Genomic predictors of response to PD-1 inhibition in children with germline DNA replication repair deficiency
Authors: Das Anirban , Sudhaman Sumedha , Morgenstern Daniel , Coblentz Ailish , Chung Jiil , Stone Simone C. , Alsafwani Noor , Liu Zhihui Amy , Karsaneh Ola Abu Al , Soleimani Shirin , Ladany Hagay , Chen David , Zatzman Matthew , Cabric Vanja , Nobre Liana , Bianchi Vanessa , Edwards Melissa , Sambira Nahum Lauren C, , Ercan Ayse B. , Nabbi Arash , Constantini Shlomi , Dvir Rina , Yalon-Oren Michal , Campino Gadi Abebe , Caspi Shani , Larouche Valerie , Reddy Alyssa , Osborn Michael , Mason Gary , Lindhorst Scott , Bronsema Annika , Magimairajan Vanan , Opocher Enrico , De Mola Rebecca Loret , Sabel Magnus , Frojd Charlotta , Sumerauer David , Samuel David , Cole Kristina , Chiaravalli Stefano , Massimino Maura , Tomboc Patrick , Ziegler David S. , George Ben , Van Damme An , Hijiya Nobuko , Gass David , McGee Rose B. , Mordechai Oz , Bowers Daniel C. , Laetsch Theodore W. , Lossos Alexander , Blumenthal Deborah T. , Sarosiek Tomasz , Yen Lee Yi , Knipstein Jeffrey , Bendel Anne , Hoffman Lindsey M. , Luna-Fineman Sandra , Zimmermann Stefanie , Scheers Isabelle , Nichols Kim E. , Zapotocky Michal , Hansford Jordan R. , Maris John M. , Dirks Peter , Taylor Michael D. , Kulkarni Abhaya V. , Shroff Manohar , Tsang Derek S. , Villani Anita , Xu Wei , Aronson Melyssa , Durno Carol , Shlien Adam , Malkin David , Getz Gad , Maruvka Yosef E. , Ohashi Pamela S. , Hawkins Cynthia , Pugh Trevor J. , Bouffet Eric , Tabori Uri 
Published: January 2022

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.