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Science. 2017 Jul 28;357(6349):409-413. doi: 10.1126/science.aan6733. Epub 2017 Jun 8.

Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade.

Author information

1
Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore, MD 21287, USA.
2
Swim Across America Laboratory at Johns Hopkins, Baltimore, MD 21287, USA.
3
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21287, USA.
4
Ludwig Center and Howard Hughes Medical Institute at Johns Hopkins, Baltimore, MD 21287, USA.
5
Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
6
Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
7
Providence Cancer Center at Providence Health & Services, Portland, OR 97213, USA.
8
Department of Medicine, University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15232, USA.
9
Gastrointestinal Malignancies Section, Thoracic-GI Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
10
Division of Medical Oncology, Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA.
11
Merck & Co. Inc., Kenilworth, NJ 07033, USA.
12
West Virginia University Cancer Institute, Morgantown, WV 26506, USA.
13
Department of Gynecology and Obstetrics, Johns Hopkins Medicine, Baltimore, MD 21287, USA.
14
Caris Life Sciences, Phoenix, AZ 85040, USA.
15
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
16
Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore, MD 21287, USA. ldiaz@mskcc.org.

Abstract

The genomes of cancers deficient in mismatch repair contain exceptionally high numbers of somatic mutations. In a proof-of-concept study, we previously showed that colorectal cancers with mismatch repair deficiency were sensitive to immune checkpoint blockade with antibodies to programmed death receptor-1 (PD-1). We have now expanded this study to evaluate the efficacy of PD-1 blockade in patients with advanced mismatch repair-deficient cancers across 12 different tumor types. Objective radiographic responses were observed in 53% of patients, and complete responses were achieved in 21% of patients. Responses were durable, with median progression-free survival and overall survival still not reached. Functional analysis in a responding patient demonstrated rapid in vivo expansion of neoantigen-specific T cell clones that were reactive to mutant neopeptides found in the tumor. These data support the hypothesis that the large proportion of mutant neoantigens in mismatch repair-deficient cancers make them sensitive to immune checkpoint blockade, regardless of the cancers' tissue of origin.

PMID:
28596308
PMCID:
PMC5576142
DOI:
10.1126/science.aan6733
[Indexed for MEDLINE]
Free PMC Article

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