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

2021-07-08

Andrews, Miles C

Duong, Connie P M

Gopalakrishnan, Vancheswaran

Iebba, Valerio

Chen, Wei-Shen

Derosa, Lisa

Khan, Md Abdul Wadud

Cogdill, Alexandria P

White, Michael G

Wong, Matthew C

Ferrere, Gladys

Fluckiger, Aurélie

Roberti, Maria P

Opolon, Paule

Alou, Maryam Tidjani

Yonekura, Satoru

Roh, Whijae

Spencer, Christine N

Curbelo, Irina Fernandez

Vence, Luis

Reuben, Alexandre

Johnson, Sarah

Arora, Reetakshi

Morad, Golnaz

Lastrapes, Matthew

Baruch, Erez N

Little, Latasha

Gumbs, Curtis

Cooper, Zachary A

Prieto, Peter A

Wani, Khalida

Lazar, Alexander J

Tetzlaff, Michael T

Hudgens, Courtney W

Callahan, Margaret K

Adamow, Matthew

Postow, Michael A

Ariyan, Charlotte E

Gaudreau, Pierre-Olivier

Nezi, Luigi

Raoult, Didier

Mihalcioiu, Catalin

Elkrief, Arielle

Pezo, Rossanna C

Haydu, Lauren E

Simon, Julie M

Tawbi, Hussein A

McQuade, Jennifer

Hwu, Patrick

Hwu, Wen-Jen

Amaria, Rodabe N

Burton, Elizabeth M

Woodman, Scott E

Watowich, Stephanie

Diab, Adi

Patel, Sapna P

Glitza, Isabella C

Wong, Michael K

Zhao, Li

Zhang, Jianhua

Ajami, Nadim J

Petrosino, Joseph

Jenq, Robert R

Davies, Michael A

Gershenwald, Jeffrey E

Futreal, P Andrew

Sharma, Padmanee

Allison, James P

Routy, Bertrand

Zitvogel, Laurence

Wargo, Jennifer A

Journal Article

0000-0003-1231-8641

0000-0002-9067-8557

0000-0002-0716-306X

0000-0003-0527-2964

0000-0001-5022-5505

0000-0001-5788-6840

0000-0003-4047-3016

0000-0002-7395-9939

0000-0003-3441-4095

0000-0003-4510-0382

0000-0002-9460-618X

0000-0003-1059-0940

0000-0002-6395-4499

0000-0001-8312-7485

0000-0002-9087-0012

0000-0002-7709-0126

0000-0002-4670-7656

0000-0002-0633-5974

0000-0003-1942-851X

0000-0002-2393-2172

0000-0001-6876-278X

0000-0003-1969-659X

0000-0001-5412-9860

0000-0002-0977-0912

0000-0001-8663-2671

0000-0003-4658-055X

0000-0003-1596-0998

0000-0003-3438-7576

10.1038/s41591-021-01406-6

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.

link

Nature Medicine 2021; 27(8): 1432-1441

Nature Medicine