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Building IP: BMY Patent Application re "CYTOKINE PROFILING ANALYSIS"
CYTOKINE PROFILING ANALYSIS This invention relates to methods for predicting a prognosis of a patient with cancer in need of an anti-cancer treatment comprising measuring a cytokine score from a sample obtained from the patient. In some embodiments, the subject is administered an anti-cancer treatment, e.g., an anti-PD-1 antibody, following the cytokine score measurement. In some embodiments, the cancer is lung cancer.
1. A method of treating a patient in need of an anti-cancer treatment comprising administering to the patient an effective amount of an anti-PD-1 antibody or antigen-binding portion thereof ("anti-PD-1 antibody") or an effective amount of an anti-PD-L1 antibody or antigen-binding portion thereof ("anti-PD-L1 antibody"); wherein the patient has been identified as having a cytokine score that is higher than an average cytokine score; wherein the cytokine score is the sum of a point designated to the level of at least two cytokines in a sample obtained from the patient, wherein the point is X if the sample has a high concentration of a cytokine that is positively associated with overall survival of the patient following the administration of the anti-PD-1 antibody or the anti-PD-L1 antibody or a low concentration of a cytokine that is negatively associated with overall survival of the patient following the administration of the anti-PD-1 antibody or the anti-PD-L1 antibody, wherein the point is Z if the sample has a low concentration of a cytokine that is positively associated with the overall survival of the patient following the administration of the anti-PD-1 antibody or the anti-PD-L1 antibody or a high concentration of a cytokine that is negatively associated with the overall survival of the patient following the administration of the anti-PD-1 antibody or the anti-PD-L1 antibody, and, optionally, wherein the point is Y if the sample has a medium concentration of a cytokine that is either negatively or positively associated with overall survival of the patient following the administration of the anti-PD-1 antibody or the anti-PD-L1 antibody; wherein the at least two cytokines are selected from the group consisting of MIG, IL-1RA, MMP-3, IL-8, FRTN, ICAM, VWF, MICA, IP-10, CRP, IL-18, VDBP, IL-6, MIP1B, MCP2, ENRAGE, IL-2RA, B2M, RANTES, TNFR2, and any combination thereof. 2. The method of claim 1, further comprising measuring the cytokine score from the sample obtained from the subject prior to administering the anti-PD-1 antibody or the anti-PD-L1 antibody. 3. The method of claim 2, wherein the cytokine score is at least about 1% higher than the average cytokine score. 4. The method of claim 1, wherein X is any value, Z is a value that is lower than X, and, optionally, Y is a value that is between X and Z. 5. The method of claim 1, wherein Z is 0, Y is 1, and X is 2. 6. The method of claim 1, wherein the average cytokine score is any integer between 1 and 100. 7. The method of claim 1, wherein the at least two cytokines comprises three cytokines. 8. The method of claim 1, wherein the patient has lung cancer. 9. The method of claim 8, wherein the lung cancer is non-small cell lung cancer. 10. The method of claim 1, wherein the at least two cytokines are selected from the group consisting of MIG, IL-1RA, MMP-3, IL-8, FRTN, ICAM, VWF, MICA, IP-10, CRP, IL-18, VDBP, IL-6, MIP1B, and any combination thereof. 11. The method of claim 1, wherein the at least two cytokines are selected from the group consisting of FRTN, MMP-3, IL-8, MCP2, ENRAGE, IL-2RA, IL-18, VWF, B2M, RANTES, MICA, TNFR2, VDBP, and any combination thereof. 12. The method of claim 1, wherein the positively associated cytokines are selected from the group consisting of MIG, IL-1RA, MMP-3, and any combination thereof. 13. The method of claim 1, wherein the negatively associated cytokines are selected from the group consisting of IL-8, FRTN, ICAM, VWF, MICA, IP-10, CRP, IL-18, VDBP, IL-6, MIP1B, and any combination thereof. 14. The method of claim 1, wherein the positively associated cytokines are B2M, VDBP, or both. 15. The method of claim 1, wherein the negatively associated cytokines are selected from the group consisting of FRTN, MMP-3, IL-8, MCP2, ENRAGE, IL-2RA, IL-18, VWF, RANTES, MICA, TNFR2, and any combination thereof. 16-17. (canceled) 18. The method of claim 1, wherein the anti-PD-1 antibody is nivolumab. 19. (canceled) 20. The method of claim 1, wherein the anti-PD-L1 antibody is selected from BMS-936559, MPDL3280A, MEDI4736, and MSB0010718C. 21. The method of claim 1, wherein the anti-PD-1 antibody is pembrolizumab. 22. The method of claim 1, wherein the at least two cytokines comprise four cytokines. 23. The method of claim 1, wherein the at least two cytokines comprise five cytokines. [0001] Cross-Reference to Earlier Filed Applications: this application claims benefit to U.S. Provisional Application No. 62/318,701, filed Apr. 5, 2016, which is incorporated herein by reference in its entirety. FIELD OF THE INVENTION [0002] This invention relates to methods for predicting the prognosis of a patient with cancer in need of an anti-cancer treatment comprising measuring cytokine concentrations and determining a cytokine score from a sample obtained from the patient. In some embodiments, the subject is administered an anti-cancer treatment, e.g., an anti-PD-1 or anti-PD-L1 antibody, following the cytokine score measurement. In some embodiments, the cancer is lung cancer. BACKGROUND OF THE INVENTION [0003] Human cancers harbor numerous genetic and epigenetic alterations, generating neoantigens potentially recognizable by the immune system (Sjoblom et al., (2006) Science 314:268-74). The adaptive immune system, comprised of T and B lymphocytes, has powerful anti-cancer potential, with a broad capacity and exquisite specificity to respond to diverse tumor antigens. Further, the immune system demonstrates considerable plasticity and a memory component. The successful harnessing of all these attributes of the adaptive immune system would make immunotherapy unique among all cancer treatment modalities. [0004] Until recently, cancer immunotherapy had focused substantial effort on approaches that enhance anti-tumor immune responses by adoptive-transfer of activated effector cells, immunization against relevant antigens, or providing non-specific immune-stimulatory agents such as cytokines. In the past decade, however, intensive efforts to develop specific immune checkpoint pathway inhibitors have begun to provide new immunotherapeutic approaches for treating cancer, including the development of an antibody, ipilimumab (YERVOY.RTM.), that binds to and inhibits CTLA-4 for the treatment of patients with advanced melanoma (Hodi et al., (2010) N Engl J Med 363:711-23) and the development of antibodies, such as nivolumab and pembrolizumab (formerly lambrolizumab; USAN Council Statement, 2013), that bind specifically to the Programmed Death-1 (PD-1) receptor and block the inhibitory PD-1/PD-1 ligand pathway (Topalian et al., N Engl J Med 366:2443-54 (2012a); Topalian et al., Curr Opin Immunol 24:207-12 (2012b); Topalian et al., J Clin Oncol 32(10):1020-30 (2014); Hamid et al., N Engl J Med 369:134-144 (2013); Hamid and Carvajal, Expert Opin Biol Ther 13(6):847-61 (2013); and McDermott and Atkins, Cancer Med 2(5):662-73 (2013)). [0005] Anti-cancer agents often vary in their effectiveness based on the unique patient characteristics. There is a need for designing targeted therapeutic strategies that can predict which patients will respond to anti-cancer drugs and, thus, improve the clinical outcome for patients diagnosed with cancer. SUMMARY OF THE INVENTION [0006] The present invention relates to a method of predicting a prognosis of a patient in need of an anti-cancer treatment comprising measuring a cytokine score from a sample obtained from the patient. The cytokine score is the sum of a point designated to the level of at least one cytokine in the sample. The point is X if the sample has a high concentration of a cytokine that is positively associated with overall survival of the patient during the anti-cancer treatment or a low concentration of a cytokine that is negatively associated with overall survival of the patient during the anti-cancer treatment. The point is Z if the sample has a low concentration of a cytokine that is positively associated with the overall survival of the patient during the anti-cancer treatment or a high concentration of a cytokine that is negatively associated with the overall survival of the patient during the anti-cancer treatment. Optionally, the point is Y if the sample has a medium concentration of a cytokine that is either negatively or positively associated with overall survival of the patient during the anti-cancer treatment. [0007] In certain embodiments, the method further comprises administering to the patient an anti-cancer treatment, wherein the cytokine score is higher than the average cytokine score. [0008] In one embodiment, the cytokine score is at least about 1%, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 99%, or 100% higher than the average cytokine score. [0009] In one embodiment, X is any value, Z is a value that is lower than X, and, optionally, Y is a value that is between X and Z. In one embodiment, Z is 0, Y is 1, and X is 2. [0010] In certain embodiments, the average cytokine score is any integer between 1 and 100, between 1 and 50, between 1 and 40, between 1 and 25, between 1 and 20, between 1 and 15, between 5 and 50, between 5 and 40, between 5 and 30, between 5 and 25, between 5 and 20, between 10 and 50, between 10 and 40, between 10 and 30, between 10 and 25, between 10 and 20, between 15 and 50, between 15 and 40, between 15 and 30, between 15 and 25, or between 15 and 20. In one embodiment, the average cytokine score is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, about 50, about 60, about 70, about 80, about 90, or about 100. [0011] In certain embodiments, the at least one cytokine comprises two cytokines, three cytokines, four cytokines, five cytokines, six cytokines, seven cytokines, eight cytokines, nine cytokines, ten cytokines, cytokines, 12 cytokines, 13 cytokines, 14 cytokines, 15 cytokines 16 cytokines, 17 cytokines, 18 cytokines, 19 cytokines, or at least 20 cytokines. [0012] In embodiments, the patient has lung cancer. In further embodiments, the lung cancer is non-small cell lung cancer. In other embodiments, the non-small cell lung cancer is squamous non-small cell lung cancer. In still further embodiments, the non-small cell lung cancer is non-squamous non-small cell lung cancer. [0013] In an embodiment, the at least one cytokine is selected from the group consisting of monokine induced by gamma interferon (MIG), interleukin-1 receptor antagonist (IL-1RA), matrix metalloproteinase-3 (MMP-3), interleukin-8 ferritin (FRTN), intracellular adhesion molecule (ICAM), von Willebrand factor (VWF), majorhistocompatibility-complex class I-related chain A (MICA), interferon gamma-induced protein 10 (IP-10), C-reactive protein (CRP), interleukin-18 (IL-18), vitamin D binding protein (VDBP), interleukin-6 (IL-6), microphage inflammatory protein-1.beta. (MIP1B), and any combination thereof. In another embodiment, the at least one cytokine is selected from the group consisting of ferritin (FRTN), matrix metalloproteinase-3 (MMP-3), interleukin-8 (IL-8), monocyte chemoattractant protein 2 (MCP2), extracellular newly identified receptor for advanced glycation end-products binding protein (ENRAGE), interleukin-2 receptor antagonist (IL-2RA), interleukin-18 (IL-18), von Willebrand factor (VWF), beta-2-microglobulin (B2M), regulated on activation, normal T cell expressed and secreted (RANTES), majorhistocompatibility-complex class I-related chain A (MICA), tumor necrosis receptor factor 2 (TNFR2), vitamin D binding protein (VDBP), and any combination thereof. In one embodiment, the positively associated cytokines are selected from the group consisting of MIG, IL-1RA, MMP-3, and any combination thereof. In an embodiment, the negatively associated cytokines are selected from the group consisting of IL-8, FRTN, ICAM, VWF, MICA, IP-10, CRP, IL-18, VDBP, IL-6, MIP1B, and any combination thereof. In a further embodiment, the positively associated cytokines are B2M, VDBP, or both. In embodiments, the negatively associated cytokines are selected from the group consisting of FRTN, MMP-3, IL-8, MCP2, ENRAGE, IL-2RA, IL-18, VWF, RANTES, MICA, TNFR2, and any combination thereof. [0014] In certain embodiments, the anti-cancer treatment is an effective amount of an anti-PD-1 antibody or antigen-binding portion thereof ("anti-PD-1 antibody") or an effective amount of an anti-PD-L1 antibody or antigen-binding portion thereof ("anti-PD-L1 antibody"). In one embodiment, the anti-PD-1 antibody cross-competes with a reference antibody, which is nivolumab, for binding to human PD-1. In an embodiment, the anti-PD-1 antibody comprises a heavy chain constant region that is of a human IgG1, IgG2, IgG3, or IgG4 isotype. In other embodiments, the anti-PD-1 antibody is a chimeric, humanized, or human monoclonal anti-PD-1 antibody or an antigen-binding portion thereof. In further embodiments, the anti-PD-1 antibody is nivolumab. In other embodiments, the anti-PD-1 antibody is pembrolizumab. [0015] In one embodiment, the anti-PD-L1 antibody cross-competes with a reference antibody selected from BMS-936559, MPDL3280A, MEDI4736, and MSB0010718C for binding to human PD-L1. In an embodiment, the anti-PD-L1 antibody is selected from BMS-936559, MPDL3280A, MEDI4736, and MSB0010718C. Embodiments [0016] E1. A method of predicting a prognosis of a patient in need of an anti-cancer treatment comprising measuring a cytokine score from a sample obtained from the patient, wherein the cytokine score is the sum of a point designated to the level of at least one cytokine in the sample, wherein the point is X if the sample has a high concentration of a cytokine which is positively associated with overall survival of the patient during the anti-cancer treatment or a low concentration of a cytokine which is negatively associated with overall survival of the patient during the anti-cancer treatment, wherein the point is Z if the sample has a low concentration of a cytokine which is positively associated with the overall survival of the patient during the anti-cancer treatment or a high concentration of a cytokine which is negatively associated with the overall survival of the patient during the anti-cancer treatment, and, optionally, wherein the point is Y if the sample has a medium concentration of a cytokine which is either negatively or positively associated with overall survival of the patient during the anti-cancer treatment. [0017] E2. The method of embodiment E1, further comprising administering to the patient an anti-cancer treatment, wherein the cytokine score is higher than the average cytokine score. [0018] E3. The method of embodiment E2, wherein the cytokine score is at least about 1%, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 99% or 100% higher than the average cytokine score. [0019] E4. The method of any one of embodiments E1 to E3, wherein X is any value, Z is a value that is lower than X, and, optionally, Y is a value that is between X and Z. [0020] E5. The method of any one of embodiments E1 to E4, wherein Z is 0, Y is 1, and X is 2. [0021] E6. The method of any one of embodiments E1 to E5, wherein the average cytokine score is any integer between 1 and 50, between 1 and 40, between 1 and 100, between 1 and 25, between 1 and 20, between 1 and 15, between 5 and 50, between 5 and 40, between 5 and 30, between 5 and 25, between 5 and 20, between 10 and 50, between 10 and 40, between 10 and 30, between 10 and 25, between 10 and 20, between 15 and 50, between 15 and 40, between 15 and 30, between 15 and 25, or between 15 and 20. [0022] E7. The method of any one of embodiments E1 to E6, wherein the average cytokine score is 1, 2, 3, 4, 5, 6, 7, 8, 9, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, about 50, about 60, about 70, about 80, about 90, or about 100. [0023] E8. The method of any one of embodiments E1 to E7, wherein the at least one cytokine comprises at least two cytokines, at least three cytokines, at least four cytokines, at least five cytokines, at least six cytokines, at least seven cytokines, at least eight cytokines, at least nine cytokines, at least ten cytokines, at least 11 cytokines, at least 12 cytokines, at least 13 cytokines, at least 14 cytokines, at least 15 cytokines at least 16 cytokines, at least 17 cytokines, at least 18 cytokines, at least 19 cytokines, or at least 20 cytokines. [0024] E9. The method of any one of embodiments E1 to E8, wherein the patient has lung cancer. [0025] E10. The method of embodiment E9, wherein the lung cancer is non-small cell lung cancer. [0026] E11. The method of embodiment E10, wherein the non-small cell lung cancer is squamous non-small cell lung cancer. [0027] E12. The method of embodiment E10, wherein the non-small cell lung cancer is non-squamous non-small cell lung cancer. [0028] E13. The method of any one of embodiments E1 to E11, wherein the at least one cytokine is selected from the group consisting of: MIG, IL-1RA, MMP-3, IL-8, FRTN, ICAM, VWF, MICA, IP-10, CRP, IL-18, VDBP, IL-6, MIP1B, and any combination thereof. [0029] E14. The method of any one of embodiments E1 to E10 or E12, wherein the at least one cytokine is selected from the group consisting of: FRTN, MMP-3, IL-8, MCP2, ENRAGE, IL-2RA, IL-18, VWF, B2M, RANTES, MICA, TNFR2, VDBP, and any combination thereof. [0030] E15. The method of any one of embodiments E1 to E11 or E13, wherein the positively associated cytokines are selected from the group consisting of MIG, IL-1RA, MMP-3, and any combination thereof. [0031] E16. The method of any one of embodiments E1 to E11, E13 or E15, wherein the negatively associated cytokines are selected from the group consisting of IL-8, FRTN, ICAM, VWF, MICA, IP-10, CRP, IL-18, VDBP, IL-6, MIP1B, and any combination thereof. [0032] E17. The method of any one of embodiments E1 to E10, E12 or E14, wherein the positively associated cytokines are B2M, VDBP, or both. [0033] E18. The method of any one of embodiments E1 to E10, E12, E14 or E17, wherein the negatively associated cytokines are selected from the group consisting of: FRTN, MMP-3, IL-8, MCP2, ENRAGE, IL-2RA, IL-18, VWF, RANTES, MICA, TNFR2, and any combination thereof. [0034] E19. The method of any one of embodiments E1 to E18, wherein the anti-cancer treatment is an effective amount of an anti-PD-1 antibody or antigen-binding portion thereof ("anti-PD-1 antibody") or an effective amount of an anti-PDL-1 antibody or antigen-binding portion thereof ("anti-PDL-1 antibody"). [0035] E20. The method of embodiment E19, wherein the anti-PD-1 antibodies cross-competes with a reference antibody which is nivolumab for binding to human PD-1. [0036] E21. The method of embodiment E19 or E20, wherein the anti-PD-1 antibody comprises a heavy chain constant region which is of a human IgG1, IgG2, IgG3, or IgG4 isotype. [0037] E22. The method of any one of embodiments E19 to E21, wherein the anti-PD-1 antibody is a chimeric, humanized or human monoclonal anti-PD-1 antibody or an antigen-binding portion thereof. [0038] E23. The method of any one of embodiments E19 to E22, wherein the anti-PD-1 antibody is nivolumab. [0039] E24. The method of any one of embodiments E19 to E22, wherein the anti-PD-1 antibody is pembrolizumab. [0040] E25. The method of embodiment E19, wherein the anti-PD-L1 antibody crosses-competes with a reference antibody selected from the group consisting of BMS-936559, MPDL3280A, MEDI4736, and MSB0010718C for binding to human PD-L1. [0041] E26. The method of embodiment E19 or E25, wherein the anti-PD-L1 antibody is selected from the group consisting of BMS-936559, MPDL3280A, MEDI4736, and MSB0010718C. BRIEF DESCRIPTION OF THE DRAWINGS [0042] FIG. 1 shows a schematic of the method of determining cytokines associated with overall survival (OS) and calculating the cytoscore in patients with squamous cell non-small cell lung cancer. Sbjts, subjects; ROC, receiver-operating characteristic. [0043] FIGS. 2A-2F provide a model evaluation of selected cytokines in the validation set. The selected cytokines (FIG. 2A) were measured 6 months (FIG. 2B), 9 months (FIG. 2C), 12 months (FIG. 2D), 15 months (FIG. 2E), and 18 months (FIG. 2F) after treatment. AIC, Akaike information criterion. AUC, area under the curve. [0044] FIG. 3 shows the calculation of cytokines associated with overall survival (OS) in nivolumab-treated squamous cell non-small cell lung cancer patients via stepwise variable selection in a Cox model. AIC, Akaike information criterion. [0045] FIGS. 4A-4J show the time-varying receiver-operating characteristic (ROC) analysis of selected cytokines in the training set (FIGS. 4A-4E) and validation set (FIGS. 4F-4J) of advanced or metastatic squamous cell non-small cell lung cancer patients. [0046] FIGS. 5A-5C show the method of calculating the cytokine score for patients with advanced or metastatic squamous cell non-small cell lung cancer (SQ-Cytoscore) (FIG. 5A), and representative tertile bin distributions for select cytokines associated positively with overall survival (OS) (FIG. 5B) or negatively associated with overall survival (OS) (FIG. 5C). [0047] FIGS. 6A-6B show the overall survival (OS) of nivolumab-treated squamous cell non-small cell lung cancer patients with a high cytoscore or a low cytoscore (FIG. 6A) compared to the OS of docetaxel-treated squamous cell non-small cell lung cancer patients with high cytoscore or low cytoscore (FIG. 6B). [0048] FIGS. 7A-7B shows the overall survival (OS) of high cytoscore squamous cell non-small cell lung cancer patients treated with nivolumab or docetaxel (FIG. 7A) compared to the OS of low cytoscore squamous cell non-small cell lung cancer patients treated with nivolumab or docetaxel (FIG. 7B). [0049] FIG. 8 shows a schematic of the method of determining cytokines associated with overall survival (OS) and calculating the cytoscore in patients with non-squamous cell non-small cell lung cancer. Sbjts, subjects; ROC, receiver-operating characteristic. [0050] FIG. 9 shows the calculation of cytokines associated with overall survival (OS) in nivolumab-treated metastatic non-squamous non-small cell lung cancer patients via stepwise variable selection in a Cox model. [0051] FIGS. 10A-10J show the time-varying receiver-operating characteristic (ROC) analysis of selected cytokines in the training set (FIGS. 10A-10E) and validation set (FIGS. 10F-10J) of non-squamous non-small cell lung cancer patients. [0052] FIGS. 11A-11B show the overall survival (OS) of nivolumab-treated non-squamous non-small cell lung cancer patients with a high cytoscore or a low cytoscore (FIG. 11A) compared to the OS of docetaxel-treated non-squamous non-small cell lung cancer patients with a high cytoscore or a low cytoscore (FIG. 11B). [0053] FIGS. 12A-12B show the overall survival (OS) of high cytoscore non-squamous non-small cell lung cancer patients treated with nivolumab or docetaxel (FIG. 12A) compared to the OS of low cytoscore non-squamous non-small cell lung cancer patients treated with nivolumab or docetaxel (FIG. 12B). |
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