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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.
| Original language | English |
|---|---|
| Pages (from-to) | 1432–1441 |
| Number of pages | 10 |
| Journal | Nature Medicine |
| Volume | 27 |
| Issue number | 8 |
| DOIs | |
| Publication status | Published - Aug 2021 |
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Andrews, M. C., Duong, C. P. M., Gopalakrishnan, V., Iebba, V., Chen, W. S., Derosa, L., Khan, M. A. W., Cogdill, A. P., White, M. G., Wong, M. C., Ferrere, G., Fluckiger, A., Roberti, M. P., Opolon, P., Alou, M. T., Yonekura, S., Roh, W., Spencer, C. N., Curbelo, I. F., ... Wargo, J. A. (2021). Gut microbiota signatures are associated with toxicity to combined CTLA-4 and PD-1 blockade. Nature Medicine, 27(8), 1432–1441. https://doi.org/10.1038/s41591-021-01406-6
Andrews, Miles C. ; Duong, Connie P.M. ; Gopalakrishnan, Vancheswaran et al. / Gut microbiota signatures are associated with toxicity to combined CTLA-4 and PD-1 blockade. In: Nature Medicine. 2021 ; Vol. 27, No. 8. pp. 1432–1441.
@article{fdca99326a8842e59a5a0ea722f6f1ba,
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 = "Funding Information: M.C.A. reports advisory board participation and honoraria from Merck Sharp and Dohme, outside the submitted work. V.G. and Z.A.C. are currently employees of AstraZeneca. R.N.A. reports research funding from Bristol-Myers Squibb (BMS), Merck and Genentech, all outside the submitted work. R.C.P. reports honoraria EMD Serono, Merck, Norvartis and Pfizer as well as consulting for Merck, BMS, Novartis, Pfizer and AstraZeneca, and research funding from Merck and Novartis outside the submitted work. H.A.T. reports personal fees from Novartis, grants from Merck and Celgene and grants and personal fees from BMS and Genentech, all outside the submitted work. M.A.D. has been a consultant to Roche/Genentech, Array, Novartis, BMS, GlaxoSmithKline (GSK), Sanofi-Aventis, Vaccinex and Apexigen, and he has been the PI of research grants to UT MD Anderson by Roche/Genentech, GSK, Sanofi-Aventis, Merck, Myriad and Oncothyreon. W.-J.H. reports research grants from Merck, BMS, MedImmune and GSK and has served on an advisory board for Merck, all outside the submitted work. J.E.G. reports advisory board participation with Merck, Regeneron, BMS, Novartis and Syndax. A.J.L. reports personal fees from BMS, Novartis, Genentech/Roche and Merck; personal fees and non-financial support from ArcherDX and Beta-Cat; grants and non-financial support from Medimmune/AstraZeneca and Sanofi; grants, personal fees and non-financial support from Janssen, all outside the submitted work. M.T.T. reports personal fees from Myriad Genetics, Seattle Genetics and Novartis, all outside the submitted work. A.P.C. reports advisory roles and/or stock ownership for Immunai and Vastbiome. M.A.P. reports honoraria from BMS and Merck, consulting fees from BMS, Merck, Array BioPharma, Novartis, Incyte, NewLink Genetics, Aduro, Eisai and Pfizer and institutional support from RGenix, Infinity, BMS, Merck, Array BioPharma, Novartis and AstraZeneca. S.P.P. reports institutional support for a clinical trial from InxMed. J.L.M. reports honoraria from Roche, BMS and Merck. R.R.J. has consulted for Karius, Merck, Microbiome DX and Prolacta, and is on the scientific advisory boards of Kaleido, LISCure, Maat Pharma and Seres, and has received patent royalties licensed to Seres. P.S. reports consulting, advisory roles and/ or stocks/ownership for Achelois, Adaptive Biotechnologies, Apricity Health, BioAlta, BioNTech, Codiak Biosciences, Constellation, Dragonfly Therapeutics, Forty-Seven Inc., Hummingbird, ImaginAb, Infinity Pharma, Jounce Therapeutics, Lave Therapeutics, Lytix Biopharma, Marker Therapeutics, Oncolytics, Phenomics and Polaris, and owns a patent licensed to Jounce Therapeutics. J.P.A. reports consulting, advisory roles and/ or stocks/ownership for Achelois, Adaptive Biotechnologies, Apricity Health, BioAlta, BioNTech, Codiak Biosciences, Constellation, Dragonfly Therapeutics, Forty-Seven Inc., Hummingbird, ImaginAb, Jounce Therapeutics, Lave Therapeutics, Lytix Biopharma, Marker Therapeutics, Phenomics and Polaris, and owns a patent licensed to Jounce Therapeutics. B.R. reports advisory board membership for Vedanta and research funding from Vedanta, Davoltera and Kaleido. V.G., C.N.S., A.R. and J.A.W. are co-inventors on US patent PCT/US17/53,717, relating to the microbiome. J.A.W., V.G., M.C.A., L. Zitvogel and V.I. are co-inventors on a provisional US patent (WO2020106983A1) relating to the microbiome, relevant to the current work. L. Zitvogel is the main founder of EverImmune, a biotech company devoted to the use of commensal bacteria for the treatment of cancers, is on the board of administrators of Transgene and in the scientific advisory board of EpiVax, Lytix Biopharma, and has received research contracts from Kaleido, BMS, Incyte, Transgene, MERUS and GSK. J.A.W. reports speaker fees from Imedex, Dava Oncology, Omniprex, Illumina, Gilead, MedImmune and BMS; consultant/advisor roles or advisory board membership for Roche-Genentech, Novartis, AstraZeneca, GSK, BMS, Merck/MSD, Biothera Pharma and Microbiome DX; and receives clinical trial support from GSK, Roche-Genentech, BMS and Novartis, all outside the current work. The remaining authors declare no competing interests. Funding Information: This research was supported by generous philanthropic contributions to The University of Texas MD Anderson Cancer Center Moon Shots Program from the Lyda Hill Foundation and utilized platform assistance from the Cancer Genomics Laboratory and Immunotherapy Platform, from the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation and the AIM at Melanoma Foundation. Additional support was provided to P.A.F. from the Cancer Prevention Research Institute of Texas and the Welch Foundation. M.A.D. is supported by the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, the AIM at Melanoma Foundation, the NIH/NCI (1 P50 CA221703-02 and 1U54CA224070-03), the American Cancer Society and the Melanoma Research Alliance, Cancer Fighters of Houston, the Anne and John Mendelsohn Chair for Cancer Research, and philanthropic contributions to the Melanoma Moon Shots Program of MD Anderson. M.C.A. is supported by a National Health and Medical Research Council of Australia CJ Martin Early Career Fellowship (#1148680). W.-S.C. was supported by a National Institutes of Health T32 Training Grant (T32CA163185). A.P.C. is supported by the CPRIT Research Training Program (RP170067), the Fulbright France Commission Franco-Americain{\'e} and the John J. Kopchick Foundation. A.R. is supported by the Kimberley Clark Foundation Award for Scientific Achievement provided by MD Anderson{\textquoteright}s Odyssey Fellowship Program. P.-O.G. was supported by the Fonds de Recherche Qu{\'e}bec–Sant{\'e}{\textquoteright}s (FRQS) Resident Physician Health Research Career Training Program (32667). M.G.W. was supported by National Institutes of Health (T32CA009599) and an MD Anderson Cancer Center support grant (P30 CA016672). M.A.P. received support from the MSK Cancer Center Support Grant/Core Grant (P30 CA008748). We acknowledge the assistance of the animal facility team at Gustave Roussy. L. Zitvogel is funded by grants from EU H2020 ONCOBIOME, Ligue contre le Cancer ({\'e}quipe labelis{\'e}e); Agence Nationale de la Recherche (ANR)—Projets blancs; ANR under the frame of E-Rare-2, the ERA-Net for Research on Rare Diseases; Association pour la recherche sur le cancer (ARC); Canc{\'e}rop{\^o}le Ile-de-France; Chancellerie des universit{\'e}s de Paris (Legs Poix), Fondation de France; Fondation pour la Recherche M{\'e}dicale (FRM); a donation by Elior; Fondation Carrefour; Institut National du Cancer (INCa); Inserm (HTE); ANR germanofrench; LabEx Immuno-Oncology; the French Ministry of Health PIA2, RHU Torino Lumi{\`e}re (ANR-16-RHUS-0008); the Swiss Bridge Foundation; the Seerave and Carrefour Foundation; the SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE). This work was supported by the French Government under the {\textquoteleft}Investissements d{\textquoteright}avenir{\textquoteright} (Investments for the Future) program managed by the Agence Nationale de la Recherche (ANR, fr: National Agency for Research, M{\'e}diterran{\'e}e Infection 10-IAHU-03; L. Zitvogel). M.K.C. is supported by an institutional grant (NIH P30 CA008748). L.D. is supported by {\textquoteleft}Parcours d{\textquoteright}excellence en canc{\'e}rologie—Fondation Philanthropia{\textquoteright}. This work was supported by R{\'e}gion Provence Alpes C{\^o}te d{\textquoteright}Azur and European funding FEDER PRIMI. R.C.P. was supported by a Strategic Innovation Grant from the Division of Medical Oncology, University of Toronto. R.C.P. was supported by a Strategic Innovation Grant from the Division of Medical Oncology, University of Toronto. J.A.W. is supported by the National Institutes of Health (1R01CA219896-01A1), the Melanoma Research Alliance (4022024), American Association for Cancer Research Stand Up To Cancer (SU2C-AACR-IRG-19-17) and the MD Anderson Melanoma Moonshot Program. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. Publisher Copyright: {\textcopyright} 2021, The Author(s), under exclusive licence to Springer Nature America, Inc. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.",
year = "2021",
month = aug,
doi = "10.1038/s41591-021-01406-6",
language = "English",
volume = "27",
pages = "1432–1441",
journal = "Nature Medicine",
issn = "1078-8956",
publisher = "Nature Publishing Group",
number = "8",
}
Andrews, MC, Duong, CPM, Gopalakrishnan, V, Iebba, V, Chen, WS, Derosa, L, Khan, MAW, Cogdill, AP, White, MG, Wong, MC, Ferrere, G, Fluckiger, A, Roberti, MP, Opolon, P, Alou, MT, Yonekura, S, Roh, W, Spencer, CN, Curbelo, IF, Vence, L, Reuben, A, Johnson, S, Arora, R, Morad, G, Lastrapes, M, Baruch, EN, Little, L, Gumbs, C, Cooper, ZA, Prieto, PA, Wani, K, Lazar, AJ, Tetzlaff, MT, Hudgens, CW, Callahan, MK, Adamow, M, Postow, MA, Ariyan, CE, Gaudreau, PO, Nezi, L, Raoult, D, Mihalcioiu, C, Elkrief, A, Pezo, RC, Haydu, LE, Simon, JM, Tawbi, HA, McQuade, J, Hwu, P, Hwu, WJ, Amaria, RN, Burton, EM, Woodman, SE, Watowich, S, Diab, A, Patel, SP, Glitza, IC, Wong, MK, Zhao, L, Zhang, J, Ajami, NJ, Petrosino, J, Jenq, RR, Davies, MA, Gershenwald, JE, Futreal, PA, Sharma, P, Allison, JP, Routy, B, Zitvogel, L & Wargo, JA 2021, 'Gut microbiota signatures are associated with toxicity to combined CTLA-4 and PD-1 blockade', Nature Medicine, vol. 27, no. 8, pp. 1432–1441. https://doi.org/10.1038/s41591-021-01406-6
Gut microbiota signatures are associated with toxicity to combined CTLA-4 and PD-1 blockade. / Andrews, Miles C.; Duong, Connie P.M.; Gopalakrishnan, Vancheswaran et al.
In: Nature Medicine, Vol. 27, No. 8, 08.2021, p. 1432–1441.
In: Nature Medicine, Vol. 27, No. 8, 08.2021, p. 1432–1441.
Research output: Contribution to journal › Article › Research › peer-review
TY - JOUR
T1 - Gut microbiota signatures are associated with toxicity to combined CTLA-4 and PD-1 blockade
AU - Andrews, Miles C.
AU - Duong, Connie P.M.
AU - Gopalakrishnan, Vancheswaran
AU - Iebba, Valerio
AU - Chen, Wei Shen
AU - Derosa, Lisa
AU - Khan, Md Abdul Wadud
AU - Cogdill, Alexandria P.
AU - White, Michael G.
AU - Wong, Matthew C.
AU - Ferrere, Gladys
AU - Fluckiger, Aurélie
AU - Roberti, Maria P.
AU - Opolon, Paule
AU - Alou, Maryam Tidjani
AU - Yonekura, Satoru
AU - Roh, Whijae
AU - Spencer, Christine N.
AU - Curbelo, Irina Fernandez
AU - Vence, Luis
AU - Reuben, Alexandre
AU - Johnson, Sarah
AU - Arora, Reetakshi
AU - Morad, Golnaz
AU - Lastrapes, Matthew
AU - Baruch, Erez N.
AU - Little, Latasha
AU - Gumbs, Curtis
AU - Cooper, Zachary A.
AU - Prieto, Peter A.
AU - Wani, Khalida
AU - Lazar, Alexander J.
AU - Tetzlaff, Michael T.
AU - Hudgens, Courtney W.
AU - Callahan, Margaret K.
AU - Adamow, Matthew
AU - Postow, Michael A.
AU - Ariyan, Charlotte E.
AU - Gaudreau, Pierre Olivier
AU - Nezi, Luigi
AU - Raoult, Didier
AU - Mihalcioiu, Catalin
AU - Elkrief, Arielle
AU - Pezo, Rossanna C.
AU - Haydu, Lauren E.
AU - Simon, Julie M.
AU - Tawbi, Hussein A.
AU - McQuade, Jennifer
AU - Hwu, Patrick
AU - Hwu, Wen Jen
AU - Amaria, Rodabe N.
AU - Burton, Elizabeth M.
AU - Woodman, Scott E.
AU - Watowich, Stephanie
AU - Diab, Adi
AU - Patel, Sapna P.
AU - Glitza, Isabella C.
AU - Wong, Michael K.
AU - Zhao, Li
AU - Zhang, Jianhua
AU - Ajami, Nadim J.
AU - Petrosino, Joseph
AU - Jenq, Robert R.
AU - Davies, Michael A.
AU - Gershenwald, Jeffrey E.
AU - Futreal, P. Andrew
AU - Sharma, Padmanee
AU - Allison, James P.
AU - Routy, Bertrand
AU - Zitvogel, Laurence
AU - Wargo, Jennifer A.
N1 - Funding Information: M.C.A. reports advisory board participation and honoraria from Merck Sharp and Dohme, outside the submitted work. V.G. and Z.A.C. are currently employees of AstraZeneca. R.N.A. reports research funding from Bristol-Myers Squibb (BMS), Merck and Genentech, all outside the submitted work. R.C.P. reports honoraria EMD Serono, Merck, Norvartis and Pfizer as well as consulting for Merck, BMS, Novartis, Pfizer and AstraZeneca, and research funding from Merck and Novartis outside the submitted work. H.A.T. reports personal fees from Novartis, grants from Merck and Celgene and grants and personal fees from BMS and Genentech, all outside the submitted work. M.A.D. has been a consultant to Roche/Genentech, Array, Novartis, BMS, GlaxoSmithKline (GSK), Sanofi-Aventis, Vaccinex and Apexigen, and he has been the PI of research grants to UT MD Anderson by Roche/Genentech, GSK, Sanofi-Aventis, Merck, Myriad and Oncothyreon. W.-J.H. reports research grants from Merck, BMS, MedImmune and GSK and has served on an advisory board for Merck, all outside the submitted work. J.E.G. reports advisory board participation with Merck, Regeneron, BMS, Novartis and Syndax. A.J.L. reports personal fees from BMS, Novartis, Genentech/Roche and Merck; personal fees and non-financial support from ArcherDX and Beta-Cat; grants and non-financial support from Medimmune/AstraZeneca and Sanofi; grants, personal fees and non-financial support from Janssen, all outside the submitted work. M.T.T. reports personal fees from Myriad Genetics, Seattle Genetics and Novartis, all outside the submitted work. A.P.C. reports advisory roles and/or stock ownership for Immunai and Vastbiome. M.A.P. reports honoraria from BMS and Merck, consulting fees from BMS, Merck, Array BioPharma, Novartis, Incyte, NewLink Genetics, Aduro, Eisai and Pfizer and institutional support from RGenix, Infinity, BMS, Merck, Array BioPharma, Novartis and AstraZeneca. S.P.P. reports institutional support for a clinical trial from InxMed. J.L.M. reports honoraria from Roche, BMS and Merck. R.R.J. has consulted for Karius, Merck, Microbiome DX and Prolacta, and is on the scientific advisory boards of Kaleido, LISCure, Maat Pharma and Seres, and has received patent royalties licensed to Seres. P.S. reports consulting, advisory roles and/ or stocks/ownership for Achelois, Adaptive Biotechnologies, Apricity Health, BioAlta, BioNTech, Codiak Biosciences, Constellation, Dragonfly Therapeutics, Forty-Seven Inc., Hummingbird, ImaginAb, Infinity Pharma, Jounce Therapeutics, Lave Therapeutics, Lytix Biopharma, Marker Therapeutics, Oncolytics, Phenomics and Polaris, and owns a patent licensed to Jounce Therapeutics. J.P.A. reports consulting, advisory roles and/ or stocks/ownership for Achelois, Adaptive Biotechnologies, Apricity Health, BioAlta, BioNTech, Codiak Biosciences, Constellation, Dragonfly Therapeutics, Forty-Seven Inc., Hummingbird, ImaginAb, Jounce Therapeutics, Lave Therapeutics, Lytix Biopharma, Marker Therapeutics, Phenomics and Polaris, and owns a patent licensed to Jounce Therapeutics. B.R. reports advisory board membership for Vedanta and research funding from Vedanta, Davoltera and Kaleido. V.G., C.N.S., A.R. and J.A.W. are co-inventors on US patent PCT/US17/53,717, relating to the microbiome. J.A.W., V.G., M.C.A., L. Zitvogel and V.I. are co-inventors on a provisional US patent (WO2020106983A1) relating to the microbiome, relevant to the current work. L. Zitvogel is the main founder of EverImmune, a biotech company devoted to the use of commensal bacteria for the treatment of cancers, is on the board of administrators of Transgene and in the scientific advisory board of EpiVax, Lytix Biopharma, and has received research contracts from Kaleido, BMS, Incyte, Transgene, MERUS and GSK. J.A.W. reports speaker fees from Imedex, Dava Oncology, Omniprex, Illumina, Gilead, MedImmune and BMS; consultant/advisor roles or advisory board membership for Roche-Genentech, Novartis, AstraZeneca, GSK, BMS, Merck/MSD, Biothera Pharma and Microbiome DX; and receives clinical trial support from GSK, Roche-Genentech, BMS and Novartis, all outside the current work. The remaining authors declare no competing interests. Funding Information: This research was supported by generous philanthropic contributions to The University of Texas MD Anderson Cancer Center Moon Shots Program from the Lyda Hill Foundation and utilized platform assistance from the Cancer Genomics Laboratory and Immunotherapy Platform, from the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation and the AIM at Melanoma Foundation. Additional support was provided to P.A.F. from the Cancer Prevention Research Institute of Texas and the Welch Foundation. M.A.D. is supported by the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, the AIM at Melanoma Foundation, the NIH/NCI (1 P50 CA221703-02 and 1U54CA224070-03), the American Cancer Society and the Melanoma Research Alliance, Cancer Fighters of Houston, the Anne and John Mendelsohn Chair for Cancer Research, and philanthropic contributions to the Melanoma Moon Shots Program of MD Anderson. M.C.A. is supported by a National Health and Medical Research Council of Australia CJ Martin Early Career Fellowship (#1148680). W.-S.C. was supported by a National Institutes of Health T32 Training Grant (T32CA163185). A.P.C. is supported by the CPRIT Research Training Program (RP170067), the Fulbright France Commission Franco-Americainé and the John J. Kopchick Foundation. A.R. is supported by the Kimberley Clark Foundation Award for Scientific Achievement provided by MD Anderson’s Odyssey Fellowship Program. P.-O.G. was supported by the Fonds de Recherche Québec–Santé’s (FRQS) Resident Physician Health Research Career Training Program (32667). M.G.W. was supported by National Institutes of Health (T32CA009599) and an MD Anderson Cancer Center support grant (P30 CA016672). M.A.P. received support from the MSK Cancer Center Support Grant/Core Grant (P30 CA008748). We acknowledge the assistance of the animal facility team at Gustave Roussy. L. Zitvogel is funded by grants from EU H2020 ONCOBIOME, Ligue contre le Cancer (équipe labelisée); Agence Nationale de la Recherche (ANR)—Projets blancs; ANR under the frame of E-Rare-2, the ERA-Net for Research on Rare Diseases; Association pour la recherche sur le cancer (ARC); Cancéropôle Ile-de-France; Chancellerie des universités de Paris (Legs Poix), Fondation de France; Fondation pour la Recherche Médicale (FRM); a donation by Elior; Fondation Carrefour; Institut National du Cancer (INCa); Inserm (HTE); ANR germanofrench; LabEx Immuno-Oncology; the French Ministry of Health PIA2, RHU Torino Lumière (ANR-16-RHUS-0008); the Swiss Bridge Foundation; the Seerave and Carrefour Foundation; the SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE). This work was supported by the French Government under the ‘Investissements d’avenir’ (Investments for the Future) program managed by the Agence Nationale de la Recherche (ANR, fr: National Agency for Research, Méditerranée Infection 10-IAHU-03; L. Zitvogel). M.K.C. is supported by an institutional grant (NIH P30 CA008748). L.D. is supported by ‘Parcours d’excellence en cancérologie—Fondation Philanthropia’. This work was supported by Région Provence Alpes Côte d’Azur and European funding FEDER PRIMI. R.C.P. was supported by a Strategic Innovation Grant from the Division of Medical Oncology, University of Toronto. R.C.P. was supported by a Strategic Innovation Grant from the Division of Medical Oncology, University of Toronto. J.A.W. is supported by the National Institutes of Health (1R01CA219896-01A1), the Melanoma Research Alliance (4022024), American Association for Cancer Research Stand Up To Cancer (SU2C-AACR-IRG-19-17) and the MD Anderson Melanoma Moonshot Program. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. Publisher Copyright: © 2021, The Author(s), under exclusive licence to Springer Nature America, Inc. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2021/8
Y1 - 2021/8
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85109895475&partnerID=8YFLogxK
U2 - 10.1038/s41591-021-01406-6
DO - 10.1038/s41591-021-01406-6
M3 - Article
C2 - 34239137
AN - SCOPUS:85109895475
SN - 1078-8956
VL - 27
SP - 1432
EP - 1441
JO - Nature Medicine
JF - Nature Medicine
IS - 8
ER -
Andrews MC, Duong CPM, Gopalakrishnan V, Iebba V, Chen WS, Derosa L et al. Gut microbiota signatures are associated with toxicity to combined CTLA-4 and PD-1 blockade. Nature Medicine. 2021 Aug;27(8):1432–1441. doi: 10.1038/s41591-021-01406-6