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Integrated molecular analysis of tumor biopsies on sequential CTLA-4 and PD-1 blockade reveals markers of response and resistance.
- Source :
-
Science translational medicine [Sci Transl Med] 2017 Mar 01; Vol. 9 (379). - Publication Year :
- 2017
-
Abstract
- Immune checkpoint blockade produces clinical benefit in many patients. However, better biomarkers of response are still needed, and mechanisms of resistance remain incompletely understood. To address this, we recently studied a cohort of melanoma patients treated with sequential checkpoint blockade against cytotoxic T lymphocyte antigen-4 (CTLA-4) followed by programmed death receptor-1 (PD-1) and identified immune markers of response and resistance. Building on these studies, we performed deep molecular profiling including T cell receptor sequencing and whole-exome sequencing within the same cohort and demonstrated that a more clonal T cell repertoire was predictive of response to PD-1 but not CTLA-4 blockade. Analysis of CNAs identified a higher burden of copy number loss in nonresponders to CTLA-4 and PD-1 blockade and found that it was associated with decreased expression of genes in immune-related pathways. The effect of mutational load and burden of copy number loss on response was nonredundant, suggesting the potential utility of a combinatorial biomarker to optimize patient care with checkpoint blockade therapy.<br /> (Copyright © 2017, American Association for the Advancement of Science.)
- Subjects :
- Biomarkers, Tumor metabolism
Biopsy
CTLA-4 Antigen metabolism
Clone Cells
Cohort Studies
DNA Copy Number Variations genetics
Gene Dosage
Genome
Humans
Mutation genetics
Neoplasms genetics
Neoplasms immunology
Programmed Cell Death 1 Receptor metabolism
T-Lymphocytes immunology
CTLA-4 Antigen antagonists & inhibitors
Drug Resistance, Neoplasm
Neoplasms drug therapy
Neoplasms pathology
Programmed Cell Death 1 Receptor antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1946-6242
- Volume :
- 9
- Issue :
- 379
- Database :
- MEDLINE
- Journal :
- Science translational medicine
- Publication Type :
- Academic Journal
- Accession number :
- 28251903
- Full Text :
- https://doi.org/10.1126/scitranslmed.aah3560