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Genomic predictors of response to PD-1 inhibition in children with germline DNA replication repair deficiency
A. Das, S. Sudhaman, D. Morgenstern, A. Coblentz, J. Chung, SC. Stone, N. Alsafwani, ZA. Liu, OAA. Karsaneh, S. Soleimani, H. Ladany, D. Chen, M. Zatzman, V. Cabric, L. Nobre, V. Bianchi, M. Edwards, LC. Sambira Nahum, AB. Ercan, A. Nabbi, S....
Jazyk angličtina Země Spojené státy americké
Typ dokumentu časopisecké články, pozorovací studie, práce podpořená grantem
Grantová podpora
PJT-156006
CIHR - Canada
NLK
ProQuest Central
od 2000-01-01 do Před 1 rokem
Health & Medicine (ProQuest)
od 2000-01-01 do Před 1 rokem
- MeSH
- analýza přežití MeSH
- antigeny CD274 antagonisté a inhibitory MeSH
- dítě MeSH
- dospělí MeSH
- inhibitory kontrolních bodů farmakologie terapeutické užití MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- nádorové biomarkery MeSH
- nádorové mikroprostředí MeSH
- nádory farmakoterapie MeSH
- oprava DNA genetika MeSH
- prospektivní studie MeSH
- replikace DNA genetika MeSH
- retrospektivní studie MeSH
- zárodečné mutace * MeSH
- Check Tag
- dítě MeSH
- dospělí MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- pozorovací studie MeSH
- práce podpořená grantem MeSH
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.
Atrium Health Levine Children's Hospital Charlotte NC USA
Biotechnology and Food Engineering Technion Israel Institute of Technology Tel Aviv Israel
Broad Institute of Harvard and MIT Cambridge MA USA
Dalla Lana School of Public Health University of Toronto Toronto Ontario Canada
Department of Basic Medical Sciences Faculty of Medicine The Hashemite University Zarqa Jordan
Department of Diagnostic Imaging The Hospital for Sick Children Toronto Ontario Canada
Department of Immunology University of Toronto Toronto Ontario Canada
Department of Laboratory Medicine and Pathobiology University of Toronto Toronto Ontario Canada
Department of Medical Biophysics University of Toronto Toronto Ontario Canada
Department of Neurosurgery Neurological Institute Taipei Veterans General Hospital Taipei Taiwan
Department of Oncology Sahlgrenska University Hospital Gothenburg Sweden
Department of Paediatric Haematology Oncology Tata Medical Centre Kolkata India
Department of Paediatric Laboratory Medicine The Hospital for Sick Children Toronto Ontario Canada
Department of Paediatrics University of Melbourne Parkville Victoria Australia
Department of Paediatrics University of Toronto Toronto Ontario Canada
Department of Pediatric Hematology Oncology Rambam Health Care Campus Haifa Israel
Department of Pediatric Hematology Oncology Sheba Medical Centre Ramat Gan Israel
Department of Pediatric Hematology Oncology Tel Aviv Sourasky Medical Centre Tel Aviv Israel
Department of Pediatric Neurosurgery Dana Children's Hospital Tel Aviv Israel
Department of Pediatric Oncology Valley Children's Hospital Madera CA USA
Department of Pediatrics Anschutz Medical Campus Children's Hospital of Colorado Aurora CO USA
Department of Pediatrics J W Ruby Memorial Hospital West Virginia University Morgantown WV USA
Department of Pediatrics The University of Texas Southwestern Medical School Dallas TX USA
Department of Pediatrics University of Pittsburgh School of Medicine Pittsburgh PA USA
Departments of Neurology and Pediatrics University of California San Francisco CA USA
Developmental and Stem Cell Biology Program The Hospital for Sick Children Toronto Ontario Canada
Division of Haematology Oncology The Hospital for Sick Children Toronto Ontario Canada
Division of Neurosurgery The Hospital for Sick Children Toronto Ontario Canada
Division of Pediatric Hematology Oncology BMT Medical College of Wisconsin Milwaukee WI USA
Institute of Medical Science Faculty of Medicine University of Toronto Toronto Ontario Canada
Kids Cancer Centre Sydney Children's Hospital Randwick New South Wales Australia
Lux Med Onkologia Warsaw Poland
Massachusetts General Hospital Cancer Center and Department of Pathology Charlestown MA USA
Ontario Institute for Cancer Research Toronto Ontario Canada
Paediatric Haematology and Oncology University Hospital Frankfurt Frankfurt Germany
Paediatric Unit Fondazione IRCCS Istituto Nazionale dei Tumori Milan Italy
Pediatric Hematology Oncology Helen DeVos Children's Hospital Grand Rapids MI USA
Phoenix Children's Hospital Phoenix AZ USA
Princess Margaret Cancer Centre University Health Network Toronto Ontario Canada
Program in Cell Biology The Hospital for Sick Children Toronto Ontario Canada
Program in Genetics and Genome Biology The Hospital for Sick Children Toronto Ontario Canada
Queen Silvia Children's Hospital Sahlgrenska University Hospital Gothenburg Sweden
Radiation Medicine Program Princess Margaret Cancer Centre Toronto Ontario Canada
Women's and Children's Hospital North Adelaide South Australia Australia
Zane Cohen Centre for Digestive Diseases Mount Sinai Hospital Toronto Ontario Canada
Citace poskytuje Crossref.org
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- $a Genomic predictors of response to PD-1 inhibition in children with germline DNA replication repair deficiency / $c A. Das, S. Sudhaman, D. Morgenstern, A. Coblentz, J. Chung, SC. Stone, N. Alsafwani, ZA. Liu, OAA. Karsaneh, S. Soleimani, H. Ladany, D. Chen, M. Zatzman, V. Cabric, L. Nobre, V. Bianchi, M. Edwards, LC. Sambira Nahum, AB. Ercan, A. Nabbi, S. Constantini, R. Dvir, M. Yalon-Oren, GA. Campino, S. Caspi, V. Larouche, A. Reddy, M. Osborn, G. Mason, S. Lindhorst, A. Bronsema, V. Magimairajan, E. Opocher, RL. De Mola, M. Sabel, C. Frojd, D. Sumerauer, D. Samuel, K. Cole, S. Chiaravalli, M. Massimino, P. Tomboc, DS. Ziegler, B. George, A. Van Damme, N. Hijiya, D. Gass, RB. McGee, O. Mordechai, DC. Bowers, TW. Laetsch, A. Lossos, DT. Blumenthal, T. Sarosiek, LY. Yen, J. Knipstein, A. Bendel, LM. Hoffman, S. Luna-Fineman, S. Zimmermann, I. Scheers, KE. Nichols, M. Zapotocky, JR. Hansford, JM. Maris, P. Dirks, MD. Taylor, AV. Kulkarni, M. Shroff, DS. Tsang, A. Villani, W. Xu, M. Aronson, C. Durno, A. Shlien, D. Malkin, G. Getz, YE. Maruvka, PS. Ohashi, C. Hawkins, TJ. Pugh, E. Bouffet, U. Tabori
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- $a 2022 $b 28 $c 1 $d 125-135 $e 20220106 $i 1546-170X $m Nature medicine $n Nat Med $x MED00003459
- GRA __
- $a PJT-156006 $p CIHR $2 Canada
- LZP __
- $a Pubmed-20220425
