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Journal Articles Nature Medicine Year : 2021

Gut microbiota signatures are associated with toxicity to combined CTLA-4 and PD-1 blockade

Miles Andrews (1, 2, 3) , Connie Duong (4, 5, 6) , Vancheswaran Gopalakrishnan (1) , Valerio Iebba (4, 5) , Wei-Shen Chen (1, 7) , Lisa Derosa (5, 4, 6) , Md Abdul Wadud Khan (1) , Alexandria Cogdill (5, 6, 1) , Michael G. White (1) , Matthew Wong (1) , Gladys Ferrere (5, 4, 6) , Aurélie Fluckiger (5, 4, 6) , Maria Roberti (5, 4, 6) , Paule Opolon (4) , Maryam Tidjani Alou (5, 4, 6) , Satoru Yonekura (5, 4, 6) , Whijae Roh (1) , Christine Spencer (8) , Irina Fernandez Curbelo (1) , Luis Vence (1) , Alexandre Reuben (1) , Sarah Johnson (1) , Reetakshi Arora (1) , Golnaz Morad (1) , Matthew Lastrapes (1) , Erez Baruch (1) , Latasha Little (1) , Curtis Gumbs (1) , Zachary Cooper (9) , Peter Prieto (10) , Khalida Wani (1) , Alexander Lazar (1) , Michael Tetzlaff (1) , Courtney Hudgens (1) , Margaret Callahan (8, 11) , Matthew Adamow (11) , Michael Postow (11) , Charlotte Ariyan (11) , Pierre-Olivier Gaudreau (1) , Luigi Nezi (12) , Didier Raoult (13, 14) , Catalin Mihalcioiu (15) , Arielle Elkrief (15) , Rossanna Pezo (16) , Lauren Haydu (1) , Julie Simon (1) , Hussein Tawbi (1) , Jennifer Mcquade (1) , Patrick Hwu (1) , Wen-Jen Hwu (1) , Rodabe Amaria (1) , Elizabeth Burton (1) , Scott Woodman (1) , Stephanie Watowich (1) , Adi Diab (1) , Sapna Patel (1) , Isabella Glitza (1) , Michael Wong (1) , Li Zhao (1) , Jianhua Zhang (1) , Nadim Ajami (1) , Joseph Petrosino (17) , Robert Jenq (1) , Michael Davies (1) , Jeffrey Gershenwald (1) , P. Andrew Futreal (1) , Padmanee Sharma (1) , James Allison (1) , Bertrand Routy (5, 4, 6) , Laurence Zitvogel (4, 5, 6) , Jennifer Wargo (1)
Zachary Cooper
Luigi Nezi

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.
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Dates and versions

hal-03333724 , version 1 (06-09-2021)

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Attribution - CC BY 4.0

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Miles Andrews, Connie Duong, Vancheswaran Gopalakrishnan, Valerio Iebba, Wei-Shen Chen, et al.. Gut microbiota signatures are associated with toxicity to combined CTLA-4 and PD-1 blockade. Nature Medicine, 2021, 27 (8), pp.1432-1441. ⟨10.1038/s41591-021-01406-6⟩. ⟨hal-03333724⟩
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