@article{08b46d7b13174aafbe17a0b7718b2ba2,
title = "Gut microbiota signatures are associated with toxicity to combined CTLA-4 and PD-1 blockade",
abstract = "Treatment with combined immune checkpoint blockade (CICB) targeting CTLA-4 and PD-1 is associated with clinical benefit across tumor types, but also a high rate of immune-related adverse events. Insights into biomarkers and mechanisms of response and toxicity to CICB are needed. To address this, we profiled the blood, tumor and gut microbiome of 77 patients with advanced melanoma treated with CICB, with a high rate of any ≥grade 3 immune-related adverse events (49%) with parallel studies in pre-clinical models. Tumor-associated immune and genomic biomarkers of response to CICB were similar to those identified for ICB monotherapy, and toxicity from CICB was associated with a more diverse peripheral T-cell repertoire. Profiling of gut microbiota demonstrated a significantly higher abundance of Bacteroides intestinalis in patients with toxicity, with upregulation of mucosal IL-1β in patient samples of colitis and in pre-clinical models. Together, these data offer potential new therapeutic angles for targeting toxicity to CICB.",
author = "Andrews, {Miles C.} and Duong, {Connie P.M.} and Vancheswaran Gopalakrishnan and Valerio Iebba and Chen, {Wei Shen} and Lisa Derosa and Khan, {Md Abdul Wadud} and Cogdill, {Alexandria P.} and White, {Michael G.} and Wong, {Matthew C.} and Gladys Ferrere and Aur{\'e}lie Fluckiger and Roberti, {Maria P.} and Paule Opolon and Alou, {Maryam Tidjani} and Satoru Yonekura and Whijae Roh and Spencer, {Christine N.} and Curbelo, {Irina Fernandez} and Luis Vence and Alexandre Reuben and Sarah Johnson and Reetakshi Arora and Golnaz Morad and Matthew Lastrapes and Baruch, {Erez N.} and Latasha Little and Curtis Gumbs and Cooper, {Zachary A.} and Prieto, {Peter A.} and Khalida Wani and Lazar, {Alexander J.} and Tetzlaff, {Michael T.} and Hudgens, {Courtney W.} and Callahan, {Margaret K.} and Matthew Adamow and Postow, {Michael A.} and Ariyan, {Charlotte E.} and Gaudreau, {Pierre Olivier} and Luigi Nezi and Didier Raoult and Catalin Mihalcioiu and Arielle Elkrief and Pezo, {Rossanna C.} and Haydu, {Lauren E.} and Simon, {Julie M.} and Tawbi, {Hussein A.} and Jennifer McQuade and Patrick Hwu and Hwu, {Wen Jen} and Amaria, {Rodabe N.} and Burton, {Elizabeth M.} and Woodman, {Scott E.} and Stephanie Watowich and Adi Diab and Patel, {Sapna P.} and Glitza, {Isabella C.} and Wong, {Michael K.} and Li Zhao and Jianhua Zhang and Ajami, {Nadim J.} and Joseph Petrosino and Jenq, {Robert R.} and Davies, {Michael A.} and Gershenwald, {Jeffrey E.} and Futreal, {P. Andrew} and Padmanee Sharma and Allison, {James P.} and Bertrand Routy and Laurence Zitvogel and Wargo, {Jennifer A.}",
note = "Publisher Copyright: {\textcopyright} 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.",
year = "2021",
month = aug,
doi = "10.1038/s41591-021-01406-6",
language = "English (US)",
volume = "27",
pages = "1432--1441",
journal = "Nature medicine",
issn = "1078-8956",
publisher = "Nature Publishing Group",
number = "8",
}