Guanylyl Cyclase C-Targeted CAR-T Cell Therapy for the Treatment of Metastatic Colorectal Cancer
The role of the immune system in promoting antitumor immunity has been a controversial issue since the discovery of Coley's toxins in the late 19 th century. However, the reemergence of the concept of tumor immunosurveillance in the early 21st century has initiated a renaissance in the field of cancer immunotherapy that is highlighted in therapeutics such as vaccines and immune checkpoint inhibitors that have the potential to transform the treatment of cancer. Adoptive T cell therapy (ACT) is an emerging form of immunotherapy that has demonstrated considerable potential in promoting complete remissions in patients with advanced melanomas. Further, advances in genetic engineering approaches have permitted the insertion of tumor-specific immune receptors into T cells that offer the potential to extend ACT to many different types of cancer including initial successes in B cell leukemia's. Extending this approach to the treatment of colorectal cancer would offer a significant treatment option for the estimated 50,000 patients who die of metastatic disease annually in the United States. However, to date ACT treatments for metastatic colorectal cancer have been limited by a paucity of suitable antigen targets that have to date been hindered by antigen-specific toxicities. Guanylyl cyclase C (GUCY2C) is a receptor expressed on the apical surfaces of intestinal epithelial cells whose expression is maintained in >95% of colorectal cancer metastases. Moreover, GUCY2C has limited expression outside of the intestine highlighting its potential as a selective marker for metastatic disease. Here we explored the use of T cells engineered to express antibody-based chimeric antigen receptors (CARs) targeting both mouse and human GUCY2C for the treatment of metastatic colorectal cancer. We postulated that luminal GUCY2C-expression on intestinal epithelial cells would limit exposure of systemically administered CAR-T cells permitting the targeting of systemic colorectal cancer metastases in the absence of intestinal toxicities. GUCY2C-specific CARs induced antigen-specific T cell activation, cytokine production, and cytolytic activity. Further, GUCY2C-specific CAR-T cells extended survival in models of colorectal cancer metastatic to the lung and peritoneal cavity. Moreover, therapeutic efficacy occurred with the lack of intestinal toxicities suggesting GUCY2C is a safe target for the treatment of metastatic disease.
Magee, Michael S, "Guanylyl Cyclase C-Targeted CAR-T Cell Therapy for the Treatment of Metastatic Colorectal Cancer" (2015). ETD Collection for Thomas Jefferson University. AAI3705084.