Patients with 12 advanced cancer types with MMR deficiency, bearing a large number of mutation-associated neoantigens, responded strongly to pembrolizumab therapy. Neoantigen-specific intratumoral T cells expanded in the periphery in response to therapy. Thus, MMR deficiency could be used as a marker to identify potential responders to PD-1 blockade.
The genomes of cancers deficient in mismatch repair (MMR) contain exceptionally high numbers of somatic mutations. In a proof-of-concept study, we previously showed that colorectal cancers with MMR deficiency were sensitive to immune checkpoint blockade with anti-PD-1 antibodies. We have expanded this study to now evaluate efficacy of PD-1 blockade in patients with advanced MMR-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 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 MMR-deficient cancers make them sensitive to immune checkpoint blockade, regardless of the cancers' tissue of origin.
Author Info: (1) Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore, MD 21287, USA. Swim Across America Laboratory at Johns Hopkins, Baltimore, MD 21287, USA. Sidne
Author Info: (1) Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore, MD 21287, USA. Swim Across America Laboratory at Johns Hopkins, Baltimore, MD 21287, USA. Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21287, USA. (2) Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore, MD 21287, USA. Swim Across America Laboratory at Johns Hopkins, Baltimore, MD 21287, USA. Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21287, USA. (3) Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore, MD 21287, USA. Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21287, USA. (4) Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21287, USA. (5) Swim Across America Laboratory at Johns Hopkins, Baltimore, MD 21287, USA. Ludwig Center and Howard Hughes Medical Institute at Johns Hopkins, Baltimore, MD 21287, USA. (6) Swim Across America Laboratory at Johns Hopkins, Baltimore, MD 21287, USA. Ludwig Center and Howard Hughes Medical Institute at Johns Hopkins, Baltimore, MD 21287, USA. (7) Swim Across America Laboratory at Johns Hopkins, Baltimore, MD 21287, USA. Ludwig Center and Howard Hughes Medical Institute at Johns Hopkins, Baltimore, MD 21287, USA. (8) Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21287, USA. (9) Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21287, USA. (10) Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21287, USA. (11) Swim Across America Laboratory at Johns Hopkins, Baltimore, MD 21287, USA. Ludwig Center and Howard Hughes Medical Institute at Johns Hopkins, Baltimore, MD 21287, USA. (12) Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore, MD 21287, USA. Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21287, USA. (13) Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore, MD 21287, USA. Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21287, USA. (14) Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21287, USA. (15) Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21287, USA. (16) Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. (17) Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA. (18) Providence Cancer Center at Providence Health & Services, Portland, OR 97213, USA. (19) Department of Medicine, University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15232, USA. (20) Gastrointestinal Malignancies Section, Thoracic-GI Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA. (21) Gastrointestinal Malignancies Section, Thoracic-GI Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA. (22) Division of Medical Oncology, Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA. (23) Merck & Co. Inc., Kenilworth, NJ 07033, USA. (24) Merck & Co. Inc., Kenilworth, NJ 07033, USA. (25) Merck & Co. Inc., Kenilworth, NJ 07033, USA. (26) Merck & Co. Inc., Kenilworth, NJ 07033, USA. (27) Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21287, USA. (28) Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore, MD 21287, USA. Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21287, USA. (29) Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore, MD 21287, USA. Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21287, USA. (30) Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21287, USA. (31) Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore, MD 21287, USA. Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21287, USA. Ludwig Center and Howard Hughes Medical Institute at Johns Hopkins, Baltimore, MD 21287, USA. (32) West Virginia University Cancer Institute, Morgantown, WV 26506, USA. (33) Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21287, USA. (34) Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21287, USA. (35) Department of Gynecology and Obstetrics, Johns Hopkins Medicine, Baltimore, MD 21287, USA. (36) Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore, MD 21287, USA. Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21287, USA. (37) Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore, MD 21287, USA. Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21287, USA. (38) Caris Life Sciences, Phoenix, AZ 85040, USA. (39) Caris Life Sciences, Phoenix, AZ 85040, USA. (40) Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore, MD 21287, USA. Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21287, USA. (41) Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21287, USA. Ludwig Center and Howard Hughes Medical Institute at Johns Hopkins, Baltimore, MD 21287, USA. (42) Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21287, USA. Ludwig Center and Howard Hughes Medical Institute at Johns Hopkins, Baltimore, MD 21287, USA. (43) Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. (44) Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore, MD 21287, USA. Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21287, USA. Ludwig Center and Howard Hughes Medical Institute at Johns Hopkins, Baltimore, MD 21287, USA. (45) Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore, MD 21287, USA. Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21287, USA. Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. (46) Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore, MD 21287, USA. ldiaz@mskcc.org. Swim Across America Laboratory at Johns Hopkins, Baltimore, MD 21287, USA. Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21287, USA.
