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.

Atrium Health Levine Children's Hospital Charlotte NC USA

Biotechnology and Food Engineering Technion Israel Institute of Technology Tel Aviv Israel

Broad Institute of Harvard and MIT Cambridge MA USA

Cancer Predisposition Division Oncology Department St Jude Children's Research Hospital Memphis TN USA

Child Health Evaluative Sciences Research Institute The Hospital for Sick Children Toronto Ontario Canada

Children's Cancer Centre Royal Children's Hospital Murdoch Children's Research Institute University of Melbourne Parkville Victoria Australia

Dalla Lana School of Public Health University of Toronto Toronto Ontario Canada

Department of Basic Medical Sciences Faculty of Medicine The Hashemite University Zarqa Jordan

Department of Biostatistics Princess Margaret Cancer Center University Health Network Toronto Ontario Canada

Department of Diagnostic Imaging The Hospital for Sick Children Toronto Ontario Canada

Department of Immunology University of Toronto Toronto Ontario Canada

Department of Laboratory Medicine and Pathobiology Faculty of Medicine University of Toronto Toronto Ontario Canada

Department of Laboratory Medicine and Pathobiology University of Toronto Toronto Ontario Canada

Department of Medical Biophysics University of Toronto Toronto Ontario Canada

Department of Neurosurgery Neurological Institute Taipei Veterans General Hospital Taipei Taiwan

Department of Oncology Leslie and Michael Gaffin Center for Neuro Oncology Hadassah Hebrew University Medical Center Jerusalem Israel

Department of Oncology Sahlgrenska University Hospital Gothenburg Sweden

Department of Paediatric Haematology and Oncology 2nd Faculty of Medicine Motol University Hospital Charles University Prague Czech Republic

Department of Paediatric Haematology and Oncology Saint Luc University Hospital Université Catholique de Louvain Brussels Belgium

Department of Paediatric Haematology and Oncology University Medical Centre Hamburg Eppendorf Hamburg Germany

Department of Paediatric Haematology Oncology Cancer Care Manitoba Research Institute in Oncology and Haematology University of Manitoba Winnipeg Manitoba Canada

Department of Paediatric Haematology Oncology Centre Hospitalier de Quebec Universite Laval Quebec City Quebec Canada

Department of Paediatric Haematology Oncology Tata Medical Centre Kolkata India

Department of Paediatric Laboratory Medicine The Hospital for Sick Children Toronto Ontario Canada

Department of Paediatrics Institute of Clinical Sciences Sahlgrenska Academy University of Gothenburg Sahlgrenska University Hospital Gothenburg Sweden

Department of Paediatrics University of Melbourne Parkville Victoria Australia

Department of Paediatrics University of Toronto Toronto Ontario Canada

Department of Pathology College of Medicine Imam Abdulrahman Bin Faisal University Dammam Saudi Arabia

Department of Pediatric Hematology Oncology Children's Hospitals and Clinics of Minnesota St Paul MN USA

Department of Pediatric Hematology Oncology Rambam Health Care Campus Haifa Israel

Department of Pediatric Hematology Oncology Sheba Medical Centre Ramat Gan Israel

Department of Pediatric Hematology Oncology Tel Aviv Sourasky Medical Centre Tel Aviv Israel

Department of Pediatric Neurosurgery Dana Children's Hospital Tel Aviv Israel

Department of Pediatric Oncology Valley Children's Hospital Madera CA USA

Department of Pediatrics Anschutz Medical Campus Children's Hospital of Colorado Aurora CO USA

Department of Pediatrics J W Ruby Memorial Hospital West Virginia University Morgantown WV USA

Department of Pediatrics The University of Texas Southwestern Medical School Dallas TX USA

Department of Pediatrics University of Pittsburgh School of Medicine Pittsburgh PA USA

Departments of Neurology and Pediatrics University of California San Francisco CA USA

Developmental and Stem Cell Biology Program The Hospital for Sick Children Toronto Ontario Canada

Division of Haematology Oncology The Hospital for Sick Children Toronto Ontario Canada

Division of Hematology and Oncology Department of Medicine Medical College of Wisconsin Milwaukee WI USA

Division of Neurosurgery The Hospital for Sick Children Toronto Ontario Canada

Division of Oncology and Center for Childhood Cancer Research Children's Hospital of Philadelphia Department of Pediatrics Perelman School of Medicine at the University of Pennsylvania Philadelpha PA USA

Division of Pediatric Hematology Oncology BMT Medical College of Wisconsin Milwaukee WI USA

Division of Pediatric Hematology Oncology Stem Cell Transplantation Columbia University Irving Medical Centre New York NY USA

Institute of Medical Science Faculty of Medicine University of Toronto Toronto Ontario Canada

Kids Cancer Centre Sydney Children's Hospital Randwick New South Wales Australia

Lux Med Onkologia Warsaw Poland

Massachusetts General Hospital Cancer Center and Department of Pathology Charlestown MA USA

Neuro Oncology Department of Neurosurgery and Department of Medicine Division of Hematology Medical Oncology Medical University of South Carolina Charleston SC USA

Neuro Oncology Service Tel Aviv Medical Center Sackler Faculty of Medicine Tel Aviv University Tel Aviv Israel

Ontario Institute for Cancer Research Toronto Ontario Canada

Paediatric Gastroenterology Hepatology and Nutrition Unit Cliniques Universitaires St Luc Université Catholique de Louvain Brussels Belgium

Paediatric Haematology and Oncology University Hospital Frankfurt Frankfurt Germany

Paediatric Haematology Oncology and Stem Cell Transplant Division Padua University Hospital Padua Italy

Paediatric Unit Fondazione IRCCS Istituto Nazionale dei Tumori Milan Italy

Pediatric Hematology Oncology Helen DeVos Children's Hospital Grand Rapids MI USA

Phoenix Children's Hospital Phoenix AZ USA

Princess Margaret Cancer Centre University Health Network Toronto Ontario Canada

Program in Cell Biology The Hospital for Sick Children Toronto Ontario Canada

Program in Genetics and Genome Biology The Hospital for Sick Children Toronto Ontario Canada

Queen Silvia Children's Hospital Sahlgrenska University Hospital Gothenburg Sweden

Radiation Medicine Program Princess Margaret Cancer Centre Toronto Ontario Canada

School of Women's and Children's Health University of New South Wales Sydney New South Wales Australia

The Arthur and Sonia Labatt Brain Tumour Research Centre The Hospital for Sick Children Toronto Ontario Canada

Women's and Children's Hospital North Adelaide South Australia Australia

Zane Cohen Centre for Digestive Diseases Mount Sinai Hospital Toronto Ontario Canada

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Overt and covert genetic causes of pediatric acute lymphoblastic leukemia

Precision immuno-oncology approach for four malignant tumors in siblings with constitutional mismatch repair deficiency syndrome

Combined Immunotherapy Improves Outcome for Replication-Repair-Deficient (RRD) High-Grade Glioma Failing Anti-PD-1 Monotherapy: A Report from the International RRD Consortium