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Combined Immunotherapy Improves Outcome for Replication-Repair-Deficient (RRD) High-Grade Glioma Failing Anti-PD-1 Monotherapy: A Report from the International RRD Consortium
A. Das, NR. Fernandez, A. Levine, V. Bianchi, LK. Stengs, J. Chung, L. Negm, JR. Dimayacyac, Y. Chang, L. Nobre, AB. Ercan, S. Sanchez-Ramirez, S. Sudhaman, M. Edwards, V. Larouche, D. Samuel, A. Van Damme, D. Gass, DS. Ziegler, SS. Bielack, C....
Language English Country United States
Document type Journal Article
Grant support
R01 NS119231
NINDS NIH HHS - United States
- MeSH
- CTLA-4 Antigen MeSH
- Glioma * drug therapy genetics MeSH
- Immunotherapy MeSH
- Humans MeSH
- Tumor Microenvironment MeSH
- Brain Neoplasms * drug therapy genetics MeSH
- Antineoplastic Agents * therapeutic use MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
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
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 Medical Biophysics University of Toronto Toronto Canada
Department of Neurosurgery Neurological Institute Taipei Veterans General Hospital Taipei Taiwan
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 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 University of Toronto Toronto Canada
Department of Pediatric Hematology Oncology Randall Children's Hospital Portland Oregon
Department of Pediatrics London Health Sciences Centre London Canada
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 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
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
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
Women's and Children's Hospital North Adelaide Australia
Zane Cohen Centre for Digestive Diseases Mount Sinai Hospital Toronto Canada
References provided by Crossref.org
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