|
|
Bristol-Myers Squibb Co.
|
 |
||||||||
|
 |
  |
 |
|
|
||
 |
 |
 
|
return to message board, top of board |
Building IP: BMY Patent Application re "METHODS OF IDENTIFYING A SUBJECT SUITABLE ...
METHODS OF IDENTIFYING A SUBJECT SUITABLE FOR AN IMMUNO-ONCOLOGY (I-O) THERAPY The present disclosure provides methods of identifying a subject suitable for an immunooncology (I-O) therapy comprising measuring the expression of one or more of STAT1, IFN.gamma., NECTIN2, and CSFIR. In some aspects, the I-O therapy comprises administering an anti-PD-1 antibody or antigen-binding portion thereof or an anti-PD-L1 antibody or antigen-binding portion thereof to the subject.
1. A pharmaceutical composition comprising an anti-PD-1/PD-L1 antagonist for use in a method of identifying a human subject suitable for the anti-PD-1/PD-L1 antagonist, wherein the method comprises measuring expression of a panel of genes in a tumor sample obtained from a subject in need of the anti-PD-1/PD-L1 antagonist, wherein the gene panel comprises at least three of STAT1, IFN.gamma., NECTIN2, and CSFIR. 2. The pharmaceutical composition for use of claim 1, wherein the gene panel comprises all of STAT1, IFN.gamma., NECTIN2, CSFIR, and an additional gene, two additional genes, three additional genes, four additional genes, five additional genes, six additional genes, seven additional genes, eight additional genes, or ten additional genes. 3. The pharmaceutical composition for use of claim 1, wherein the gene panel consists of STAT1, IFN.gamma., NECTIN2, CSFIR, and an additional gene, two additional genes, or three additional genes. 4. The pharmaceutical composition for use of any one of claims 1 to 3, wherein the subject is identified as being suitable when the tumor sample exhibits: (i) an increased expression of one or more of STAT1 and IFN.gamma. ("upregulated genes") in the sample compared to the expression of the one or more of STAT1 and IFN.gamma. in a reference sample; (ii) a decreased expression of one or more of NECTIN2 and CSFIR ("down-regulated genes") in the sample compared to the expression of one or more of NECTIN2 and CSFIR in a reference sample or (iii) both (i) and (ii). 5. The pharmaceutical composition for use of any one of claims 1 to 5, wherein the subject is to be administered an anti-PD-1/PD-L1 antagonist. 6. A pharmaceutical composition comprising an anti-PD-1/PD-L1 antagonist for use in a method of treating a human subject afflicted with a tumor, wherein a tumor sample obtained from the subject exhibits: (i) an increased expression of one or more of STAT1 and IFN.gamma. ("upregulated genes") in a tumor sample obtained from the subject compared to the expression of the one or more of STAT1 and IFN.gamma. in a reference sample; (ii) a decreased expression of one or more of NECTIN2 and CSFIR ("down-regulated genes") in a tumor sample obtained from the subject compared to the expression of one or more of NECTIN2 and CSFIR in a reference sample; or (iii) both (i) and (ii). 7. The pharmaceutical composition of any one of claims 4 to 6, wherein the reference sample comprises a non-tumor tissue of the subject, a corresponding non-tumor tissue of the subject, or the corresponding tissue of subjects without a tumor. 8. A method of identifying a human subject suitable for an anti-PD-1/PD-L1 antagonist, comprising in vitro measuring expression of a panel of genes in a tumor sample obtained from a subject in need of the anti-PD-1/PD-L1 antagonist, wherein the gene panel comprises at least three of STAT1, IFN.gamma., NECTIN2, and CSFIR. 9. The method of claim 8, wherein the gene panel comprises all of STAT1, IFN.gamma., NECTIN2, CSFIR and an additional gene, two additional genes, three additional genes, four additional genes, five additional genes, six additional genes, seven additional genes, eight additional genes, or ten additional genes. 10. The method of claim 8, wherein the gene panel consists of STAT1, IFN.gamma., NECTIN2, CSFIR, and an additional gene, two additional genes, or three additional genes. 11. The method of any one of claims 8 to 10, wherein the subject is identified as being suitable when the tumor sample exhibits: (i) an increased expression of one or more of STAT1 and IFN.gamma. ("upregulated genes") in the tumor sample compared to the expression of the one or more of STAT1 and IFN.gamma. in a reference sample; (ii) a decreased expression of one or more of NECTIN2 and CSFIR ("down-regulated genes") in the tumor sample compared to the expression of one or more of NECTIN2 and CSFIR in a reference sample; or (iii) both (i) and (ii). 12. The method of claim 11, further comprising administering the anti-PD-1/PD-L1 antagonist. 13. A method of treating a human subject afflicted with a tumor, comprising administering an anti-PD-1/PD-L1 antagonist to the subject, wherein a tumor sample obtained from the subject exhibits: (i) an increased expression of one or more of STAT1 and IFN.gamma. ("upregulated genes") in a tumor sample obtained from the subject compared to the expression of the one or more of STAT1 and IFN.gamma. in a reference sample; (ii) a decreased expression of one or more of NECTIN2 and CSFIR ("down-regulated genes") in a tumor sample obtained from the subject compared to the expression of one or more of NECTIN2 and CSFIR in a reference sample; or (iii) both (i) and (ii). 14. The method of any one of claims 11 to 13, wherein the reference sample comprises a non-tumor tissue of the subject, a corresponding non-tumor tissue of the subject, or the corresponding tissue of subjects without a tumor. 15. The pharmaceutical composition for use of claim 6 or 7 or the method of claim 13 or 14, wherein the subject is identified as being suitable for the anti-PD-1/PD-L1 antagonist prior to the anti-PD-1/PD-L1 antagonist. 16. The pharmaceutical composition for use of any one of claims 1 to 7 and 15 or the method of any one of claims 8 to 15, wherein the tumor sample exhibits increased expression of at least two of the upregulated genes. 17. The pharmaceutical composition for use of any one of claims 1 to 7, 15, and 16 or the method of any one of claims 8 to 16, wherein the tumor sample exhibits decreased expression of at least two of the down-regulated genes. 18. The pharmaceutical composition for use of any one of claims 1 to 7, and 15 to 17 or the method of any one of claims 8 to 17, wherein the tumor sample exhibits increased expression of all of the upregulated genes; and the tumor sample exhibits decreased expression of all of the down-regulated genes. 19. The pharmaceutical composition for use of any one of claims 1 to 7, and 15 to 18 or the method of any one of claims 11 to 18, wherein the expression of one or more of the upregulated genes is increased at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 100%, at least about 125%, at least about 150%, at least about 175%, at least about 200%, at least about 225%, at least about 250%, at least about 275%, or at least about 300% higher than the expression of one or more of STAT1 and IFN.gamma. in the reference sample. 20. The pharmaceutical composition for use of any one of claims 1 to 7, and 15 to 18 or the method of any one of claims 11 to 18, wherein the expression of one or more of the upregulated genes is increased at least about 50% higher than the expression of one or more of STAT1 and IFN.gamma. in the reference sample. 21. The pharmaceutical composition for use of any one of claims 1 to 7, and 15 to 18 or the method of any one of claims 11 to 18, wherein the expression of one or more of the upregulated genes is increased at least about 75% higher than the expression of one or more of STAT1 and IFN.gamma. in the reference sample. 22. The pharmaceutical composition for use of any one of claims 1 to 7, and 15 to 21 or the method of any one of claims 11 to 21, wherein the expression of one or more of the upregulated genes is decreased at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 100%, at least about 125%, at least about 150%, at least about 175%, at least about 200%, at least about 225%, at least about 250%, at least about 275%, or at least about 300% lower than the expression of one or more of NECTIN2 and CSFIR in the reference sample. 23. The pharmaceutical composition for use of any one of claims 1 to 7, and 15 to 21 or the method of any one of claims 11 to 21, wherein the expression of one or more of the upregulated genes is decreased at least about 50% lower than the expression of one or more of NECTIN2 and CSFIR in the reference sample. 24. The pharmaceutical composition for use of any one of claims 1 to 7, and 15 to 21 or the method of any one of claims 11 to 21, wherein the expression of one or more of the upregulated genes is decreased at least about 75% lower than the expression of one or more of NECTIN2 and CSFIR in the reference sample. 25. The pharmaceutical composition for use of any one of claims 1 to 7, and 15 to 24 or the method of any one of claims 11 to 24, wherein the tumor sample is a tumor tissue biopsy. 26. The pharmaceutical composition for use of any one of claims 1 to 7, and 15 to 25 or the method of any one of claims 11 to 25, wherein the tumor sample is a formalin-fixed, paraffin-embedded tumor tissue or a fresh-frozen tumor tissue. 27. The pharmaceutical composition for use of any one of claims 1 to 7, and 15 to 26 or the method of any one of claims 11 to 26, wherein the tumor sample is obtained from a parenchyma of the tumor. 28. The pharmaceutical composition for use of any one of claims 1 to 7, and 15 to 27 or the method of any one of claims 11 to 27, wherein gene expression is determined by detecting the presence of gene mRNA, the presence of a protein encoded by the gene, or both. 29. The pharmaceutical composition for use or method of claim 28, wherein the presence of gene mRNA is determined using reverse transcriptase PCR. 30. The pharmaceutical composition for use or method of claim 27 or 28, wherein the presence of the protein encoded by the gene is determined using an IHC assay. 31. The pharmaceutical composition for use or method of claim 29, wherein the IHC assay is an automated IHC assay. 32. The pharmaceutical composition for use of any one of claims 1 to 7, and 15 to 31 or the method of any one of claims 11 to 31, wherein the tumor sample does not exhibit: (i) an increased expression of one or more of CSFIR and NECTIN2 compared to the expression of the one or more of CSFIR and NECTIN2 in a reference sample; (ii) a decreased expression of one or more of STAT1 and IFN.gamma. compared to the expression of one or more of STAT1 and IFN.gamma. in a reference sample; or (iii) both (i) and (ii). 33. The pharmaceutical composition for use or the method of claim 32, wherein the tumor sample does not exhibit: (iv) an increased expression of two or three of CSFIR and NECTIN2 compared to the expression of two or three of CSFIR and NECTIN2 in a reference sample; (v) a decreased expression of two, three, or four of STAT1 and IFN.gamma. compared to the expression of two, three, or four of STAT1 and IFN.gamma. in a reference sample; or (vi) both (i) and (ii). 34. The pharmaceutical composition for use or method of claim 32 or 33, wherein the tumor sample is obtained from a stroma of the tumor. 35. The pharmaceutical composition for use of any one of claims 1 to 7, and 15 to 34 or the method of any one of claims 11 to 34, wherein the anti-PD-1/PD-L1 antagonist comprises an antibody or antigen-binding fragment thereof that specifically binds a target protein selected from programmed death 1 (PD-1; an "anti-PD-1 antibody") or programmed death ligand 1 (PD-L1; an "anti-PD-L1 antibody). 36. The pharmaceutical composition for use or method of claim 35, wherein the anti-PD-1/PD-L1 antagonist is an anti-PD-1 antibody. 37. The pharmaceutical composition for use or method of claim 36, wherein the anti-PD-1 antibody comprises nivolumab or pembrolizumab. 38. The pharmaceutical composition for use or method of claim 35, wherein the anti-PD-1/PD-L1 antagonist is an anti-PD-L1 antibody. 39. The pharmaceutical composition for use or method of claim 36, wherein the anti-PD-1 antibody comprises avelumab, atezolizumab, or durvalumab. 40. The pharmaceutical composition for use of any one of claims 1 to 7, and 15 to 39 or the method of any one of claims 11 to 39, wherein the anti-PD-1/PD-L1 antagonist is administered as a monotherapy. 41. The pharmaceutical composition for use of any one of claims 1 to 7, and 15 to 39 or the method of any one of claims 11 to 39, wherein the anti-PD-1/PD-L1 antagonist is administered with an anti-cancer agent. 42. The pharmaceutical composition for use or method of claim 41, wherein the anti-cancer agent comprises an antibody that specifically binds a protein of Inducible T cell Co-Stimulator (ICOS), CD137 (4-1BB), CD134 (OX40), NKG2A, CD27, CD96, Glucocorticoid-Induced TNFR-Related protein (GITR), and Herpes Virus Entry Mediator (HVEM), Programmed Death-1 (PD-1), Programmed Death Ligand-1 (PD-L1), CTLA-4, B and T Lymphocyte Attenuator (BTLA), T cell Immunoglobulin and Mucin domain-3 (TIM-3), Lymphocyte Activation Gene-3 (LAG-3), adenosine A2a receptor (A2aR), Killer cell Lectin-like Receptor G1 (KLRG-1), Natural Killer Cell Receptor 2B4 (CD244), CD160, T cell Immunoreceptor with Ig and ITIM domains (TIGIT), and the receptor for V-domain Ig Suppressor of T cell Activation (VISTA), KIR, TGF.beta., IL-10, IL-8, B7-H4, Fas ligand, CSF1R, CXCR4, mesothelin, CEACAM-1, CD52, HER2, or any combination thereof. 43. The pharmaceutical composition for use or method of claim 41, wherein the anti-cancer agent comprises an anti-CSF1R antibody. 44. The pharmaceutical composition for use of any one of claims 1 to 7, and 15 to 43 or the method of any one of claims 11 to 43, wherein the tumor is derived from a cancer selected from the group consisting of hepatocellular cancer, gastroesophageal cancer, melanoma, bladder cancer, lung cancer, kidney cancer, head and neck cancer, colon cancer, pancreatic cancer, prostate cancer, ovarian cancer, urothelial cancer, colorectal cancer, and any combination thereof. 45. The pharmaceutical composition for use of any one of claims 1 to 7, and 15 to 44 or the method of any one of claims 11 to 44, wherein the tumor is relapsed. 46. The pharmaceutical composition for use of any one of claims 1 to 7, and 15 to 44 or the method of any one of claims 11 to 44, wherein the tumor is refractory. 47. The pharmaceutical composition for use of any one of claims 1 to 7, and 15 to 44 or the method of any one of claims 11 to 44, wherein the tumor is locally advanced. 48. The pharmaceutical composition for use of any one of claims 1 to 7, and 15 to 44 or the method of any one of claims 11 to 44, wherein the tumor is metastatic. 49. The pharmaceutical composition for use of any one of claims 5 to 7, and 15 to 48 or the method of any one of claims 12 to 48, wherein the administering treats the tumor. 50. The pharmaceutical composition for use of any one of claims 5 to 7, and 15 to 48 or the method of any one of claims 12 to 48, wherein the administering reduces the size of the tumor. 51. The pharmaceutical composition or method of claim 50, wherein the size of the tumor is reduced by at least about 10%, about 20%, about 30%, about 40%, or about 50% compared to the tumor size prior to the administration. 52. The pharmaceutical composition for use of any one of claims 5 to 7, and 15 to 51 or the method of any one of claims 12 to 51, wherein the subject exhibits progression-free survival of at least about one month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about one year, at least about eighteen months, at least about two years, at least about three years, at least about four years, or at least about five years after the initial administration. 53. The pharmaceutical composition for use of any one of claims 5 to 7, and 15 to 51 or the method of any one of claims 12 to 51, wherein the subject exhibits stable disease after the administration. 54. The pharmaceutical composition for use of any one of claims 5 to 7, and 15 to 51 or the method of any one of claims 12 to 51, wherein the subject exhibits a partial response after the administration. 55. The pharmaceutical composition for use of any one of claims 5 to 7, and 15 to 51 or the method of any one of claims 12 to 51, wherein the subject exhibits a complete response after the administration. 56. A kit for treating a subject afflicted with a tumor, the kit comprising: (a) an anti-PD-1/PD-L1 antagonist; and (b) instructions for using the anti-PD-1/PD-L1 antagonist in the pharmaceutical composition for use of any one of claims 1 to 7, and 15 to 55 or the method of any one of claims 11 to 55. 57. The kit of claim 56, wherein the anti-PD-1/PD-L1 antagonist comprises an anti-PD-1 antibody. 58. The kit of claim 56, wherein the anti-PD-1/PD-L1 antagonist comprises an anti-PD-L1 antibody. 59. A gene panel comprising at least three of STAT1, IFN.gamma., NECTIN2, and CSFIR, for use in identifying a subject suitable for an anti-PD-1/PD-L1 antagonist. 60. The gene panel for use of claim 59, which comprises at least four, at least five, or at least six of STAT1, IFN.gamma., NECTIN2, and CSFIR. 61. The gene panel for use of claim 59, which comprises STAT1, IFN.gamma., NECTIN2, and CSFIR. 62. The gene panel for use of claim 59, which consists of STAT1, IFN.gamma., NECTIN2, and CSFIR and one additional gene, two additional genes, three additional genes, four additional genes, five additional genes, six additional genes, seven additional genes, eight additional genes, nine additional genes, or ten additional genes. 63. The gene panel for use of claim 59, which consists of STAT1, IFN.gamma., NECTIN2, and CSFIR, and one additional gene, two additional genes, three additional genes, four additional genes, five additional genes, six additional genes, seven additional genes, eight additional genes, nine additional genes, or ten additional genes. 64. The gene panel for use of any one of claims 59 to 62, which comprises about 90 genes, about 95 genes, or about 100 genes. 65. A method for preparing a nucleic acid fraction from a tumor of a subject in need of an I/O therapy, comprising: (a) extracting a tumor biopsy from the subject; (b) producing a fraction of nucleic acids extracted in (a) by the isolating nucleic acids; and (c) analyzing the expression level of one or more genes in a gene panel selected from STAT1, IFN.gamma., NECTIN2, and CSFIR. 66. The method of claim 65, wherein the nucleic acids are mRNA. 67. The method of claim 65 or 66, wherein one or both of CSFIR and NECTIN2 genes are downregulated. 68. The method of any one of claims 65 to 67, wherein one or both of STAT1 and IFN.gamma. are upregulated. 69. The method of any one of claims 65 to 68, wherein CSFIR and NECTIN2 are downregulated, and wherein STAT1 and IFN.gamma. are upregulated. 70. The method of any one of claims 65 to 69, wherein the expression level is analyzed by measuring an mRNA level of the one or more genes in the gene panel in the tumor sample. 71. The method of any one of claims 65 to 70, wherein the expression level is measured using a nuclease protection assay. 72. The method of any one of claims 65 to 70, wherein the expression level is measured using next-generation sequencing. 73. The method of any one of claims 65 to 72, wherein the expression level is measured using reverse transcriptase polymerase chain reaction (RT-PCR). 74. The method any one of claims 65 to 73, wherein the expression of one or both of STAT1 and IFN.gamma. is increased at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 100%, at least about 125%, at least about 150%, at least about 175%, at least about 200%, at least about 225%, at least about 250%, at least about 275%, or at least about 300% higher than the expression of one or both of STAT1 and IFN.gamma. in the reference sample. 75. The method any one of claims 65 to 74, wherein the expression of one or both of STAT1 and IFN.gamma. is increased at least about 50% higher than the expression of one or both of STAT1 and IFN.gamma. in the reference sample. 76. The method any one of claims 65 to 75, wherein the expression of one or both of STAT1 and IFN.gamma. is increased at least about 75% higher than the expression of one or both of STAT1 and IFN.gamma. in the reference sample. 77. The method any one of claims 65 to 76, wherein the expression of one or both of NECTIN2 and CSFIR is decreased at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 100%, at least about 125%, at least about 150%, at least about 175%, at least about 200%, at least about 225%, at least about 250%, at least about 275%, or at least about 300% lower than the expression of one or more of NECTIN2 and CSFIR in the reference sample. 78. The method any one of claims 65 to 77, wherein the expression of one or both of NECTIN2 and CSFIR is decreased at least about 50% lower than the expression of one or more of NECTIN2 and CSFIR in the reference sample. 79. The method any one of claims 65 to 78, wherein the expression of one or both of NECTIN2 and CSFIR is decreased at least about 75% lower than the expression of one or more of NECTIN2 and CSFIR in the reference sample. CROSS REFERENCE TO RELATED APPLICATIONS [0001] This PCT application claims the priority benefit of U.S. Provisional Application No. 62/854,883, filed May 30, 2019, and 62/931,724, filed Nov. 6, 2019, each of which is incorporated herein by reference in its entirety. FIELD OF THE DISCLOSURE [0002] The present disclosure provides a method for treating a subject afflicted with a tumor using an immunotherapy. BACKGROUND OF THE DISCLOSURE [0003] Human cancers harbor numerous genetic and epigenetic alterations, generating neoantigens potentially recognizable by the immune system (Sjoblom et al., Science (2006) 314(5797):268-274). 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] In the past decade, intensive efforts to develop specific immune checkpoint pathway inhibitors have begun to provide new immunotherapeutic approaches for treating cancer, including the development of antibodies that block the inhibitory Programmed Death-1 (PD-1)/Programmed Death ligand 1 (PD-L1) pathway such as nivolumab and pembrolizumab (formerly lambrolizumab; USAN Council Statement, 2013) that bind specifically to the PD-1 receptor and atezolizumab, durvalumab, and avelumab that bind specifically to PD-L1 (Topalian et al., 2012a, b; Topalian et al., 2014; Hamid et al., 2013; Hamid and Carvajal, 2013; McDermott and Atkins, 2013). [0005] The immune system and response to immuno-therapy have shown to be complex. Additionally, anti-cancer agents can vary in their effectiveness based on the unique patient characteristics. Accordingly, there is a need for targeted therapeutic strategies that identify patients who are more likely to respond to a particular anti-cancer agent and, thus, improve the clinical outcome for patients diagnosed with cancer. SUMMARY OF THE DISCLOSURE [0006] Certain aspects of the present disclosure are directed to a pharmaceutical composition comprising an anti-PD-1/PD-L1 antagonist for use in a method of identifying a human subject suitable for the anti-PD-1/PD-L1 antagonist, wherein the method comprises measuring expression of a panel of genes in a tumor sample obtained from a subject in need of the anti-PD-1/PD-L1 antagonist, wherein the gene panel comprises at least three of STAT1, IFN.gamma., NECTIN2, and CSFIR. In some aspects, the gene panel comprises all of STAT1, IFN.gamma., NECTIN2, CSFIR, and an additional gene, two additional genes, three additional genes, four additional genes, five additional genes, six additional genes, seven additional genes, eight additional genes, or ten additional genes. In some aspects, the gene panel consists of STAT1, IFN.gamma., NECTIN2, CSFIR, and an additional gene, two additional genes, or three additional genes. [0007] In some aspects, the subject is identified as being suitable when the tumor sample exhibits: (i) an increased expression of one or more of STAT1 and IFN.gamma. ("upregulated genes") in the sample compared to the expression of the one or more of STAT1 and IFN.gamma. in a reference sample; (ii) a decreased expression of one or more of NECTIN2 and CSFIR ("down-regulated genes") in the sample compared to the expression of one or more of NECTIN2 and CSFIR in a reference sample or (iii) both (i) and (ii). [0008] In some aspects, the subject is to be administered an anti-PD-1/PD-L1 antagonist. [0009] Certain aspects of the present disclosure are directed to a pharmaceutical composition comprising an anti-PD-1/PD-L1 antagonist for use in a method of treating a human subject afflicted with a tumor, wherein a tumor sample obtained from the subject exhibits: (i) an increased expression of one or more of STAT1 and IFN.gamma. ("upregulated genes") in a tumor sample obtained from the subject compared to the expression of the one or more of STAT1 and IFN.gamma. in a reference sample; (ii) a decreased expression of one or more of NECTIN2 and CSFIR ("down-regulated genes") in a tumor sample obtained from the subject compared to the expression of one or more of NECTIN2 and CSFIR in a reference sample; or (iii) both (i) and (ii). In some aspects, the reference sample comprises a non-tumor tissue of the subject, a corresponding non-tumor tissue of the subject, or the corresponding tissue of subjects without a tumor. [0010] Certain aspects of the present disclosure are directed to a method of identifying a human subject suitable for an anti-PD-1/PD-L1 antagonist, comprising in vitro measuring expression of a panel of genes in a tumor sample obtained from a subject in need of the anti-PD-1/PD-L1 antagonist, wherein the gene panel comprises at least three of STAT1, IFN.gamma., NECTIN2, and CSFIR. In some aspects, the gene panel comprises all of STAT1, IFN.gamma., NECTIN2, CSFIR and an additional gene, two additional genes, three additional genes, four additional genes, five additional genes, six additional genes, seven additional genes, eight additional genes, or ten additional genes. In some aspects, wherein the gene panel consists of STAT1, IFN.gamma., NECTIN2, CSFIR, and an additional gene, two additional genes, or three additional genes. [0011] In some aspects, the subject is identified as being suitable when the tumor sample exhibits: (i) an increased expression of one or more of STAT1 and IFN.gamma. ("upregulated genes") in the tumor sample compared to the expression of the one or more of STAT1 and IFN.gamma. in a reference sample; (ii) a decreased expression of one or more of NECTIN2 and CSFIR ("down-regulated genes") in the tumor sample compared to the expression of one or more of NECTIN2 and CSFIR in a reference sample; or (iii) both (i) and (ii). [0012] In some aspects, further comprising administering the anti-PD-1/PD-L1 antagonist. [0013] Certain aspects of the present disclosure are directed to a method of treating a human subject afflicted with a tumor, comprising administering an anti-PD-1/PD-L1 antagonist to the subject, wherein a tumor sample obtained from the subject exhibits: (i) an increased expression of one or more of STAT1 and IFN.gamma. ("upregulated genes") in a tumor sample obtained from the subject compared to the expression of the one or more of STAT1 and IFN.gamma. in a reference sample; (ii) a decreased expression of one or more of NECTIN2 and CSFIR ("down-regulated genes") in a tumor sample obtained from the subject compared to the expression of one or more of NECTIN2 and CSFIR in a reference sample; or (iii) both (i) and (ii); In some aspects, the reference sample comprises a non-tumor tissue of the subject, a corresponding non-tumor tissue of the subject, or the corresponding tissue of subjects without a tumor. [0014] In some aspects, the subject is identified as being suitable for the anti-PD-1/PD-L1 antagonist prior to the anti-PD-1/PD-L1 antagonist. In some aspects, the tumor sample exhibits increased expression of at least two of the upregulated genes. In some aspects, the tumor sample exhibits decreased expression of at least two of the down-regulated genes. In some aspects, the tumor sample exhibits increased expression of all of the upregulated genes; and the tumor sample exhibits decreased expression of all of the down-regulated genes. [0015] In some aspects, the expression of one or more of the upregulated genes is increased at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 100%, at least about 125%, at least about 150%, at least about 175%, at least about 200%, at least about 225%, at least about 250%, at least about 275%, or at least about 300% higher than the expression of one or more of STAT1 and IFN.gamma. in the reference sample. In some aspects, the expression of one or more of the upregulated genes is increased at least about 50% higher than the expression of one or more of STAT1 and IFN.gamma. in the reference sample. In some aspects, the expression of one or more of the upregulated genes is increased at least about 75% higher than the expression of one or more of STAT1 and IFN.gamma. in the reference sample. [0016] In some aspects, the expression of one or more of the upregulated genes is decreased at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 100%, at least about 125%, at least about 150%, at least about 175%, at least about 200%, at least about 225%, at least about 250%, at least about 275%, or at least about 300% lower than the expression of one or more of NECTIN2 and CSFIR in the reference sample. In some aspects, the expression of one or more of the upregulated genes is decreased at least about 50% lower than the expression of one or more of NECTIN2 and CSFIR in the reference sample. In some aspects, the expression of one or more of the upregulated genes is decreased at least about 75% lower than the expression of one or more of NECTIN2 and CSFIR in the reference sample. [0017] In some aspects, the tumor sample is a tumor tissue biopsy. In some aspects, the tumor sample is a formalin-fixed, paraffin-embedded tumor tissue or a fresh-frozen tumor tissue. In some aspects, the tumor sample is obtained from a parenchyma of the tumor. [0018] In some aspects, gene expression is determined by detecting the presence of gene mRNA, the presence of a protein encoded by the gene, or both. In some aspects, the presence of gene mRNA is determined using reverse transcriptase PCR. In some aspects, the presence of the protein encoded by the gene is determined using an IHC assay. In some aspects, the IHC assay is an automated IHC assay. [0019] In some aspects, the tumor sample does not exhibit: an increased expression of one or more of CSFIR and NECTIN2 compared to the expression of the one or more of CSFIR and NECTIN2 in a reference sample; a decreased expression of one or more of STAT1 and IFN.gamma. compared to the expression of one or more of STAT1 and IFN.gamma. in a reference sample; or both (i) and (ii). In some aspects, the tumor sample does not exhibit: an increased expression of two or three of CSFIR and NECTIN2 compared to the expression of two or three of CSFIR and NECTIN2 in a reference sample; a decreased expression of two, three, or four of STAT1 and IFN.gamma. compared to the expression of two, three, or four of STAT1 and IFN.gamma. in a reference sample; or both (i) and (ii). [0020] In some aspects, the tumor sample is obtained from a stroma of the tumor. [0021] In some aspects, the anti-PD-1/PD-L1 antagonist comprises an antibody or antigen-binding fragment thereof that specifically binds a target protein selected from programmed death 1 (PD-1; an "anti-PD-1 antibody") or programmed death ligand 1 (PD-L1; an "anti-PD-L1 antibody). In some aspects, the anti-PD-1/PD-L1 antagonist is an anti-PD-1 antibody. In some aspects, the anti-PD-1 antibody comprises nivolumab or pembrolizumab. [0022] In some aspects, the anti-PD-1/PD-L1 antagonist is an anti-PD-L1 antibody. In some aspects, the anti-PD-1 antibody comprises avelumab, atezolizumab, or durvalumab. [0023] In some aspects, the anti-PD-1/PD-L1 antagonist is administered as a monotherapy. In some aspects, the anti-PD-1/PD-L1 antagonist is administered with an anti-cancer agent. In some aspects, the anti-cancer agent comprises an antibody that specifically binds a protein of Inducible T cell Co-Stimulator (ICOS), CD137 (4-1BB), CD134 (OX40), NKG2A, CD27, CD96, Glucocorticoid-Induced TNFR-Related protein (GITR), and Herpes Virus Entry Mediator (HVEM), Programmed Death-1 (PD-1), Programmed Death Ligand-1 (PD-L1), CTLA-4, B and T Lymphocyte Attenuator (BTLA), T cell Immunoglobulin and Mucin domain-3 (TIM-3), Lymphocyte Activation Gene-3 (LAG-3), adenosine A2a receptor (A2aR), Killer cell Lectin-like Receptor G1 (KLRG-1), Natural Killer Cell Receptor 2B4 (CD244), CD160, T cell Immunoreceptor with Ig and ITIM domains (TIGIT), and the receptor for V-domain Ig Suppressor of T cell Activation (VISTA), KIR, TGF.beta., IL-10, IL-8, B7-H4, Fas ligand, CSFIR, CXCR4, mesothelin, CEACAM-1, CD52, HER2, or any combination thereof. In some aspects, the anti-cancer agent comprises an anti-CSFIR antibody. [0024] In some aspects, the tumor is derived from a cancer selected from the group consisting of hepatocellular cancer, gastroesophageal cancer, melanoma, bladder cancer, lung cancer, kidney cancer, head and neck cancer, colon cancer, pancreatic cancer, prostate cancer, ovarian cancer, urothelial cancer, colorectal cancer, and any combination thereof. [0025] In some aspects, the tumor is relapsed. In some aspects, the tumor is refractory. In some aspects, the tumor is locally advanced. In some aspects, the tumor is metastatic. In some aspects, the administering treats the tumor. In some aspects, the administering reduces the size of the tumor. In some aspects, the size of the tumor is reduced by at least about 10%, about 20%, about 30%, about 40%, or about 50% compared to the tumor size prior to the administration. In some aspects, the subject exhibits progression-free survival of at least about one month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about one year, at least about eighteen months, at least about two years, at least about three years, at least about four years, or at least about five years after the initial administration. [0026] In some aspects, the subject exhibits stable disease after the administration. In some aspects, the subject exhibits a partial response after the administration. In some aspects, the subject exhibits a complete response after the administration. [0027] Certain aspects of the present disclosure are directed to a kit for treating a subject afflicted with a tumor, the kit comprising: (a) an anti-PD-1/PD-L1 antagonist; and (b) instructions for using the anti-PD-1/PD-L1 antagonist in any method disclosed herein. In some aspects, the anti-PD-1/PD-L1 antagonist comprises an anti-PD-1 antibody. In some aspects, the anti-PD-1/PD-L1 antagonist comprises an anti-PD-L1 antibody. [0028] Certain aspects of the present disclosure are directed to a gene panel comprising at least three of STAT1, IFN.gamma., NECTIN2, and CSFIR, for use in identifying a subject suitable for an anti-PD-1/PD-L1 antagonist. In some aspects, the gene panel comprises at least four, at least five, or at least six of STAT1, IFN.gamma., NECTIN2, and CSFIR. In some aspects, the gene panel comprises STAT1, IFN.gamma., NECTIN2, and CSFIR. In some aspects, the gene panel consists of STAT1, IFN.gamma., NECTIN2, and CSFIR and one additional gene, two additional genes, three additional genes, four additional genes, five additional genes, six additional genes, seven additional genes, eight additional genes, nine additional genes, or ten additional genes. In some aspects, the gene panel consists of STAT1, IFN.gamma., NECTIN2, and CSFIR, and one additional gene, two additional genes, three additional genes, four additional genes, five additional genes, six additional genes, seven additional genes, eight additional genes, nine additional genes, or ten additional genes. In some aspects, the gene panel comprises about 90 genes, about 95 genes, or about 100 genes. [0029] A method for preparing a nucleic acid fraction from a tumor of a subject in need of an I/O therapy, comprising: (a) extracting a tumor biopsy from the subject; (b) producing a fraction of nucleic acids extracted in (a) by isolating the nucleic acids; and (c) analyzing the expression level of one or more genes in a gene panel selected from STAT1, IFN.gamma., NECTIN2, and CSFIR. In some aspects, the nucleic acids are mRNA. [0030] In some aspects, one or both of CSFIR and NECTIN2 genes are downregulated. In some aspects, one or both of STAT1 and IFN.gamma. genes are upregulated. In some aspects, CSFIR and NECTIN2 are downregulated, and STAT1 and IFN.gamma. are upregulated. [0031] In some aspects, the expression level is analyzed by measuring an mRNA level of the one or more genes in the gene panel in the tumor sample. In some aspects, the expression level is measured using a nuclease protection assay. In some aspects, the expression level is measured using next-generation sequencing. In some aspects, the expression level is measured using reverse transcriptase polymerase chain reaction (RT-PCR). [0032] In some aspects, the expression of one or both of STAT1 and IFN.gamma. is increased at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 100%, at least about 125%, at least about 150%, at least about 175%, at least about 200%, at least about 225%, at least about 250%, at least about 275%, or at least about 300% higher than the expression of one or both of STAT1 and IFN.gamma. in the reference sample. In some aspects, the expression of one or both of STAT1 and IFN.gamma. is increased at least about 50% higher than the expression of one or both of STAT1 and IFN.gamma. in the reference sample. In some aspects, the expression of one or both of STAT1 and IFN.gamma. is increased at least about 75% higher than the expression of one or both of STAT1 and IFN.gamma. in the reference sample. [0033] In some aspects, the expression of one or both of NECTIN2 and CSFIR is decreased at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 100%, at least about 125%, at least about 150%, at least about 175%, at least about 200%, at least about 225%, at least about 250%, at least about 275%, or at least about 300% lower than the expression of one or more of NECTIN2 and CSFIR in the reference sample. In some aspects, the expression of one or both of NECTIN2 and CSFIR is decreased at least about 50% lower than the expression of one or more of NECTIN2 and CSFIR in the reference sample. In some aspects, the expression of one or both of NECTIN2 and CSFIR is decreased at least about 75% lower than the expression of one or more of NECTIN2 and CSFIR in the reference sample. |
|
|
return to message board, top of board |
