Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade
Dung T. LeBloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore, MD 21287, USAJennifer N. DurhamBloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore, MD 21287, USAKellie N. SmithBloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore, MD 21287, USAHao WangSidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21287, USABjarne R. BartlettLudwig Center and Howard Hughes Medical Institute at Johns Hopkins, Baltimore, MD 21287, USALaveet K. AulakhLudwig Center and Howard Hughes Medical Institute at Johns Hopkins, Baltimore, MD 21287, USASteve LuLudwig Center and Howard Hughes Medical Institute at Johns Hopkins, Baltimore, MD 21287, USAHolly KemberlingSidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21287, USACara WiltSidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21287, USABrandon LuberSidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21287, USAFay WongLudwig Center and Howard Hughes Medical Institute at Johns Hopkins, Baltimore, MD 21287, USANilofer S. AzadBloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore, MD 21287, USAAgnieszka A. RuckiBloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore, MD 21287, USADan LaheruSidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21287, USARoss C. DonehowerSidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21287, USAAtif ZaheerDepartment of Radiology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USAGeorge A. FisherDepartment of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USATodd S. CrocenziProvidence Cancer Center at Providence Health & Services, Portland, OR 97213, USAJames J. LeeDepartment of Medicine, University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15232, USATim F. GretenGastrointestinal Malignancies Section, Thoracic-GI Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USAAustin G. DuffyGastrointestinal Malignancies Section, Thoracic-GI Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USAKristen K. CiomborDivision of Medical Oncology, Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USAAleksandra EyringMerck & Co. Inc., Kenilworth, NJ 07033, USABao H. LamMerck & Co. Inc., Kenilworth, NJ 07033, USAAndrew K. JoeMerck & Co. Inc., Kenilworth, NJ 07033, USASoonmo Peter KangMerck & Co. Inc., Kenilworth, NJ 07033, USAMatthias HoldhoffSidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21287, USALudmila DanilovaBloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore, MD 21287, USALeslie CopeBloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore, MD 21287, USAChristian F. MeyerSidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21287, USAShibin ZhouBloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore, MD 21287, USARichard M. GoldbergWest Virginia University Cancer Institute, Morgantown, WV 26506, USADeborah K. ArmstrongSidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21287, USAKatherine M. BeverSidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21287, USAAmanda N. FaderJohns Hopkins HospitalJanis M. TaubeBloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore, MD 21287, USAFranck HousseauBloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore, MD 21287, USADavid SpetzlerCaris Life Sciences, Phoenix, AZ 85040, USANianqing XiaoCaris Life Sciences, Phoenix, AZ 85040, USADrew M. PardollBloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore, MD 21287, USANickolas PapadopoulosLudwig Center and Howard Hughes Medical Institute at Johns Hopkins, Baltimore, MD 21287, USAKenneth W. KinzlerLudwig Center and Howard Hughes Medical Institute at Johns Hopkins, Baltimore, MD 21287, USAJames R. EshlemanDepartment of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USABert VogelsteinBloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore, MD 21287, USARobert A. AndersBloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore, MD 21287, USALuis A. DíazBloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore, MD 21287, USA
2017en
ABI
Аннотация
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.
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