Team Leader
John Wherry, PhD – University of Pennsylvania
Team Members
Shelley Berger, PhD
Perelman School of Medicine University of Pennsylvania |
Robert Burger, MD, FACOG, FACS
The Hospital of the University of Pennsylvania |
Erica Carpenter, MBA, PhD
Perelman School of Medicine University of Pennsylvania |
Claire Friedman, MD
Memorial Sloan Kettering Cancer Center |
Travis Hollman, MD, PhD
Memorial Sloan Kettering Cancer Center |
Dana Pe’er, PhD
Memorial Sloan Kettering Cancer Center |
Daniel Powell, PhD
University of Pennsylvania |
Dmitriy Zamarin, MD, PhD
Memorial Sloan Kettering Cancer Center |
Collaborators
Benjamin Greenbaum, PhD
Icahn School of Medicine at Mount Sinai |
Ernest Fraenkel, PhD
Massachusetts Institute of Technology |
David Ting, MD
Massachusetts General Hospital/Harvard Medical School |
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Project Summary
Mismatch repair (MMR)-deficiency, the inability to repair base pairing within the DNA helix, can give rise to a weakened DNA structure, which leads to the accumulation of mutations. The response to immune checkpoint inhibitors has been varied in gynecologic cancers, possibly due to the number of mutations carried by each tumor cell (mutational burden). The team hypothesizes that the tumors with a high mutational burden fail to respond to checkpoint inhibition because of an immune dysfunction that is based on the mechanism for the MMR deficiency. The team plans to initiate two clinical trials that will test whether a) tumor-intrinsic factors affect the response to checkpoint inhibition; b) baseline immune function and quality affects response to checkpoint inhibition; and c) on-treatment blood markers may reflect the tumor-immune interaction. Understanding the mechanism that leads to this phenomenon has the potential to dramatically affect those patients who do not respond to current treatments.