Genomic predictors of response to PD-1 inhibition in children with germline DNA replication repair deficiency

Anirban Das; Sumedha Sudhaman; Daniel Morgenstern; Ailish Coblentz; Jiil Chung; Simone C Stone; Noor Alsafwani; Zhihui Amy Liu; Ola Abu Al Karsaneh; Shirin Soleimani; Hagay Ladany; David Chen; Matthew Zatzman; Vanja Cabric; Liana Nobre; Vanessa Bianchi; Melissa Edwards; Lauren C Sambira Nahum; Ayse B Ercan; Arash Nabbi; Shlomi Constantini; Rina Dvir; Michal Yalon-Oren; Gadi Abebe Campino; Shani Caspi; Valerie Larouche; Alyssa Reddy; Michael Osborn; Gary Mason; Scott Lindhorst; Annika Bronsema; Vanan Magimairajan; Enrico Opocher; Rebecca Loret De Mola; Magnus Sabel; Charlotta Frojd; David Sumerauer; David Samuel; Kristina Cole; Stefano Chiaravalli; Maura Massimino; Patrick Tomboc; David S Ziegler; Ben George; An Van Damme; Nobuko Hijiya; David Gass; Rose B McGee; Oz Mordechai; Daniel C Bowers; Theodore W Laetsch; Alexander Lossos; Deborah T Blumenthal; Tomasz Sarosiek; Lee Yi Yen; Jeffrey Knipstein; Anne Bendel; Lindsey M Hoffman; Sandra Luna-Fineman; Stefanie Zimmermann; Isabelle Scheers; Kim E Nichols; Michal Zapotocky; Jordan R Hansford; John M Maris; Peter Dirks; Michael D Taylor; Abhaya V Kulkarni; Manohar Shroff; Derek S Tsang; Anita Villani; Wei Xu; Melyssa Aronson; Carol Durno; Adam Shlien; David Malkin; Gad Getz; Yosef E Maruvka; Pamela S Ohashi; Cynthia Hawkins; Trevor J Pugh; Eric Bouffet; Uri Tabori; Sahlgrenska akademin

doi:10.1038/s41591-021-01581-6

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Genomic predictors of response to PD-1 inhibition in children with germline DNA replication repair deficiency

Journal article

Open access

Peer reviewed

Genomic predictors of response to PD-1 inhibition in children with germline DNA replication repair deficiency

Anirban Das, Sumedha Sudhaman, Daniel Morgenstern, Ailish Coblentz, Jiil Chung, Simone C Stone, Noor Alsafwani, Zhihui Amy Liu, Ola Abu Al Karsaneh, Shirin Soleimani, …

Nature medicine, Vol.28(1), pp.125-135

2022

DOI: https://doi.org/10.1038/s41591-021-01581-6

PMID: 34992263

Abstract

Adolescent

Adult

B7-H1 Antigen - antagonists & inhibitors

Biomarkers, Tumor

Child

DNA Repair - genetics

DNA Replication - genetics

Female

Germ-Line Mutation

Humans

Immune Checkpoint Inhibitors - pharmacology

Immune Checkpoint Inhibitors - therapeutic use

Male

Neoplasms - drug therapy

Prospective Studies

Retrospective Studies

Survival Analysis

Tumor Microenvironment

Young Adult

Cancers arising from germline DNA mismatch repair deficiency or polymerase proofreading deficiency (MMRD and PPD) in children harbour the highest mutational and microsatellite insertion-deletion (MS-indel) burden in humans. MMRD and PPD cancers are commonly lethal due to the inherent resistance to chemo-irradiation. Although immune checkpoint inhibitors (ICIs) have failed to benefit children in previous studies, we hypothesized that hypermutation caused by MMRD and PPD will improve outcomes following ICI treatment in these patients. Using an international consortium registry study, we report on the ICI treatment of 45 progressive or recurrent tumors from 38 patients. Durable objective responses were observed in most patients, culminating in a 3 year survival of 41.4%. High mutation burden predicted response for ultra-hypermutant cancers (>100 mutations per Mb) enriched for combined MMRD + PPD, while MS-indels predicted response in MMRD tumors with lower mutation burden (10-100 mutations per Mb). Furthermore, both mechanisms were associated with increased immune infiltration even in 'immunologically cold' tumors such as gliomas, contributing to the favorable response. Pseudo-progression (flare) was common and was associated with immune activation in the tumor microenvironment and systemically. Furthermore, patients with flare who continued ICI treatment achieved durable responses. This study demonstrates improved survival for patients with tumors not previously known to respond to ICI treatment, including central nervous system and synchronous cancers, and identifies the dual roles of mutation burden and MS-indels in predicting sustained response to immunotherapy.

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Title: Genomic predictors of response to PD-1 inhibition in children with germline DNA replication repair deficiency
Creators - without role: Anirban Das - Hospital for Sick Children
Sumedha Sudhaman - Hospital for Sick Children
Daniel Morgenstern - University of Toronto
Ailish Coblentz - Hospital for Sick Children
Jiil Chung - Hospital for Sick Children
Simone C Stone - Princess Margaret Cancer Centre
Noor Alsafwani - University of Toronto
Zhihui Amy Liu - Princess Margaret Cancer Centre
Ola Abu Al Karsaneh - Hashemite University
Shirin Soleimani - University of Toronto
Hagay Ladany - Technion – Israel Institute of Technology
David Chen - Hospital for Sick Children
Matthew Zatzman - University of Toronto
Vanja Cabric - University of Toronto
Liana Nobre - The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada
Vanessa Bianchi - Hospital for Sick Children
Melissa Edwards - Hospital for Sick Children
Lauren C Sambira Nahum - Division of Haematology Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada
Ayse B Ercan - Hospital for Sick Children
Arash Nabbi - Princess Margaret Cancer Centre
Shlomi Constantini - Department of Pediatric Neurosurgery, Dana Children’s Hospital, Tel-Aviv, Israel
Rina Dvir - Tel Aviv Sourasky Medical Center
Michal Yalon-Oren - Sheba Medical Center
Gadi Abebe Campino - Sheba Medical Center
Shani Caspi - Sheba Medical Center
Valerie Larouche - Centre hospitalier de l'Université Laval
Alyssa Reddy - University of California, San Francisco
Michael Osborn - Women's and Children's Hospital
Gary Mason - University of Pittsburgh
Scott Lindhorst - Medical University of South Carolina
Annika Bronsema - Eppendorf
Vanan Magimairajan - Research Institute in Oncology and Hematology
Enrico Opocher - University of Padua
Rebecca Loret De Mola - Helen DeVos Children's Hospital
Magnus Sabel - Sahlgrenska University Hospital
Charlotta Frojd - Sahlgrenska University Hospital
David Sumerauer - University Hospital in Motol
David Samuel - Children's Hospital Central California
Kristina Cole - Children's Hospital of Philadelphia
Stefano Chiaravalli - Fondazione IRCCS Istituto Nazionale dei Tumori
Maura Massimino - Fondazione IRCCS Istituto Nazionale dei Tumori
Patrick Tomboc - West Virginia University
David S Ziegler - UNSW Sydney
Ben George - Medical College of Wisconsin
An Van Damme - UCLouvain
Nobuko Hijiya - Columbia University Irving Medical Center
David Gass - Levine Children's Hospital
Rose B McGee - St. Jude Children's Research Hospital
Oz Mordechai - Rambam Health Care Campus
Daniel C Bowers - The University of Texas Southwestern Medical Center
Theodore W Laetsch - Children's Hospital of Philadelphia
Alexander Lossos - Hadassah Medical Center
Deborah T Blumenthal - Tel Aviv University
Tomasz Sarosiek - College Station Medical Center
Lee Yi Yen - Taipei Veterans General Hospital
Jeffrey Knipstein - Medical College of Wisconsin
Anne Bendel - Children’s Minnesota - St. Paul Hospital
Lindsey M Hoffman - Phoenix Children's Hospital
Sandra Luna-Fineman - Children's Hospital Colorado
Stefanie Zimmermann - University Hospital Frankfurt
Isabelle Scheers - Cliniques Universitaires Saint-Luc
Kim E Nichols - St. Jude Children's Research Hospital
Michal Zapotocky - University Hospital in Motol
Jordan R Hansford - University of Melbourne
John M Maris - Children's Hospital of Philadelphia
Peter Dirks - Hospital for Sick Children
Michael D Taylor - Hospital for Sick Children
Abhaya V Kulkarni - Institute for Clinical Evaluative Sciences
Manohar Shroff - Hospital for Sick Children
Derek S Tsang - Princess Margaret Cancer Centre
Anita Villani - University of Toronto
Wei Xu - Princess Margaret Cancer Centre
Melyssa Aronson - Mount Sinai Hospital
Carol Durno - Mount Sinai Hospital
Adam Shlien - University of Toronto
David Malkin - University of Toronto
Gad Getz - Broad Institute
Yosef E Maruvka - Technion – Israel Institute of Technology
Pamela S Ohashi - Princess Margaret Cancer Centre
Cynthia Hawkins - Hospital for Sick Children
Trevor J Pugh - Ontario Institute for Cancer Research
Eric Bouffet - Hospital for Sick Children
Uri Tabori - University of Toronto
Sahlgrenska akademin
Publication Details: Nature medicine, Vol.28(1), pp.125-135
Grant note: PJT-156006 / CIHR
Identifiers: 9915330708331
Academic Unit: Imam Abdulrahman Bin Faisal University
Language: English
Resource Type: Journal article