Patients with adenocarcinomas, such as pancreatic ductal adenocarcinoma (PDAC), rarely respond to checkpoint immunotherapies targeting the PD-1/PD-L1 pathway because killer T cells are prevented from accumulating in the vicinity of cancer cells. Therefore, the major challenge in cancer immunology is to discover a therapy that overcomes this restricted distribution of T cells.
Dr. Fearon’s pre-clinical study in a mouse model of pancreatic cancer, and his recent phase 1 study of patients with microsatellite stable (MSS) metastatic PDAC or colorectal cancer (CRC) have shown that inhibiting a single receptor—CXCR4—on immune cells promoted the accumulation of T cells in cancer cell nests. This decreased the frequency of cancer cells in human PDAC and CRC and made mice with PDAC more sensitive to checkpoint immunotherapy, leading to immune killing of >99% of cancer cells. These results indicate that there is a hierarchy of immune suppression in PDAC and CRC, and that CXCR4 must be inhibited before PD-1/PD-L1 antagonists will be effective. However, current inhibitors of the CXCR4 pathway are suboptimal, so Dr. Fearon’s work aims to solve this issue by developing a more effective therapy to target CXCR4 in humans.
Projects and Grants
Development of a Proprietary Lead CXCR4 Inhibitor for Cancer Immunotherapy
Weill Cornell Medicine | Colorectal Cancer, Pancreatic Cancer | 2020
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