune checkpoint modulator.

91. The method of claim 90, wherein the cancer comprises lung carcinoma. 116

92. The method of claim 90, wherein the immune checkpoint modulator interacts with cytotoxic T-lymphocyte antigen 4 (CTLA4), programmed death 1 (PD-1) or its ligands, lymphocyte activation gene-3 (LAG3), B7 homolog 3 (B7-H3), B7 homolog 4 (B7-H4), indoleamine (2,3)-dioxygenase (IDO), adenosine A2a receptor, neuritin, B- and T- lymphocyte attenuator (BTLA), killer immunoglobulin-like receptors (KIR), T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3), inducible T cell costimulator (ICOS), CD27, CD28, CD40, CD137, or combinations thereof.

93. The method of claim 92, wherein the immune checkpoint modulator is an antibody agent.

94. The method of claim 93, wherein the antibody agent is or comprises a monoclonal antibody or antigen binding fragment thereof.

95. The method of claim 94, wherein the antibody is pembrolizumab.

96. The method of claim 90, wherein the subject has not previously been treated with a cancer therapeutic.

97. The method of claim 90, wherein the subject has not previously been treated with a cancer immunotherapeutic.

98. A method of treating a subject with an immune checkpoint modulator wherein the subject has previously been identified to have a cancer with a high marker of mutations, wherein the one mutations comprise a neoepitope recognized by a T cell. 117

99. The method of claim 98, wherein the cancer comprises lung carcinoma.

100. The method of claim 98, wherein the immune checkpoint modulator interacts with cytotoxic T-lymphocyte antigen 4 (CTLA4), programmed death 1 (PD-1) or its ligands, lymphocyte activation gene-3 (LAG3), B7 homolog 3 (B7-H3), B7 homolog 4 (B7-H4), indoleamine (2,3)-dioxygenase (IDO), adenosine A2a receptor, neuritin, B- and T- lymphocyte attenuator (BTLA), killer immunoglobulin-like receptors (KIR), T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3), inducible T cell costimulator (ICOS), CD27, CD28, CD40, CD137, or combinations thereof.

101. The method of claim 98, wherein the immune checkpoint modulator is an antibody agent.

102. The method of claim 101, wherein the antibody agent is or comprises a monoclonal antibody or antigen binding fragment thereof.

103. The method of claim 102, wherein the antibody is pembrolizumab.

104. The method of claim 98, wherein the subject has not previously been treated with a cancer therapeutic.

105. The method of claim 98, wherein the subject has not previously been treated with a cancer immunotherapeutic. 118

106. A method of improving efficacy of cancer therapy with an immune checkpoint modulator, the method comprising a step of: selecting for receipt of the therapy a subject identified as having a cancer with markers of high mutation comprising a neoepitope recognized by a T cell.

107. In a method of treating cancer by administering immune checkpoint modulator therapy, the improvement that comprises: administering the therapy to a subject identified as having a cancer with one or more markers of high mutation comprising a neoepitope recognized by a T cell.

108. A method of treating a cancer selected from the group consisting of carcinoma, sarcoma, myeloma, leukemia, or lymphoma, the method comprising a step of: administering immune checkpoint modulator therapy to a subject identified as having a cancer with a marker of high mutations comprising a neoepitope recognized by a T cell.

109. The method of claim 108, wherein the cancer is or comprises lung carcinoma.

110. A method of defining a mutation signature that correlates with responsiveness to therapy with an immune checkpoint modulator, the method comprising: determining one or more mutation characteristics in a plurality of samples of tumors sharing a response characteristic to immune checkpoint modulator therapy; comparing the determined one or more mutation characteristics with those in a plurality of samples of tumors that do not share the response characteristic; and identifying a set of mutation characteristics whose presence correlates with the response characteristic. 119

111. The method of claim 110, wherein the one or more mutation characteristics include a mutation characteristic selected from the group consisting of mutation burden,

nonsynonymous mutation burden, neoantigen burden, transversion burden, transition burden, relative transversion vs transition burden, mutation burden in genes associated with DNA repair, presence of mutation in one or more particular genes associated with DNA repair, identity of mutation in one or more particular genes associated with DNA repair, and combinations thereof.

112. The method of claim 111, wherein the determined burden is or comprises rate or number.

113. The method of claim 111, wherein the genes associated with DNA repair are or include a genes selected from the group consisting of POLD1, PRKDC, DNA-PK, RAD 17, POLE, and MSH2.

114. The method of any one of claims 111-113, wherein the response characteristic is or comprises a characteristic selected from the group consisting of partial or stable response lasting longer than 6 months ("durable clinical benefit"; "DCB"), a reduction in tumor size for more than 4 weeks ("objective response rate"; "ORR"); no disease progression for more than 9 weeks ("progression-free survival"; "PFS"), and combinations thereof.

115. A method of characterizing a tumor sample by determining presence of a set of mutation characteristics that correlates with a response characteristic to immune checkpoint modulator therapy.

116. The method of claim 115, wherein the set of mutation characteristics includes a mutation characteristic selected from the group consisting of mutation burden,

nonsynonymous mutation burden, neoantigen burden, transversion burden, transition burden, 120

relative transversion vs transition burden, mutation burden in genes associated with DNA repair, presence of mutation in one or more particular genes associated with DNA repair, identity of mutation in one or more particular genes associated with DNA repair, and combinations thereof.

117. The method of claim 1 16, wherein the determined burden is or comprises rate or number.

1 18. The method of claim 1 16, wherein the genes associated with DNA repair are or include genes selected from the group consisting of POLD 1, PRKDC, DNA-PK, RAD 17, POLE, and MSH2.

119. The method of any one of claims 1 15-1 17, wherein the response characteristic is or comprises a characteristic selected from the group consisting of partial or stable response lasting longer than 6 months ("durable clinical benefit"; "DCB"), a reduction in tumor size for more than 4 weeks ("objective response rate"; "ORR"); no disease progression for more than 9 weeks ("progression-free survival"; "PFS"), and combinations thereof.

120. The method of any one of claims 1 15-1 18, wherein the setp of determining comprises detecting at least one of the mutation characteristics by nucleic acid sequencing.

121. The method of claim 1 19, wherein the nucleic acid sequencing is or comprises whole exome sequencing.