@article{2ce897deba2c4aaeb5a23cec0d1e866a,
title = "A Uniform computational approach improved on existing pipelines to reveal microbiome biomarkers of nonresponse to immune checkpoint inhibitors",
abstract = "Purpose: While immune checkpoint inhibitors (ICI) have revolutionized the treatment of cancer by producing durable antitumor responses, only 10%-30% of treated patients respond and the ability to predict clinical benefit remains elusive. Several studies, small in size and using variable analytic methods, suggest the gut microbiome may be a novel, modifiable biomarker for tumor response rates, but the specific bacteria or bacterial communities putatively impacting ICI responses have been inconsistent across the studied populations. Experimental Design: We have reanalyzed the available raw 16S rRNA amplicon and metagenomic sequencing data across five recently published ICI studies (n = 303 unique patients) using a uniform computational approach. Results: Herein, we identify novel bacterial signals associated with clinical responders (R) or nonresponders (NR) and develop an integrated microbiome prediction index. Unexpectedly, the NRassociated integrated index shows the strongest and most consistent signal using a random effects model and in a sensitivity and specificity analysis (P < 0.01). We subsequently tested the integrated index using validation cohorts across three distinct and diverse cancers (n = 105). Conclusions: Our analysis highlights the development of biomarkers for nonresponse, rather than response, in predicting ICI outcomes and suggests a new approach to identify patients who would benefit from microbiome-based interventions to improve response rates.",
author = "Shaikh, {Fyza Y.} and White, {James R.} and Gills, {Joell J.} and Taiki Hakozaki and Corentin Richard and Bertrand Routy and Yusuke Okuma and Mykhaylo Usyk and Abhishek Pandey and Weber, {Jeffrey S.} and Jiyoung Ahn and Lipson, {Evan J.} and Jarushka Naidoo and Pardoll, {Drew M.} and Sears, {Cynthia L.}",
note = "Funding Information: This work was funded by the Bloomberg~Kimmel Institute for Cancer Immunotherapy (BKI) and a research grant from Bristol Myers Squibb. F.Y. Shaikh was supported by NIH T32CA009071. J. Naidoo was supported by International Association for the Study of Lung Cancer (IASLC), Lung Cancer Foundation of America, NCATS KL2TR001077, and Johns Hopkins Institute for Clinical and Translational Research (ICTR). E.J. Lipson was supported by the BKI, the Barney Family Foundation, Moving for Melanoma of Delaware, The Laverna Hahn Charitable Trust, and NCI P30 CA006973. Funding Information: This work was funded by the Bloomberg-Kimmel Institute for Cancer Immunotherapy (BKI) and a research grant from Bristol Myers Squibb. F.Y. Shaikh was supported by NIH T32CA009071. J. Naidoo was supported by International Association for the Study of Lung Cancer (IASLC), Lung Cancer Foundation of America, NCATS KL2TR001077, and Johns Hopkins Institute for Clinical and Translational Research (ICTR). E.J. Lipson was supported by the BKI, the Barney Family Foundation, Moving for Melanoma of Delaware, The Laverna Hahn Charitable Trust, and NCI P30 CA006973. Funding Information: F.Y. Shaikh reports grants from Brystol Myers Squibb during the conduct of the study. J.R. White reports personal fees from Resphera Biosciences LLC outside the submitted work. J.J. Gills reports grants from Bloomberg Kimmel Foundation for Cancer Immunotherapy during the conduct of the study. Y. Okuma reports grants from AbbVie G.K.; grants and personal fees from Chugai Pharmaceutical Co., Ltd.; and personal fees from AstraZeneca, Ono Pharmaceutical Co., Ltd., Bristol Myers Squibb, and Eli Lilly outside the submitted work. J.S. Weber reports personal fees from BMS, Merck, Regeneron, Celldex, Genentech, AstraZeneca, CytoMx, Biond, and Pfizer during the conduct of the study. In addition, J.S. Weber reports is named on a patent for a PD-1 biomarker by Biodesix issued and named on a patent for a CTLA-4 biomarker by Moffitt Cancer Center issued, and equity in Biond, CytoMx, Immu-nimax and Neximmune. E.J. Lipson reports grants and personal fees from Bristol-Myers Squibb, Merck, and Sanofi/Regeneron, as well as personal fees from Novartis, EMD Serono, Array BioPharma, Macrogenics, Genentech, and Odonate Therapeutics outside the submitted work. J. Naidoo reports grants from Lung Cancer Foundation of America and International Association for the Study of Lung Cancer during the conduct of the study. In addition, J. Naidoo reports grants and personal fees from AstraZeneca, Merck, and Bristol Myers Squibb, as well as personal fees from Daiichi Sankyo, Pfizer, and Roche/Genentech outside the submitted work. D.M. Pardoll reports a patent for BMS issued to BMS. C.L. Sears reports grants from Bloomberg Philanthropies and Bristol Myers Squibb during the conduct of the study, as well as grants from Janssen outside the submitted work. No disclosures were reported by the other authors. Publisher Copyright: {\textcopyright} 2021 American Association for Cancer Research.",
year = "2021",
month = may,
day = "1",
doi = "10.1158/1078-0432.CCR-20-4834",
language = "English (US)",
volume = "27",
pages = "2571--2583",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
number = "9",
}