Observational studyNature medicine2022
Genomic predictors of response to PD-1 inhibition in children with germline DNA replication repair deficiency.
Open access · hybridAbstract readObservational Study
In one paragraph
Observational study in Nature medicine, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 91 papers, 5 of them syntheses that pooled it.
0numbers the graph read from it
0cells of the map it votes in
91citing papers in PubMed, 5 pooled it
13.0field-weighted citation impact, top 1% of its field
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
91 citing papers in PubMed, 5 syntheses or guidelines pooled it, 139 citations in OpenAlex.
- Should checkpoint inhibitors be reserved for biomarker-selected pediatric brain tumors?Journal of neuro-oncology · 2026Pooled it
- The current status of immune checkpoint inhibitors in pediatric CNS tumors: a systematic review with a representative case of CMMRD-associated glioma.Journal of neuro-oncology · 2025Pooled it
- Pediatric-type high-grade glioma of the spinal cord in the molecular era: institutional case series and updated systematic review of the literature.Child's nervous system : ChNS : official journal of the International Society for Pediatric Neurosurgery · 2025Pooled it
- 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
- TMBserval: a statistical explainable learning model reveals weighted tumor mutation burden better categorizing therapeutic benefits.Frontiers in immunology · 2023Pooled it
- Nivolumab with or without ipilimumab in pediatric patients with high-grade CNS malignancies: Safety, efficacy, biomarker, and pharmacokinetics-CheckMate 908.Neuro-oncology · 2023Trial
- Clinical Outcomes and New Treatments in Pediatric Brain Tumors.Current oncology (Toronto, Ont.) · 2026Article
- Cellular and Immunotherapy for Pediatric Brain Tumors: A Primer.Current oncology (Toronto, Ont.) · 2026Review
- Translational perspectives on immunotherapy targets, germline syndromes, and novel fusions.The oncologist · 2026Article
- Immunotherapy for Diffuse Midline Glioma: From Preclinical Modeling to Clinical Translation.Cancers · 2026Review
- Personalized neoantigen-pulsed autologous dendritic cells in newly-diagnosed glioblastoma: a phase Ib trial.Nature communications · 2026Article
- The impact of international care networks on the clinical management of constitutional mismatch repair deficiency (CMMRD): a review of recent developments.Familial cancer · 2026Review
- Tumor transcriptional state predicts survival in immune-checkpoint-blockade-treated glioblastoma.Nature cancer · 2026Article
- Immunotherapy for pediatric solid tumors: overcoming biological barriers through rational multimodal combinations.Cancer immunology, immunotherapy : CII · 2026Review
- Next generation sequencing identifies novel gene alterations with potential prognostic relevance in pediatric cancer: a single-center study.The oncologist · 2026Article
- Distinct mutational signature and clonal evolution in constitutional mismatch repair deficiency-associated high-grade gliomas.iScience · 2026Article
- Mismatch repair deficiency drives malignant progression and alters the tumor immune microenvironment in glioblastoma models.The Journal of clinical investigation · 2026Article
- Immunotherapy approaches for the treatment of relapsed or progressive medulloblastoma.Journal of neuro-oncology · 2026Review
- Imaging assessment of immunotherapy in pediatric brain tumors.Journal of neuro-oncology · 2026Review
- Immune checkpoint inhibitors in pediatric central nervous system tumors: biology, clinical experience, and translational pathways to precision immunotherapy.Journal of neuro-oncology · 2026Review
31 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
83 authors at 20 institutions in 14 countries.
Anirban Das *Division of Haematology Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada.ORCID http://orcid.org/0000-0001-7653-9529
Sumedha Sudhaman *Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
Daniel Morgenstern *Division of Haematology Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada.ORCID http://orcid.org/0000-0002-4859-1108
Ailish CoblentzDepartment of Diagnostic Imaging, The Hospital for Sick Children, Toronto, Ontario, Canada.
Jiil ChungProgram in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
Simone C StonePrincess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
Noor AlsafwaniDepartment of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.ORCID http://orcid.org/0000-0002-9449-9708
Zhihui Amy LiuDepartment of Biostatistics, Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada.
Ola Abu Al KarsanehDepartment of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
Shirin SoleimaniPrincess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
Hagay LadanyBiotechnology and Food Engineering, Technion - Israel Institute of Technology, Tel-Aviv, Israel.ORCID http://orcid.org/0000-0001-8953-6802
David ChenProgram in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
Matthew ZatzmanProgram in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
Vanja CabricDepartment of Paediatrics, University of Toronto, Toronto, Ontario, Canada.
Liana NobreDivision of Haematology Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada.
Vanessa BianchiProgram in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
Melissa EdwardsProgram in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
Lauren C Sambira NahumDivision of Haematology Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada.
Ayse B ErcanProgram in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.ORCID http://orcid.org/0000-0003-3612-3515
Arash NabbiPrincess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
Shlomi ConstantiniDepartment of Pediatric Neurosurgery, Dana Children's Hospital, Tel-Aviv, Israel.
Rina DvirDepartment of Pediatric Hematology-Oncology, Tel-Aviv Sourasky Medical Centre, Tel-Aviv, Israel.
Michal Yalon-OrenDepartment of Pediatric Hematology-Oncology, Sheba Medical Centre, Ramat Gan, Israel.
Gadi Abebe CampinoDepartment of Pediatric Hematology-Oncology, Sheba Medical Centre, Ramat Gan, Israel.
Shani CaspiDepartment of Pediatric Hematology-Oncology, Sheba Medical Centre, Ramat Gan, Israel.
Valerie LaroucheDepartment of Paediatric Haematology/Oncology, Centre Hospitalier de Quebec-Universite Laval, Quebec City, Quebec, Canada.
Alyssa ReddyDepartments of Neurology and Pediatrics, University of California, San Francisco, CA, USA.
Michael OsbornWomen's and Children's Hospital, North Adelaide, South Australia, Australia.
Gary MasonDepartment of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Scott LindhorstNeuro-Oncology, Department of Neurosurgery, and Department of Medicine, Division of Hematology/Medical Oncology, Medical University of South Carolina, Charleston, SC, USA.
Annika BronsemaDepartment of Paediatric Haematology and Oncology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.
Vanan MagimairajanDepartment of Paediatric Haematology-Oncology, Cancer Care Manitoba, Research Institute in Oncology and Haematology, University of Manitoba, Winnipeg, Manitoba, Canada.ORCID http://orcid.org/0000-0003-2015-0615
Enrico OpocherPaediatric Haematology, Oncology and Stem Cell Transplant Division, Padua University Hospital, Padua, Italy.ORCID http://orcid.org/0000-0001-8483-1618
Rebecca Loret De MolaPediatric Hematology-Oncology, Helen DeVos Children's Hospital, Grand Rapids, MI, USA.
Magnus SabelDepartment of Paediatrics, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden.ORCID http://orcid.org/0000-0002-3072-657X
Charlotta FrojdDepartment of Oncology, Sahlgrenska University Hospital, Gothenburg, Sweden.
David SumerauerDepartment of Paediatric Haematology and Oncology, Second Faculty of Medicine, Motol University Hospital, Charles University, Prague, Czech Republic.
David SamuelDepartment of Pediatric Oncology, Valley Children's Hospital, Madera, CA, USA.ORCID http://orcid.org/0000-0001-6850-4932
Kristina ColeDivision 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.
Stefano ChiaravalliPaediatric Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
Maura MassiminoPaediatric Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
Patrick TombocDepartment of Pediatrics, J.W. Ruby Memorial Hospital - West Virginia University, Morgantown, WV, USA.ORCID http://orcid.org/0000-0002-1255-4719
David S ZieglerKids Cancer Centre, Sydney Children's Hospital, Randwick, New South Wales, Australia.ORCID http://orcid.org/0000-0001-7451-7916
Ben GeorgeDivision of Hematology and Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA.
An Van DammeDepartment of Paediatric Haematology and Oncology, Saint Luc University Hospital, Université Catholique de Louvain, Brussels, Belgium.ORCID http://orcid.org/0000-0002-7114-201X
Nobuko HijiyaDivision of Pediatric Hematology/Oncology/Stem Cell Transplantation, Columbia University Irving Medical Centre, New York, NY, USA.
David GassAtrium Health Levine Children's Hospital, Charlotte, NC, USA.
Rose B McGeeCancer Predisposition Division, Oncology Department, St Jude Children's Research Hospital, Memphis, TN, USA.ORCID http://orcid.org/0000-0001-7392-6515
Oz MordechaiDepartment of Pediatric Hematology Oncology, Rambam Health Care Campus, Haifa, Israel.ORCID http://orcid.org/0000-0002-4340-9290
Daniel C BowersDepartment of Pediatrics, The University of Texas Southwestern Medical School, Dallas, TX, USA.ORCID http://orcid.org/0000-0002-3947-2481
Theodore W LaetschDivision 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.ORCID http://orcid.org/0000-0002-8497-3138
Alexander LossosDepartment of Oncology, Leslie and Michael Gaffin Center for Neuro-Oncology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
Deborah T BlumenthalNeuro-Oncology Service, Tel-Aviv Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel-Aviv, Israel.
Tomasz SarosiekLux Med Onkologia, Warsaw, Poland.
Lee Yi YenDepartment of Neurosurgery, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan.
Jeffrey KnipsteinDivision of Pediatric Hematology/ Oncology/ BMT, Medical College of Wisconsin, Milwaukee, WI, USA.ORCID http://orcid.org/0000-0002-0632-2751
Anne BendelDepartment of Pediatric Hematology-Oncology, Children's Hospitals and Clinics of Minnesota, St Paul, MN, USA.ORCID http://orcid.org/0000-0002-2062-0974
Lindsey M HoffmanPhoenix Children's Hospital, Phoenix, AZ, USA.
Sandra Luna-FinemanDepartment of Pediatrics, Anschutz Medical Campus, Children's Hospital of Colorado, Aurora, CO, USA.ORCID http://orcid.org/0000-0003-0713-7651
Stefanie ZimmermannPaediatric Haematology and Oncology, University Hospital Frankfurt, Frankfurt, Germany.
Isabelle ScheersPaediatric Gastroenterology, Hepatology and Nutrition Unit, Cliniques Universitaires St Luc, Université Catholique de Louvain, Brussels, Belgium.
Kim E NicholsCancer Predisposition Division, Oncology Department, St Jude Children's Research Hospital, Memphis, TN, USA.ORCID http://orcid.org/0000-0002-5581-6555
Michal ZapotockyDepartment of Paediatric Haematology and Oncology, Second Faculty of Medicine, Motol University Hospital, Charles University, Prague, Czech Republic.
Jordan R HansfordChildren's Cancer Centre, Royal Children's Hospital, Murdoch Children's Research Institute, University of Melbourne, Parkville, Victoria, Australia.ORCID http://orcid.org/0000-0001-7733-383X
John M MarisDivision 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.ORCID http://orcid.org/0000-0002-8088-7929
Peter DirksThe Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.ORCID http://orcid.org/0000-0001-5718-6465
Michael D TaylorThe Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.
Abhaya V KulkarniDivision of Neurosurgery, The Hospital for Sick Children, Toronto, Ontario, Canada.ORCID http://orcid.org/0000-0002-1706-7004
Manohar ShroffDepartment of Diagnostic Imaging, The Hospital for Sick Children, Toronto, Ontario, Canada.
Derek S TsangRadiation Medicine Program, Princess Margaret Cancer Centre, Toronto, Ontario, Canada.ORCID http://orcid.org/0000-0002-9762-6901
Anita VillaniDivision of Haematology Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada.
Wei XuDepartment of Biostatistics, Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada.
Melyssa AronsonZane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, Toronto, Ontario, Canada.
Carol DurnoZane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, Toronto, Ontario, Canada.
Adam ShlienProgram in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.ORCID http://orcid.org/0000-0002-0368-5370
David MalkinDivision of Haematology Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada.ORCID http://orcid.org/0000-0001-5752-9763
Gad GetzMassachusetts General Hospital Cancer Center and Department of Pathology, Charlestown, MA, USA.ORCID http://orcid.org/0000-0002-0936-0753
Yosef E MaruvkaBiotechnology and Food Engineering, Technion - Israel Institute of Technology, Tel-Aviv, Israel.
Pamela S OhashiPrincess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
Cynthia HawkinsDepartment of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.ORCID http://orcid.org/0000-0003-2618-4402
Trevor J PughPrincess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
Eric BouffetDivision of Haematology Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada.
Uri TaboriDivision of Haematology Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada. uri.tabori@sickkids.ca.ORCID http://orcid.org/0000-0002-5019-2683
Hospital for Sick Children · CAUniversity of Toronto · CAUniversity Health Network · CAChildren's Hospital of Philadelphia · USSheba Medical Center · ILCharles University · CZFondazione IRCCS Istituto Nazionale dei Tumori · ITMedical College of Wisconsin · USMount Sinai Hospital · CASahlgrenska University Hospital · SESt. Jude Children's Research Hospital · USTechnion – Israel Institute of Technology · ILBroad Institute · USCancerCare Manitoba · CACentre hospitalier de l'Université Laval · CAChildren's Hospital Central California · USChildren's Hospital Colorado · USChildren’s Minnesota - St. Paul Hospital · USCliniques Universitaires Saint-Luc · BEColumbia University Irving Medical Center · US
Funding
CIHR PJT-156006
Abstract
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.
Indexed as
Germ-Line MutationAdolescentAdultB7-H1 AntigenBiomarkers, TumorChildDNA RepairDNA ReplicationFemaleHumansImmune Checkpoint InhibitorsMaleNeoplasmsProspective StudiesRetrospective StudiesSurvival AnalysisB7-H1 AntigenBiomarkers, TumorCD274 protein, humanImmune Checkpoint Inhibitors
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.