Genomic predictors of response to PD-1 inhibition in children with germline DNA replication repair deficiency.
Adolescent
Adult
B7-H1 Antigen
/ antagonists & inhibitors
Biomarkers, Tumor
Child
DNA Repair
/ genetics
DNA Replication
/ genetics
Female
Germ-Line Mutation
Humans
Immune Checkpoint Inhibitors
/ pharmacology
Male
Neoplasms
/ drug therapy
Prospective Studies
Retrospective Studies
Survival Analysis
Tumor Microenvironment
Young Adult
Journal
Nature medicine
ISSN: 1546-170X
Titre abrégé: Nat Med
Pays: United States
ID NLM: 9502015
Informations de publication
Date de publication:
01 2022
01 2022
Historique:
received:
10
02
2021
accepted:
15
10
2021
pubmed:
8
1
2022
medline:
23
2
2022
entrez:
7
1
2022
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 34992263
doi: 10.1038/s41591-021-01581-6
pii: 10.1038/s41591-021-01581-6
pmc: PMC8799468
doi:
Substances chimiques
B7-H1 Antigen
0
Biomarkers, Tumor
0
CD274 protein, human
0
Immune Checkpoint Inhibitors
0
Types de publication
Journal Article
Observational Study
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
125-135Subventions
Organisme : CIHR
ID : PJT-156006
Pays : Canada
Informations de copyright
© 2022. The Author(s).
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