Immune modulating T cell therapy for lung cancer

Background and Innovation: The studies proposed here aim to develop a novel T cell- based platform for delivering the cytokine Interleukin 12 directly to lung cancer tumors. We have developed novel CAR-T cell engineering constructs targeting two tumor associated targets, mesothelin and C3d. We also utilize a unique form of adoptive transfer that maintains immune function and we have incorporated a novel drug inducible gene expression system to enhance user control, safety, and therapeutic index. Significance and Impact to Veterans Healthcare: Lung cancer contributes to more Veteran mortality than prostate and colon cancer combined. Immune modulating therapies have been the most promising treatments for lung cancer to emerge in the last several decades. These studies will explore new cell therapy products that will be used to treat lung cancer in Veterans. Path to translation/implementation: The studies outlined in this application will provide pre- clinical validation of this cell therapy product by validating the safety and utility of the targeting CD8+ CAR-T cells to target C3d and Mesothelin. Furthermore, it will provide pre-clinical assessment of the novel user-controlled gene expression platform. Finally, the Aim 3 studies will provide a translational framework by validating unique aspects of manufacturing and quality control that are specific to this innovative cell therapy product. We anticipate that these studies will lead to an investigational new drug application and opening of phase 1 clinical trials for Veterans fighting lung cancer.