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1. WO2020205644 - CANCER BIOMARKERS FOR DURABLE CLINICAL BENEFIT

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CLAIMS

WHAT IS CLAIMED IS:

1. A method of treating a patient having a tumor comprising:

(a) determining if a sample collected from the patient is positive or negative for a biomarker which predicts that the patient is likely to have an anti-tumor response to a first therapeutic agent comprising (i) a one or more peptides comprising a neoepitope of a protein, (ii) a polynucleotide encoding the one or more peptides, (iii) one or more APCs comprising the one or more peptides or the polynucleotide encoding the one or more peptides, or (iv) a T cell receptor (TCR) specific for a neoepitope of the one or more peptides in complex with an HLA protein, and

(b) treating the patient with a therapeutic regimen that comprises the first therapeutic agent if the biomarker is present; or treating the patient with a therapeutic regimen that does not include the first therapeutic agent if the biomarker is absent, wherein the biomarker comprises a tumor microenvironment (TME) signature.

2. The method of claim 1, wherein the TME gene signature comprises a B-cell signature, a Tertiary Lymphoid Structures (TLS) signature, a Tumor Inflammation Signature (TIS), an effector/memory-like CD8+T cell signature, an HLA-E/CD94 signature, a NK cell signature, an MHC class II signature or a functional Ig CDR3 signature.

3. The method of claim 1 or 2, wherein the B-cell signature comprises expression of a gene comprising CD20, CD21, CD3, CD22, CD24, CD27, CD38, CD40, CD72, CD79a, IGKC, IGHD, MZB1, MS4A1, CD138, BLK, CD19, FAM30A, FCRL2, MS4A1, PNOC, SPIB, TCL1A, TNFRSF17 or combinations thereof.

4. The method of claim 1 or 2, wherein the TLS signature indicates formation of tertiary

lymphoid structures.

5. The method of claim 1 or 2, wherein the tertiary lymphoid structure represents aggregates of lymphoid cells.

6. The method of claim 1 or 2, wherein the TLS signature comprises expression of a gene

comprising CCL18, CCL19, CCL21, CXCL13, LAMP3, LTB, MS4A1, or combinations thereof.

7. The method of claim 1 or 2, wherein the TIS signature comprises an inflammatory gene, a cytokine, a chemokine, a growth factor, a cell surface interaction protein, a granulation factor, or a combination thereof.

8. The method of claim 1 or 2, wherein the TIS signature comprises CCL5, CD27, CD274, CD276, CD8A, CMKLR1, CXCL9, CXCR6, HLA-DQA1, HLA-DRB1, HLA-E, IDO1, LAG3, NKG7, PDCD1LG2, PSMB10, STAT1, TIGIT or a combination thereof.

9. The method of claim 1 or 2, wherein the effector/memory-like CD8+T cell signature

comprises expression of a gene comprising CCR7, CD27, CD45RO, CCR7, FLT3LG, GRAP2, IL16, IL7R, LTB, S1PR1, SELL, TCF7, CD62L, or any combination thereof. 10. The method of claim 1 or 2, wherein the HLA-E/CD94 signature comprises expression of a gene CD94 (KLRD1), CD94 ligand, HLA-E, KLRC1 (NKG2A), KLRB1 (NKG2C) or any combination thereof.

11. The method of claim 1 or 2, wherein the HLA-E/CD94 signature further comprises an HLA- E: CD94 interaction level.

12. The method of claim 1 or 2, wherein the NK cell signature comprises expression of a gene CD56, CCL2, CCL3, CCL4, CCL5, CXCL8, IFN, IL-2, IL-12, IL-15, IL-18, NCR1, XCL1, XCL2, IL21R, KIR2DL3, KIR3DL1, KIR3DL2 or a combination thereof.

13. The method of claim 1 or 2, wherein the MHC class II signature comprises expression of a gene that is an HLA comprising HLA-DMA, HLA-DOA, HLA-DPA1, HLA-DPB1, HLA- DQB1, HLA-DRA, HLA-DRB1, HLA-DRB5 or a combination thereof.

14. The method of claim 1 or 2, wherein the biomarker comprises a subset of TME gene

signature comprising a Tertiary Lymphoid Structures (TLS) signature; wherein the TLS signature comprises a gene CCL18, CCL19, CCL21, CXCL13, LAMP3, LTB, MS4A1, or combinations thereof.

15. The method of claim 1 or 2, wherein the functional Ig CDR3 signature comprises an

abundance of functional Ig CDR3s.

16. The method of claim 15, wherein the abundance of functional Ig CDR3s is determined by RNA-seq.

17. The method of claim 15 or 16, wherein the abundance of functional Ig CDR3s is an

abundance of functional Ig CDR3s from cells of a TME sample from a subject.

18. The method of any one of claims 15-17, wherein the abundance of functional Ig CDR3s is 2^7 or more functional Ig CDR3s.

19. The method of any one of the claims 1-18, wherein the method further comprises:

administering to the biomarker positive patient the first therapeutic agent, an altered dose or time interval of the first therapeutic agent, or a second therapeutic agent.

20. The method of any one of the claims 1-18, wherein the method further comprises: not administering to the biomarker negative patient the first therapeutic agent or a second therapeutic agent.

21. The method of any one of the claims 1-18, wherein the method further comprises

administering to the biomarker positive patient, an increased dose of the first therapeutic agent.

22. The method of any one of the claims 1-18, wherein the method further comprises modifying a time interval of administration of the first therapeutic agent to the biomarker positive or negative patient.

23. A method for testing a patient having a tumor for the presence or absence of a baseline

biomarker that predicts that the patient is likely to have an anti-tumor response to a treatment with a therapeutic agent comprising (i) one or more peptides comprising a neoepitope of a protein, (ii) a polynucleotide encoding the one or more peptides, (iii) one or more APCs comprising the one or more peptides or the polynucleotide encoding the one or more peptides, or (iv) a T cell receptor (TCR) specific for a neoepitope of the one or more peptides in complex with an HLA protein, the method comprising:

(a) obtaining a baseline sample that has been isolated from the tumor of the patient; measuring the baseline expression level of each gene in a tumor microenvironment (TME) gene or a subset of said genes;

(b) normalizing the measured baseline expression levels; calculating a baseline signature score for the TME gene signature from the normalized expression levels;

(c) comparing the baseline signature score to a reference score for the TME gene signature; and,

(d) classifying the patient as biomarker positive or biomarker negative for an outcome related to a durable clinical benefit (DCB) from the therapeutic agent.

24. The method of claim 23, wherein the TME signature comprises a signature of one or more of claims 2-18, or a subset thereof.

25. A pharmaceutical composition for use in treating cancer in a patient who tests positive for a biomarker, wherein the composition the therapeutic agent comprises (a) one or more peptides comprising a neoepitope of a protein, (b) a polynucleotide encoding the one or more peptides, (c) one or more APCs comprising the one or more peptides or the polynucleotide encoding the one or more peptides, or (d) a T cell receptor (TCR) specific for a neoepitope of the one or more peptides in complex with an HLA protein; and at least one

pharmaceutically acceptable excipient; and wherein the biomarker is an on-treatment biomarker which comprises a gene signature selected from the group consisting of TME gene signature comprises a B-cell signature, a Tertiary Lymphoid Structures (TLS) signature, a Tumor Inflammation Signature (TIS), an effector/memory-like CD8+T cell signature, an HLA-E/CD94 signature, a NK cell signature, and an MHC class II signature. 26. The pharmaceutical composition of claim 25, wherein the TME signature comprises a

signature of any one or more of claims 2-18, or a subset thereof.

27. A method of treating cancer in a subject in need thereof, comprising: administering a

therapeutically effective amount of a cancer therapeutic agent, wherein the subject has an increased likelihood of responding to the cancer therapeutic agent, wherein the subject’s increased likelihood of responding to the cancer therapeutic agent is associated with the presence of one or more peripheral blood mononuclear cell signatures prior to treatment with the cancer therapeutic agent; and wherein at least one of the one or more peripheral blood mononuclear cell signatures comprises a threshold value for a ratio of cell counts of a first mononuclear cell type to a second mononuclear cell type in the peripheral blood of the subject.

28. The method of claim 27, wherein the cancer is melanoma.

29. The method of claim 27, wherein the cancer is non-small cell lung cancer.

30. The method of claim 27, wherein the cancer is bladder cancer.

31. The method of claim 27, wherein the cancer therapeutic comprises a neoantigen peptide vaccine.

32. The method of claim 27, wherein the cancer therapeutic comprises an anti-PD1 antibody. 33. The method of claim 27, wherein the cancer therapeutic comprises a combination of the neoantigen vaccine and the anti-PD1 antibody, wherein the neoantigen vaccine is administered or co-administered after a period of administering anti-PD1 antibody alone. 34. The method of claim 32 or 33, wherein the anti-PD1 antibody is nivolumab.

35. The method of claim 27, wherein the threshold value is a maximum threshold value.

36. The method of claim 27, wherein the threshold value is a minimum threshold value.

37. The method of claim 27, wherein at least one of the one or more peripheral blood

mononuclear cell signatures comprises a maximum threshold value for a ratio of naïve CD8+ T cells to total CD8+T cells in a peripheral blood sample from the subject.

38. The method of claim 37, wherein the maximum threshold value for the ratio of naïve CD8+ T cells to total CD8+T cells in the peripheral blood sample from the subject is about 20:100.

39. The method of claim 37 or 38, wherein the peripheral blood sample from the subject has a ratio of naïve CD8+ T cells to total CD8+T cells that is 20:100 or less or less than 20:100. 40. The method of claim 27, wherein at least one of the one or more peripheral blood

mononuclear cell signatures comprises a minimum threshold value for a ratio of effector memory CD8+ T cells to total CD8+T cells in a peripheral blood sample from the subject. 41. The method of claim 40, wherein the minimum threshold value for the ratio of effector

memory CD8+ T cells to total CD8+T cells in the peripheral blood sample from the subject is about 40:100.

42. The method of claim 40 or 41, wherein the peripheral blood sample from the subject has a ratio of effector memory CD8+ T cells to total CD8+T cells that is 40:100 or more or more than 40:100.

43. The method of claim 27, wherein at least one of the one or more peripheral blood

mononuclear cell signatures comprises a minimum threshold value for a ratio of class- switched memory B cells to total CD19+ B cells in a peripheral blood sample from the subject.

44. The method of claim 43, wherein the minimum threshold value for the ratio of class- switched memory B cells to total CD19+ B cells in the peripheral blood sample from the subject is about 10:100.

45. The method of claim 43 or 44, wherein the peripheral blood sample from the subject has a ratio of class-switched memory B cells to total CD19+ B cells that is 10:100 or more or more than 10:100.

46. The method of claim 27, wherein at least one of the one or more peripheral blood

mononuclear cell signatures comprises a maximum threshold value for a ratio of naïve B cells to total CD19+ B cells in a peripheral blood sample from the subject.

47. The method of claim 46, wherein the maximum threshold value for the ratio of naïve B cells to total CD19+ B cells in the peripheral blood sample from the subject is about 70:100. 48. The method of claim 46 or 47, wherein the peripheral blood sample from the subject has a ratio of naïve B cells to total CD19+ B cells that is 70:100 or less or less than 70:100.

49. The method of any one of the claims 37-48, wherein the cancer is a melanoma.

50. The method of claim 27, wherein at least one of the one or more peripheral blood

mononuclear cell signatures comprises a maximum threshold value for a ratio of

plasmacytoid dendritic cells to total Lin-/CD11c- cells in a peripheral blood sample from the subject.

51. The method of claim 50, wherein the maximum threshold value for the ratio of plasmacytoid dendritic cells to total Lin-/CD11c- cells in the peripheral blood sample from the subject is about 3:100.

52. The method of claim 50 or 51, wherein the peripheral blood sample from the subject has a ratio of plasmacytoid dendritic cells to total Lin-/CD11c- cells that is 3:100 or less or less than 3:100.

53. The method of claim 27, wherein at least one of the one or more peripheral blood

mononuclear cell signatures comprises a maximum threshold value for a ratio of CTLA4+ CD4 T cells to total CD4+ T cells in a peripheral blood sample from the subject.

54. The method of claim 50, wherein the maximum threshold value for the ratio of CTLA4+ CD4 T cells to total CD4+ T cells in the peripheral blood sample from the subject is about 9:100.

55. The method of claim 50 and 51, wherein the peripheral blood sample from the subject has a ratio of CTLA4+ CD4 T cells to total CD4+ T cells that is 9:100 or less or less than 9:100. 56. The method of any one of the claims 50-55, wherein the cancer is a non-small cell lung cancer.

57. The method of claim 27, wherein at least one of the one or more peripheral blood

mononuclear cell signatures comprises a minimum threshold value for a ratio of memory CD8+ T cells to total CD8+ T cells in a peripheral blood sample from the subject.

58. The method of claim 57, wherein the minimum threshold value for the ratio of memory CD8+ T cells to total CD8+ T cells in the peripheral blood sample from the subject is about 40:100 or about 55:100.

59. The method of claim 57 and 58, wherein the peripheral blood sample from the subject has a ratio of memory CD8+ T cells to total CD8+ T cells that is 40:100 or more or more than 40:100.

60. The method of claim 57 and 58, wherein the peripheral blood sample from the subject has a ratio of memory CD8+ T cells to total CD8+ T cells that is 55:100 or more or more than 55:100.

61. The method of any one of the claims 57-60, wherein the cancer is a bladder cancer.

62. A method of treating cancer in a subject in need thereof, comprising: administering to the subject a therapeutically effective amount of a cancer therapeutic agent, wherein the subject has an increased likelihood of responding to the cancer therapeutic agent, and wherein the subject’s increased likelihood of responding to the cancer therapeutic agent is associated with a clonal composition characteristic of TCR repertoires analyzed from peripheral blood sample of the subject at least at a timepoint prior to administering the cancer therapeutic agent.

63. The method of claim 62, wherein the clonal composition characteristic of TCR repertoires in a prospective patient is defined by a relatively low TCR diversity versus the TCR diversity in healthy donors.

64. The method of claim 62 or 63, wherein the clonal composition characteristic is analyzed by a method comprising sequencing the TCRs or fragments thereof.

65. The method of claim 62, wherein the clonal composition characteristic of TCR repertoires is defined by the clonal frequency distribution of the TCRs.

66. The method of any one of the claims 62-65, wherein the clonal composition characteristic of the TCR repertoires is further analyzed by calculating the frequency distribution pattern of TCR clones.

67. The method of claim 66, wherein the frequency distribution pattern of TCR clones is

analyzed using one or more of : Gini Coefficient, Shannon entropy, DE50, Sum of Squares, and Lorenz curve.

68. The method of claim 62, wherein the subject’s increased likelihood of responding to the cancer therapeutic agent is associated with increased clonality of the TCRs.

69. The method of claim 62, wherein the subject’s increased likelihood of responding to the cancer therapeutic agent is associated with increased frequency of medium and/or large and/or hyperexpanded sized TCR clones.

70. The method of claim 62, wherein the subject’s increased likelihood of responding to the cancer therapeutic agent is associated with a clonal composition characteristic of TCR repertoires according to any one of claims 63-69, wherein the clonal composition

characteristic is analyzed from peripheral blood sample of the subject prior to administering a therapeutically effective amount of a cancer therapeutic agent.

71. The method of claim 62, wherein a clonal composition characteristic of TCR repertoires comprises a measure of the clonal stability of the TCRs.

72. The method of claim 70 or 71, wherein the clonal stability of the TCRs is analyzed as TCR turnover between a first and a second timepoints, wherein the first timepoint is prior to administering the cancer therapeutic agent and the second timepoint is a timepoint during the duration of the treatment.

73. The method of claim 71, wherein the second timepoint is prior to administering the vaccine.

74. The method of claim 70, wherein the clonal stability of TCRs is analyzed using a Jensen- Shannon Divergence.

75. The method of claim 70, wherein the subject’s increased likelihood of responding to the cancer therapeutic agent is associated with higher TCR stability.

76. The method of claim 70, wherein the subject’s increased likelihood of responding to the cancer therapeutic agent is associated with reduced turnover of T cell clones between the first timepoint and the second timepoint.

77. A method of treating cancer in a subject in need thereof, comprising: administering a

therapeutically effective amount of a cancer therapeutic agent to the subject, wherein the subject has an increased likelihood of responding to the cancer therapeutic agent, wherein the subject’s increased likelihood of responding to the cancer therapeutic agent is associated with the presence of one or more genetic variations in the subject, wherein the subject has been tested for a presence of the one or more genetic variations with an assay and has been identified as having the one or more genetic variations, wherein the one or more genetic variations comprise an ApoE allele genetic variation comprising (i) an ApoE2 allele genetic variation comprising a sequence encoding a R158C ApoE protein or (ii) an ApoE4 allele genetic variation comprising a sequence encoding a C112R ApoE protein.

78. The method of claim 77, wherein the cancer therapeutic agent comprises a neoantigen

peptide vaccine.

79. The method of claim 77, wherein the cancer therapeutic agent further comprises an anti-PD1 antibody.

80. The method of claim 77, wherein the cancer therapeutic agent does not comprise an anti- PD1 antibody monotherapy.

81. The method of claim 77, wherein the cancer is melanoma.

82. The method of claim 77, wherein the subject is homozygous for the ApoE2 allele genetic variation.

83. The method of claim 77, wherein the subject is heterozygous for the ApoE2 allele genetic variation.

84. The method of claim 77, wherein the subject is homozygous for the ApoE4 allele genetic variation.

85. The method of claim 77, wherein the subject is heterozygous for the ApoE4 allele genetic variation.

86. The method of claim 77, wherein the subject comprises an ApoE allele comprising a sequence encoding a ApoE protein that is not a R158C ApoE protein or a C112R ApoE protein.

87. The method of claim 77, wherein the subject has rs7412-T and rs449358-T.

88. The method of claim 77, wherein the subject has rs7412-C and rs449358-C.

89. The method of claim 77, wherein a reference subject that is homozygous for the ApoE3 allele has a decreased likelihood of responding to the cancer therapeutic agent.

90. The method of claim 77, wherein the assay is a genetic assay.

91. The method of claim 77, wherein the cancer therapeutic agent comprises one or more

peptides comprising a cancer epitope.

92. The method of claim 77, wherein the cancer therapeutic agent comprises (i) a polynucleotide encoding the one or more peptides of claim 91,

a. or, (ii) one or more APCs comprising the one or more peptides or the polynucleotide

encoding the one or more peptides,

b. or (iii) a T cell receptor (TCR) specific for a cancer epitope of the one or more peptides in complex with an HLA protein.

93. The method of any one of the claims 77-92, wherein the cancer therapeutic agent further comprises an immunomodulatory agent.

94. The method of claim 93, wherein the immunotherapeutic agent is an anti-PD1 antibody. 95. The method of claim 77, wherein the cancer therapeutic agent is not nivolumab alone or pembrolizumab alone.

96. The method of claim 77, wherein the one or more genetic variations comprises

chr19:44908684 T>C; wherein chromosome positions of the one or more genetic variations are defined with respect to UCSC hg38.

97. The method of claim 77, wherein the one or more genetic variations comprises

chr19:44908822 C>T; wherein chromosome positions of the one or more genetic variations are defined with respect to UCSC hg38.

98. The method of claim 77, wherein the method further comprises testing the subject for the presence of the one or more genetic variations with the assay prior to the administering. 99. The method of claim 77, wherein the ApoE2 allele genetic variation is a germline variation. 100. The method of claim 77, wherein the ApoE4 allele genetic variation is a germline

variation.

101. The method of claim 77, wherein the method comprises administering to the subject a cancer therapeutic agent comprising one or more peptides comprising a cancer epitope; wherein the subject is determined as having the germline ApoE4 allelic variant.

102. The method of claim 101, wherein the therapeutic agent further comprises one or more of: an adjuvant therapy, a cytokine therapy, or an immunomodulator therapy.

103. The method of claim 101 or 102, wherein the immunomodulator therapy is a PD1

inhibitor, such as an anti-PD1 antibody.

104. The method of any one of the claims 101-103, wherein the therapeutic agent does not comprise a PD1 inhibitor monotherapy.

105. The method of claim 77, wherein the method further comprises administering an agent that promotes ApoE activity or comprises ApoE activity.

106. The method of claim 77, wherein the method further comprises administering an agent that inhibits ApoE activity.

107. The method of any one of the preceding claims, where the cancer is a pancreatic cell cancer.

108. The method of any one of the preceding claims, wherein the therapeutic agent comprises a vaccine.

109. The method of any one of the preceding claims, wherein the therapeutic agent comprises a peptide vaccine, comprising at least one, two, three or four antigenic peptides.

110. The method of any one of the preceding claims, wherein the therapeutic agent comprises a peptide vaccine, comprising at least one, two, three or four neoantigenic peptides.

111. The method of any one of the preceding claims, wherein the therapeutic agent comprises a nucleic acid encoding a peptide, wherein the peptide is a neoantigen peptide.

112. The method of any one of the preceding claims, wherein the therapeutic agent comprises a combination therapy comprising one or more checkpoint inhibitor antibodies, and a vaccine comprising a neoantigen peptide, or a nucleic acid encoding the neoantigenic peptide.

113. The method of claim 70, wherein the clonal composition characteristic is analyzed from peripheral blood sample of the subject prior to administering a vaccine, wherein the vaccine comprises at least one peptide or a polynucleotide encoding a peptide, wherein the cancer therapeutic agent comprises a combination of a neoantigen vaccine and an anti- PD1 antibody, wherein the neoantigen vaccine is administered or co-administered after a period of administering anti-PD1 antibody alone.