Enhanced Effector Responses In Car-Redirected Cd8+T Cells Deficient In Diacylglycerol Kinases.

The use of chimeric antigen receptor (CAR)-redirected CD8+ T cells in the treatment of malignancy is a novel strategy that has shown tremendous promise; however, it remains likely this strategy could be enhanced when combined with additional approaches. We hypothesized that deletion of signaling mediators that negatively regulate TCR signal transduction might enhance CAR signaling and function, since CARs utilize the same machinery that transduces TCR signals. We tested CAR activity and function in T cells that lacked one or both lymphocyte-specific isoforms of diacylglycerol kinase (dgk), proteins that metabolize the second messenger DAG and limit Ras/ERK activation. We found that primary murine T cells transduced with CARs specific for the human tumor antigen mesothelin demonstrated greatly enhanced cytokine production and cytotoxicity when co-cultured with a murine mesothelioma line that stably expresses mesothelin. Additionally, we found that dgk-deficient CAR transduced T cells were more effective in limiting the growth of implanted tumors, both concurrent with and after establishment of tumor. These results suggest that deletion of negative regulators of TCR signaling enhances the activity and function of CAR-expressing T cells, and identify dgks as a potential target for improving the clinical potential of CARs. Citation Format: Matthew Riese, Liang-Chuan Wang, Anjana Ranganathan, Gary Koretzky, Steven Albelda. Enhanced effector responses in CAR-redirected CD8+ T cells deficient in diacylglycerol kinases. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology: Multidisciplinary Science Driving Basic and Clinical Advances; Dec 2-5, 2012; Miami, FL. Philadelphia (PA): AACR; Cancer Res 2013;73(1 Suppl):Abstract nr A3.