| Literature DB >> 34239137 |
Miles C Andrews1,2,3, Connie P M Duong4,5,6, Vancheswaran Gopalakrishnan1, Valerio Iebba4,5, Wei-Shen Chen7,8, Lisa Derosa4,5,6, Md Abdul Wadud Khan1, Alexandria P Cogdill4,5,6,7, Michael G White1, Matthew C Wong7, Gladys Ferrere4,5,6, Aurélie Fluckiger4,5,6, Maria P Roberti4,5,6, Paule Opolon4, Maryam Tidjani Alou4,5,6, Satoru Yonekura4,5,6, Whijae Roh7, Christine N Spencer9, Irina Fernandez Curbelo10, Luis Vence10, Alexandre Reuben11, Sarah Johnson1, Reetakshi Arora1, Golnaz Morad1, Matthew Lastrapes12, Erez N Baruch7, Latasha Little7, Curtis Gumbs7, Zachary A Cooper13, Peter A Prieto14, Khalida Wani15, Alexander J Lazar7,15, Michael T Tetzlaff15, Courtney W Hudgens15, Margaret K Callahan9,16, Matthew Adamow16,17, Michael A Postow16,17, Charlotte E Ariyan18, Pierre-Olivier Gaudreau1, Luigi Nezi19, Didier Raoult20, Catalin Mihalcioiu21, Arielle Elkrief22, Rossanna C Pezo23, Lauren E Haydu1, Julie M Simon1, Hussein A Tawbi24, Jennifer McQuade24, Patrick Hwu24, Wen-Jen Hwu24, Rodabe N Amaria24, Elizabeth M Burton1, Scott E Woodman7,24, Stephanie Watowich10, Adi Diab24, Sapna P Patel24, Isabella C Glitza24, Michael K Wong24, Li Zhao7, Jianhua Zhang7, Nadim J Ajami7, Joseph Petrosino25, Robert R Jenq7, Michael A Davies24, Jeffrey E Gershenwald1, P Andrew Futreal7, Padmanee Sharma10, James P Allison10, Bertrand Routy4,5,6, Laurence Zitvogel26,27,28, Jennifer A Wargo29,30.
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.Entities:
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Year: 2021 PMID： 34239137 DOI： 10.1038/s41591-021-01406-6
Source DB: PubMed Journal: Nat Med ISSN： 1078-8956 Impact factor: 87.241