ArticleCancer discovery2024
Combined Immunotherapy Improves Outcome for Replication-Repair-Deficient (RRD) High-Grade Glioma Failing Anti-PD-1 Monotherapy: A Report from the International RRD Consortium.
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Article in Cancer discovery, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers, 1 of them a synthesis that pooled it.
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34citing papers in PubMed, 1 pooled it
12.1field-weighted citation impact, top 1% of its field
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Who cites it
34 citing papers in PubMed, 1 synthesis or guideline pooled it, 42 citations in OpenAlex.
- ERN GENTURIS guidelines on constitutional mismatch repair deficiency diagnosis, genetic counselling, surveillance, quality of life, and clinical management.European journal of human genetics : EJHG · 2024Guideline
- Interdisciplinary management and genetic evaluation of pediatric cancer predisposition syndromes: a retrospective cohort study.European journal of human genetics : EJHG · 2026Article
- Cellular and Immunotherapy for Pediatric Brain Tumors: A Primer.Current oncology (Toronto, Ont.) · 2026Review
- Brain barriers at the crossroads of glioma immune surveillance and immunotherapy response.Nature reviews. Cancer · 2026Review
- The impact of international care networks on the clinical management of constitutional mismatch repair deficiency (CMMRD): a review of recent developments.Familial cancer · 2026Review
- Article
- RAS/MAPK inhibition in pediatric gliomas.Neuro-oncology advances · 2026Review
- Molecular and clinical characteristics of glioma patients with germline pathogenic mutations of Lynch syndrome genes: a large-scale multicenter study.Journal of translational medicine · 2026Article
- Immune checkpoint inhibitors in pediatric central nervous system tumors: biology, clinical experience, and translational pathways to precision immunotherapy.Journal of neuro-oncology · 2026Review
- High-grade gliomas and Lynch syndrome: A retrospective descriptive study with a literature review.Neuro-oncology practice · 2026Article
- Review
- Informing development of brain cancer therapies within "preclinical trials" using ex vivo patient tumors.Advanced drug delivery reviews · 2026Review
- cIMPACT-NOW update 11: Proposal on adaptation of diagnostic criteria for IDH- and H3-wildtype diffuse high-grade gliomas and for posterior fossa ependymal tumors.Brain pathology (Zurich, Switzerland) · 2026Article
- Patterns of hypermutation shape tumorigenesis and immunotherapy response in mismatch-repair-deficient glioma.Nature genetics · 2026Article
- Mismatch Repair as a Dynamic and Clinically Actionable Vulnerability in Cancer.Cancer research · 2025Review
- Unveiling MMR deficiency in pediatric and AYA high-grade gliomas: insights from multiomic profiling.Journal of neuro-oncology · 2025Article
- TPD52 promotes the proliferation and metastasis of gastric cancer cells.BMC gastroenterology · 2025Article
- Establishment and validation of a recurrent prediction model for glioma: extrinsic apoptotic molecules FADD and CASP8 are closely associated with glioma recurrence.BMC immunology · 2025Article
- The Spectrum of IDH- and H3-Wildtype High-Grade Glioma Subgroups Occurring across Teenage and Young Adult Patient Populations.Clinical cancer research : an official journal of the American Association for Cancer Research · 2025Article
- BRAF/MEK inhibition induces cell state transitions boosting immune checkpoint sensitivity in BRAFCell reports. Medicine · 2025Article
Corrections and comments
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Authors and funding
63 authors at 20 institutions in 15 countries.
Anirban DasDivision of Haematology/Oncology, The Hospital for Sick Children, Toronto, Canada.ORCID 0000-0001-7653-9529
Nicholas R FernandezProgram in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Canada.ORCID 0000-0003-4844-261X
Adrian LevineDepartment of Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Canada.ORCID 0000-0003-1048-3360
Vanessa BianchiProgram in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Canada.ORCID 0009-0009-0187-3659
Lucie K StengsProgram in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Canada.ORCID 0009-0007-5125-398X
Jiil ChungProgram in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Canada.ORCID 0000-0003-4781-7635
Logine NegmProgram in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Canada.ORCID 0009-0006-9059-3824
Jose Rafael DimayacyacProgram in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Canada.ORCID 0000-0001-9535-831X
Yuan ChangProgram in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Canada.ORCID 0009-0001-8055-2723
Liana NobreDivision of Haematology/Oncology, The Hospital for Sick Children, Toronto, Canada.ORCID 0000-0001-5900-977X
Ayse B ErcanProgram in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Canada.ORCID 0000-0003-3612-3515
Santiago Sanchez-RamirezProgram in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Canada.ORCID 0000-0002-5963-9410
Sumedha SudhamanProgram in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Canada.ORCID 0000-0001-9266-7096
Melissa EdwardsProgram in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Canada.ORCID 0000-0001-5445-4671
Valerie LarouchePediatric Haematology/Oncology Department, CHU de Québec-Université Laval, Quebec City, Canada.ORCID 0000-0002-9773-0995
David SamuelDepartment of Paediatric Oncology, Valley Children's Hospital, Madera, California.ORCID 0000-0001-6850-4932
An Van DammeDepartment of Paediatric Haematology and Oncology, Saint Luc University Hospital, Université Catholique de Louvain, Brussels, Belgium.ORCID 0000-0002-7114-201X
David GassAtrium Health/Levine Children's Hospital, Charlotte, North Carolina.ORCID 0009-0004-1141-7458
David S ZieglerKids Cancer Centre, Sydney Children's Hospital, Randwick, Australia.ORCID 0000-0001-7451-7916
Stefan S BielackDepartment of Pediatric Oncology, Hematology and Immunology, Center for Childhood, Adolescent, and Women's Medicine, Stuttgart Cancer Center, Klinikum Stuttgart, Stuttgart, Germany.ORCID 0000-0003-2144-3153
Carl KoschmannPediatric Hematology/Oncology, C.S. Mott Children's Hospital, University of Michigan, Ann Arbor, Michigan.ORCID 0000-0002-0825-7615
Shayna ZelcerDepartment of Pediatrics, London Health Sciences Centre, London, Canada.ORCID 0000-0003-2825-1285
Michal Yalon-OrenDepartment of Paediatric Haematology-Oncology, Sheba Medical Centre, Ramat Gan, Israel.ORCID 0000-0001-9832-7068
Gadi Abede CampinoDepartment of Paediatric Haematology-Oncology, Sheba Medical Centre, Ramat Gan, Israel.ORCID 0000-0002-7946-8081
Tomasz SarosiekLux Med Onkologia, Warsaw, Poland.ORCID 0000-0002-1741-1733
Kim E NicholsDepartment of Oncology, St Jude Children's Research Hospital, Memphis, Tennessee.ORCID 0000-0002-5581-6555
Rebecca Loret De MolaOregon Health and Science University, Portland, Oregon.ORCID 0009-0008-2877-3765
Kevin BielamowiczDepartment of Pediatrics, Section of Pediatric Hematology/Oncology, The University of Arkansas for Medical Sciences/Arkansas Children's Hospital, Little Rock, Arkansas.ORCID 0000-0003-0790-2931
Magnus SabelDepartment of Paediatrics, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg & Queen Silvia Children's Hospital, Sahlgrenska University Hospital, Gothenburg, Sweden.ORCID 0000-0002-3072-657X
Charlotta A FrojdDepartment of Oncology, Sahlgrenska University Hospital, Gothenburg, Sweden.ORCID 0009-0005-5415-6945
Matthew D WoodNeuropathology, Oregon Health & Science University Department of Pathology, Portland, Oregon.ORCID 0000-0002-2385-8128
Jason M GloverDepartment of Pediatric Hematology/Oncology, Randall Children's Hospital, Portland, Oregon.ORCID 0009-0008-2323-9897
Yi-Yen LeeDepartment of Neurosurgery, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan.ORCID 0000-0003-3709-885X
Magimairajan VananPediatric Hematology-Oncology, CancerCare Manitoba, Winnipeg, Canada.ORCID 0000-0003-2015-0615
Jenny K AdamskiNeuro-oncology Division, Birmingham Children's Hospital, Birmingham, United Kingdom.ORCID 0000-0003-0999-6169
Sebastien PerreaultNeurosciences Department, Child Neuro-logy Division, CHU Sainte-Justine, Montreal, Canada.ORCID 0000-0002-4417-7698
Omar ChamdinePediatric Hematology Oncology, King Fahad Specialist Hospital Dammam, Eastern Province, Saudi Arabia.ORCID 0000-0002-8020-5588
Magnus Aasved HjortDepartment of Paediatric Haematology and Oncology, St. Olav's University Hospital, Trondheim, Norway.ORCID 0000-0002-9455-3110
Michal ZapotockyDepartment of Paediatric Haematology and Oncology, Second Faculty of Medicine, University Hospital Motol, Charles University, Prague, Czech Republic.ORCID 0000-0002-9013-2546
Fernando CarcellerPaediatric and Adolescent Neuro-Oncology and Drug Development, The Royal Marsden NHS Foundation Trust & Division of Clinical Studies, The Institute of Cancer Research, London, United Kingdom.ORCID 0000-0003-3094-3758
Erin WrightDivision of Neuro-Oncology, Akron Children's Hospital, Akron, Ohio.ORCID 0000-0001-5044-058X
Ivana FedorakovaClinic of Pediatric Oncology and Hematology, University Children's Hospital, Banská Bystrica, Slovakia.ORCID 0009-0001-5379-2668
Alexander LossosDepartment of Oncology, Leslie and Michael Gaffin Centre for Neuro-Oncology, Hadassah-Hebrew University Medical Centre, Jerusalem, Israel.ORCID 0009-0000-5699-9173
Ryuma TanakaDivision of Hematology/Oncology/Blood and Marrow Transplantation, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin.ORCID 0000-0002-0132-052X
Michael OsbornWomen's and Children's Hospital, North Adelaide, Australia.ORCID 0000-0002-1288-9930
Deborah T BlumenthalNeuro-Oncology Service, Tel-Aviv Medical Center, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.ORCID 0000-0002-8868-0148
Melyssa AronsonZane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, Toronto, Canada.ORCID 0000-0002-7503-5799
Ute BartelsDivision of Haematology/Oncology, The Hospital for Sick Children, Toronto, Canada.ORCID 0000-0003-2112-5251
Annie HuangDivision of Haematology/Oncology, The Hospital for Sick Children, Toronto, Canada.ORCID 0000-0002-1987-6980
Vijay RamaswamyDivision of Haematology/Oncology, The Hospital for Sick Children, Toronto, Canada.ORCID 0000-0002-6557-895X
David MalkinDivision of Haematology/Oncology, The Hospital for Sick Children, Toronto, Canada.ORCID 0000-0001-5752-9763
Adam ShlienProgram in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Canada.ORCID 0000-0002-0368-5370
Anita VillaniDivision of Haematology/Oncology, The Hospital for Sick Children, Toronto, Canada.ORCID 0000-0003-3283-2197
Peter B DirksThe Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Canada.ORCID 0000-0001-5718-6465
Trevor J PughOntario Institute for Cancer Research, Princess Margaret Cancer Centre, Toronto, Canada.ORCID 0000-0002-8073-5888
Gad GetzBroad Institute of Harvard and MIT, Cambridge, Massachusetts.ORCID 0000-0002-0936-0753
Yosef E MaruvkaTechnion-Israel Institute of Technology, Tel-Aviv, Israel.ORCID 0000-0002-8918-9887
Derek S TsangRadiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.ORCID 0000-0002-9762-6901
Birgit Ertl-WagnerDepartment of Diagnostic Imaging, The Hospital for Sick Children, Toronto, Canada.ORCID 0000-0002-7896-7049
Cynthia HawkinsThe Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Canada.ORCID 0000-0003-2618-4402
Eric BouffetDivision of Haematology/Oncology, The Hospital for Sick Children, Toronto, Canada.ORCID 0000-0002-6832-6539
Daniel A MorgensternDivision of Haematology/Oncology, The Hospital for Sick Children, Toronto, Canada.ORCID 0000-0002-4859-1108
Uri TaboriDivision of Haematology/Oncology, The Hospital for Sick Children, Toronto, Canada.ORCID 0000-0002-5019-2683
Hospital for Sick Children · CAUniversity of Toronto · CAOregon Health & Science University · USSahlgrenska University Hospital · SESheba Medical Center · ILAkron Children's Hospital · USArkansas Children's Hospital · USBirmingham Children's Hospital · GBBroad Institute · USCentre Hospitalier Universitaire Sainte-Justine · CACharles University · CZChildren's Hospital Central California · USCliniques Universitaires Saint-Luc · BEC. S. Mott Children's Hospital · USHebrew University of Jerusalem · ILKing Fahad Specialist Hospital · SAKlinikum Stuttgart · DELevine Children's Hospital · USLondon Health Sciences Centre · CAMedical College of Wisconsin · US
Funding
The role of ATRX mutation in the epigenetic dysregulation of cell cycle in pediatric high-grade gliomaR01NS119231 · NINDS · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI KOSCHMANN, CARL J · 2021 to 2025
$1.9MCIHRNINDS NIH HHS R01 NS119231
Abstract
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.
Indexed as
Antineoplastic AgentsBrain NeoplasmsGliomaCTLA-4 AntigenHumansImmunotherapyTumor MicroenvironmentAntineoplastic AgentsCTLA-4 Antigen
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