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

Autor:	Das A; Division of Haematology/Oncology, The Hospital for Sick Children, Toronto, Canada.; Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Canada.; The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Canada.; Department of Paediatric Haematology and Oncology, Tata Medical Center, Kolkata, India.; Department of Paediatrics, University of Toronto, Toronto, Canada., Fernandez NR; Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Canada.; The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Canada., Levine A; Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Canada.; Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, Canada., Bianchi V; Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Canada.; The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Canada., Stengs LK; Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Canada.; The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Canada., Chung J; Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Canada.; The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Canada., Negm L; Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Canada.; The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Canada., Dimayacyac JR; Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Canada.; The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Canada., Chang Y; Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Canada.; The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Canada., Nobre L; Division of Haematology/Oncology, The Hospital for Sick Children, Toronto, Canada.; Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Canada.; The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Canada., Ercan AB; Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Canada.; The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Canada.; Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto, Canada., Sanchez-Ramirez S; Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Canada.; The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Canada., Sudhaman S; Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Canada.; The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Canada., Edwards M; Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Canada.; The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Canada., Larouche V; Pediatric Haematology/Oncology Department, CHU de Québec-Université Laval, Quebec City, Canada., Samuel D; Department of Paediatric Oncology, Valley Children's Hospital, Madera, California., Van Damme A; Department of Paediatric Haematology and Oncology, Saint Luc University Hospital, Université Catholique de Louvain, Brussels, Belgium., Gass D; Atrium Health/Levine Children's Hospital, Charlotte, North Carolina., Ziegler DS; Kids Cancer Centre, Sydney Children's Hospital, Randwick, Australia.; School of Clinical Medicine, UNSW Sydney, Sydney, Australia., Bielack SS; Department of Pediatric Oncology, Hematology and Immunology, Center for Childhood, Adolescent, and Women's Medicine, Stuttgart Cancer Center, Klinikum Stuttgart, Stuttgart, Germany., Koschmann C; Pediatric Hematology/Oncology, C.S. Mott Children's Hospital, University of Michigan, Ann Arbor, Michigan., Zelcer S; Department of Pediatrics, London Health Sciences Centre, London, Canada., Yalon-Oren M; Department of Paediatric Haematology-Oncology, Sheba Medical Centre, Ramat Gan, Israel., Campino GA; Department of Paediatric Haematology-Oncology, Sheba Medical Centre, Ramat Gan, Israel., Sarosiek T; Lux Med Onkologia, Warsaw, Poland., Nichols KE; Department of Oncology, St Jude Children's Research Hospital, Memphis, Tennessee., Loret De Mola R; Oregon Health and Science University, Portland, Oregon., Bielamowicz K; Department of Pediatrics, Section of Pediatric Hematology/Oncology, The University of Arkansas for Medical Sciences/Arkansas Children's Hospital, Little Rock, Arkansas., Sabel M; Department of Paediatrics, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg & Queen Silvia Children's Hospital, Sahlgrenska University Hospital, Gothenburg, Sweden., Frojd CA; Department of Oncology, Sahlgrenska University Hospital, Gothenburg, Sweden., Wood MD; Neuropathology, Oregon Health & Science University Department of Pathology, Portland, Oregon., Glover JM; Department of Pediatric Hematology/Oncology, Randall Children's Hospital, Portland, Oregon., Lee YY; Department of Neurosurgery, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan., Vanan M; Pediatric Hematology-Oncology, CancerCare Manitoba, Winnipeg, Canada.; CancerCare Manitoba Research Institute, Pediatrics and Child Health, University of Manitoba, Winnipeg, Canada., Adamski JK; Neuro-oncology Division, Birmingham Children's Hospital, Birmingham, United Kingdom., Perreault S; Neurosciences Department, Child Neuro-logy Division, CHU Sainte-Justine, Montreal, Canada., Chamdine O; Pediatric Hematology Oncology, King Fahad Specialist Hospital Dammam, Eastern Province, Saudi Arabia., Hjort MA; Department of Paediatric Haematology and Oncology, St. Olav's University Hospital, Trondheim, Norway., Zapotocky M; Department of Paediatric Haematology and Oncology, Second Faculty of Medicine, University Hospital Motol, Charles University, Prague, Czech Republic., Carceller F; Paediatric 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., Wright E; Division of Neuro-Oncology, Akron Children's Hospital, Akron, Ohio., Fedorakova I; Clinic of Pediatric Oncology and Hematology, University Children's Hospital, Banská Bystrica, Slovakia., Lossos A; Department of Oncology, Leslie and Michael Gaffin Centre for Neuro-Oncology, Hadassah-Hebrew University Medical Centre, Jerusalem, Israel., Tanaka R; Division of Hematology/Oncology/Blood and Marrow Transplantation, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin., Osborn M; Women's and Children's Hospital, North Adelaide, Australia., Blumenthal DT; Neuro-Oncology Service, Tel-Aviv Medical Center, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel., Aronson M; Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, Toronto, Canada., Bartels U; Division of Haematology/Oncology, The Hospital for Sick Children, Toronto, Canada.; Department of Paediatrics, University of Toronto, Toronto, Canada., Huang A; Division of Haematology/Oncology, The Hospital for Sick Children, Toronto, Canada.; The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Canada., Ramaswamy V; Division of Haematology/Oncology, The Hospital for Sick Children, Toronto, Canada.; The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Canada., Malkin D; Division of Haematology/Oncology, The Hospital for Sick Children, Toronto, Canada.; Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Canada.; Department of Paediatrics, University of Toronto, Toronto, Canada.; Department of Medical Biophysics, University of Toronto, Toronto, Canada., Shlien A; Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Canada.; Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, Canada., Villani A; Division of Haematology/Oncology, The Hospital for Sick Children, Toronto, Canada.; Department of Paediatrics, University of Toronto, Toronto, Canada., Dirks PB; The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Canada.; Division of Neurosurgery, The Hospital for Sick Children, Toronto, Canada.; Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Canada., Pugh TJ; Ontario Institute for Cancer Research, Princess Margaret Cancer Centre, Toronto, Canada., Getz G; Broad Institute of Harvard and MIT, Cambridge, Massachusetts., Maruvka YE; Technion-Israel Institute of Technology, Tel-Aviv, Israel., Tsang DS; Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Canada., Ertl-Wagner B; Department of Diagnostic Imaging, The Hospital for Sick Children, Toronto, Canada., Hawkins C; The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Canada.; Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Canada.; Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, Canada., Bouffet E; Division of Haematology/Oncology, The Hospital for Sick Children, Toronto, Canada., Morgenstern DA; Division of Haematology/Oncology, The Hospital for Sick Children, Toronto, Canada.; Department of Paediatrics, University of Toronto, Toronto, Canada., Tabori U; Division of Haematology/Oncology, The Hospital for Sick Children, Toronto, Canada.; Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Canada.; The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Canada.; Department of Medical Biophysics, University of Toronto, Toronto, Canada.
Jazyk:	angličtina
Zdroj:	Cancer discovery [Cancer Discov] 2024 Feb 08; Vol. 14 (2), pp. 258-273.
DOI:	10.1158/2159-8290.CD-23-0559
Abstrakt:	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. (©2023 American Association for Cancer Research.)
Databáze:	MEDLINE
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