UNLABELLED: Immune checkpoint inhibition (ICI) is effective for replication-repair-deficient, high-grade gliomas (RRD-HGG). The clinical/biological impact of immune-directed approaches after failing ICI monotherapy is unknown. We performed an international study on 75 patients treated with anti-PD-1; 20 are progression free (median follow-up, 3.7 years). After second progression/recurrence (n = 55), continuing ICI-based salvage prolonged survival to 11.6 months (n = 38; P < 0.001), particularly for those with extreme mutation burden (P = 0.03). Delayed, sustained responses were observed, associated with changes in mutational spectra and the immune microenvironment. Response to reirradiation was explained by an absence of deleterious postradiation indel signatures (ID8). CTLA4 expression increased over time, and subsequent CTLA4 inhibition resulted in response/stable disease in 75%. RAS-MAPK-pathway inhibition led to the reinvigoration of peripheral immune and radiologic responses. Local (flare) and systemic immune adverse events were frequent (biallelic mismatch-repair deficiency > Lynch syndrome). We provide a mechanistic rationale for the sustained benefit in RRD-HGG from immune-directed/synergistic salvage therapies. Future approaches need to be tailored to patient and tumor biology. SIGNIFICANCE: Hypermutant RRD-HGG are susceptible to checkpoint inhibitors beyond initial progression, leading to improved survival when reirradiation and synergistic immune/targeted agents are added. This is driven by their unique biological and immune properties, which evolve over time. Future research should focus on combinatorial regimens that increase patient survival while limiting immune toxicity. This article is featured in Selected Articles from This Issue, p. 201.

Atrium Health Levine Children's Hospital Charlotte North Carolina

Broad Institute of Harvard and MIT Cambridge Massachusetts

CancerCare Manitoba Research Institute Pediatrics and Child Health University of Manitoba Winnipeg Canada

Clinic of Pediatric Oncology and Hematology University Children's Hospital Banská Bystrica Slovakia

Department of Diagnostic Imaging The Hospital for Sick Children Toronto Canada

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

Department of Medical Biophysics University of Toronto Toronto Canada

Department of Neurosurgery Neurological Institute Taipei Veterans General Hospital Taipei Taiwan

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

Department of Oncology Sahlgrenska University Hospital Gothenburg Sweden

Department of Oncology St Jude Children's Research Hospital Memphis Tennessee

Department of Paediatric Haematology and Oncology 2nd Faculty of Medicine University Hospital Motol 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 St Olav's University Hospital Trondheim Norway

Department of Paediatric Haematology and Oncology Tata Medical Center Kolkata India

Department of Paediatric Haematology Oncology Sheba Medical Centre Ramat Gan Israel

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

Department of Paediatric Oncology Valley Children's Hospital Madera California

Department of Paediatrics Institute of Clinical Sciences Sahlgrenska Academy University of Gothenburg and Queen Silvia Children's Hospital Sahlgrenska University Hospital Gothenburg Sweden

Department of Paediatrics University of Toronto Toronto Canada

Department of Pediatric Hematology Oncology Randall Children's Hospital Portland Oregon

Department of Pediatric Oncology Hematology and Immunology Center for Childhood Adolescent and Women's Medicine Stuttgart Cancer Center Klinikum Stuttgart Stuttgart Germany

Department of Pediatrics London Health Sciences Centre London Canada

Department of Pediatrics Section of Pediatric Hematology Oncology The University of Arkansas for Medical Sciences Arkansas Children's Hospital Little Rock Arkansas

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

Division of Haematology Oncology The Hospital for Sick Children Toronto Canada

Division of Hematology Oncology Blood and Marrow Transplantation Department of Pediatrics Medical College of Wisconsin Milwaukee Wisconsin

Division of Neuro Oncology Akron Children's Hospital Akron Ohio

Division of Neurosurgery The Hospital for Sick Children Toronto Canada

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

Kids Cancer Centre Sydney Children's Hospital Randwick Australia

Lux Med Onkologia Warsaw Poland

Neuro oncology Division Birmingham Children's Hospital Birmingham United Kingdom

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

Neuropathology Oregon Health and Science University Department of Pathology Portland Oregon

Neurosciences Department Child Neuro logy Division CHU Sainte Justine Montreal Canada

Ontario Institute for Cancer Research Princess Margaret Cancer Centre Toronto Canada

Oregon Health and Science University Portland Oregon

Paediatric and Adolescent Neuro Oncology and Drug Development The Royal Marsden NHS Foundation Trust and Division of Clinical Studies The Institute of Cancer Research London United Kingdom

Pediatric Haematology Oncology Department CHU de Québec Université Laval Quebec City Canada

Pediatric Hematology Oncology C S Mott Children's Hospital University of Michigan Ann Arbor Michigan

Pediatric Hematology Oncology CancerCare Manitoba Winnipeg Canada

Pediatric Hematology Oncology King Fahad Specialist Hospital Dammam Eastern Province Saudi Arabia

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

Radiation Medicine Program Princess Margaret Cancer Centre University Health Network Toronto Canada

School of Clinical Medicine UNSW Sydney Sydney Australia

Technion Israel Institute of Technology Tel Aviv Israel

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

Women's and Children's Hospital North Adelaide Australia

Zane Cohen Centre for Digestive Diseases Mount Sinai Hospital Toronto 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