Distinct Predictive Immunogenomic Profiles of Response to Immune Checkpoint Inhibitors and IL2: A Real-world Evidence Study of Patients with Advanced Renal Cancer.

Autor:	Eisner JR; GeneCentric Therapeutics, Inc., Durham, North Carolina., Beebe KD; GeneCentric Therapeutics, Inc., Durham, North Carolina., Mayhew GM; GeneCentric Therapeutics, Inc., Durham, North Carolina., Shibata Y; GeneCentric Therapeutics, Inc., Durham, North Carolina., Guo Y; GeneCentric Therapeutics, Inc., Durham, North Carolina., Farhangfar C; Levine Cancer Institute, Atrium Health, Charlotte, North Carolina., Farhangfar F; Levine Cancer Institute, Atrium Health, Charlotte, North Carolina., Uronis JM; GeneCentric Therapeutics, Inc., Durham, North Carolina., Mooney J; Synthorx, Inc - A Sanofi Company, La Jolla, California., Milburn MV; GeneCentric Therapeutics, Inc., Durham, North Carolina., Foureau D; Levine Cancer Institute, Atrium Health, Charlotte, North Carolina., White RL; Levine Cancer Institute, Atrium Health, Charlotte, North Carolina., Amin A; Levine Cancer Institute, Atrium Health, Charlotte, North Carolina., Milla ME; Synthorx, Inc - A Sanofi Company, La Jolla, California.
Jazyk:	angličtina
Zdroj:	Cancer research communications [Cancer Res Commun] 2022 Aug 30; Vol. 2 (8), pp. 894-903. Date of Electronic Publication: 2022 Aug 30 (Print Publication: 2022).
DOI:	10.1158/2767-9764.CRC-21-0153
Abstrakt:	Recombinant human high-dose IL2 (HD-IL2; aldesleukin) was one of the first approved immune-oncology agents based upon clinical activity in renal cell carcinoma (RCC) and metastatic melanoma but use was limited due to severe toxicity. Next-generation IL2 agents designed to improve tolerability are in development, increasing the need for future identification of genomic markers of clinical benefit and/or clinical response. In this retrospective study, we report clinical and tumor molecular profiling from patients with metastatic RCC (mRCC) treated with HD-IL2 and compare findings with patients with RCC treated with anti-PD-1 therapy. Genomic characteristics common and unique to IL2 and/or anti-PD-1 therapy response are presented, with insight into rational combination strategies for these agents. Residual pretreatment formalin-fixed paraffin embedded tumor samples from n = 36 patients with HD-IL2 mRCC underwent RNA-sequencing and corresponding clinical data were collected. A de novo 40-gene nearest centroid IL2 treatment response classifier and individual gene and/or immune marker signature differences were correlated to clinical response and placed into context with a separate dataset of n = 35 patients with anti-PD-1 mRCC. Immune signatures and genes, comprising suppressor and effector cells, were increased in patients with HD-IL2 clinical benefit. The 40-gene response classifier was also highly enriched for immune genes. While several effector immune signatures and genes were common between IL2 and anti-PD-1 treated patients, multiple inflammatory and/or immunosuppressive genes, previously reported to predict poor response to anti-PD-L1 immunotherapy, were only increased in IL2-responsive tumors. These findings suggest that common and distinct immune-related response markers for IL2 and anti-PD-1 therapy may help guide their use, either alone or in combination. Significance: Next-generation IL2 agents, designed for improved tolerability over traditional HD-IL2 (aldesleukin), are in clinical development. Retrospective molecular tumor profiling of patients treated with HD-IL2 or anti-PD-1 therapy provides insights into genomic characteristics of therapy response. This study revealed common and distinct immune-related predictive response markers for IL2 and anti-PD-1 therapy which may play a role in therapy guidance, and rational combination strategies for these agents. Competing Interests: J.R. Eisner reports other from Synthorx, a Sanofi company during the conduct of the study. K.D. Beebe reports other from Synthorx, a Sanofi company during the conduct of the study. G.M. Mayhew reports other from Synthorx, a Sanofi company during the conduct of the study. Y. Shibata reports other from Synthorx, a Sanofi company during the conduct of the study. Y. Guo reports other from Synthorx, a Sanofi company during the conduct of the study. C. Farhangfar reports other from GeneCentric during the conduct of the study. F. Farhangfar reports other from GeneCentric during the conduct of the study; other from GeneCentric outside the submitted work. J.M. Uronis reports other from Synthorx, a Sanofi Company during the conduct of the study. M.V. Milburn reports other from Synthorx a Sanofi Company during the conduct of the study. D. Foureau reports other from GeneCentric during the conduct of the study. A. Amin reports personal fees from BMS, Eisai; grants from Merck, Exelixis, and BMS outside the submitted work. M.E. Milla reports other from Synthorx – A Sanofi Company during the conduct of the study; other from Synthorx – A Sanofi Company outside the submitted work. No disclosures were reported by the other author. (© 2022 The Authors; Published by the American Association for Cancer Research.)
Databáze:	MEDLINE
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