1. Mutation and Microsatellite Burden Predict Response to PD-1 Inhibition in Children with Germline DNA Replication Repair Deficiency
- Author
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Uri Tabori, Magnus Sabel, Alexander Lossos, Annika Bronsema, Lauren Sambira, David Gass, Vanan Magimairajan, Gary Mason, Melissa Edwards, Vanja Cabric, Simone Stone, David Malkin, Isabelle Scheers, Ben George, Anita Villani, Deborah T. Blumenthal, An Van Damme, Rose B. McGee, Lee Yen, Sandra Luna-Fineman, John M. Maris, David Sumerauer, Charlotta Fröjd, Sumedha Sudhaman, Michael D. Taylor, Enrico Opocher, Yosef E. Maruvka, Oz Mordechai, Jeffrey Knipstein, Rebecca Loret De Mola, Melyssa Aronson, Shlomi Constantini, Abhaya Kulkarni, Daniel A. Morgenstern, Rina Dvir, Trevor J. Pugh, Patrick Tomboc, Ted Laetsch, Noor Alsafwani, Vanessa Bianchi, Kim E. Nichols, Jordan R. Hansford, Manohar Shroff, Peter B. Dirks, Shani Caspi, Anirban Das, Stefano Chiaravalli, Valerie Larouche, Eric Bouffet, Adam Shlien, Gad Getz, Maura Massimino, Alyssa Reddy, Michal Yalon, Gadi Campino, Anne Bendel, Cynthia Hawkins, Michal Zapotocky, Derek Tsang, Jiil Chung, Tomasz Sarosiek, Lindsey Hoffman, Daniel C. Bowers, Ailish Coblentz, Kristina A. Cole, Stefanie Zimmermann, Scott Lindhorst, Nobuko Hijaya, Michael Osborn, David S. Ziegler, Liana Nobre, Carol Durno, David Samuel, and Pamela Ohashi
- Subjects
Genetics ,Replication (statistics) ,Mutation (genetic algorithm) ,Microsatellite ,Biology ,Germline - Abstract
Cancers arising from germline DNA mismatch-repair or polymerase-proofreading deficiencies (MMRD and PPD) in children harbour the highest mutational and microsatellite insertion/deletion (MS-indel) burden in humans and are lethal due to inherent resistance to chemo-irradiation. Although immune checkpoint inhibitors (ICI) have failed to benefit children in previous studies, we hypothesized that hypermutation caused by MMRD and PPD will improve outcomes following ICI in these patients. ICI treatment of 45 progressive/recurrent tumours from 38 patients revealed durable objective responses in the majority, culminating in 3-year survival of 41.4%. High mutation burden predicted response for ultra-hypermutant cancers (>100 mutations/Mb) enriched for combined MMRD+PPD, while MS-indels predicted response in MMRD tumours with lower mutation burden (10-100 mutations/Mb). Further, both mechanisms were associated with increased immune infiltration even in “immunologically-cold” tumours such as gliomas, contributing to the favorable response. Pseudo-progression (flare) was common and associated with immune activation in both the tumour microenvironment and systemically. Further, patients with flare continuing ICI treatment achieved durable responses. Our study demonstrates improved survival for patients with tumours not previously known to respond to ICI, including CNS and synchronous cancers, and identifies the dual roles of mutation burden and MS-indels in predicting sustained responses to immunotherapy.
- Published
- 2021