γδ CAR T-Cellular Vaccine for Solid Cancers - Solid tumors, such as colorectal cancer (CRC) and lung adenocarcinoma (LUAD), present a formidable challenge in cancer treatment. While chimeric antigen receptor (CAR) T-cell therapies have achieved remarkable success in blood cancers, their effectiveness against solid tumors remains limited. Current CAR T-cell therapies and dendritic-cell (DC) vaccines generally lack FDA approval for CRC or LUAD, and existing clinical trials have shown limited success. The one approved DC vaccine for CRC, Sipuleucerl-T, only provides marginal improvements in survival. The urgency for novel interventions is underscored by the pressing need to improve survival rates and overcome the challenges posed by solid tumors. Luminary Therapeutics is developing a futuristic approach to targeting solid cancers: a Dual-action Antigen-presenting CAR γδ T-cell (DACART) therapy that combines the strengths of CAR T-cell therapy with those of cancer vaccination. γδ T-cells are a unique sub-type of T-cells that can function both as a direct cytotoxic immune cell and as a professional antigen presenting cell and thus can be engineered to directly kill cancer via a cancer-specific CAR like a CAR T-cell and to activate a patient’s own immune system to kill cancer by displaying cancer-specific antigens on major histocompatibility complex (MHC) like a DC vaccine. Additionally, γδ T-cells require less engineering to provide safe allogeneic cell therapy, boast high migratory capabilities, and can be reliably expanded to high numbers in the lab. This study will engineer DACART cells using TcBuster transposon technology to present common cancer antigens to endogenous T cells in combination with expressing a CAR targeting mesothelin, a common surface antigen expressed in both CRC and LUAD. In vitro studies will demonstrate the ability of DACART cells to both directly kill tumor cell lines and to activate cancer-specific T cells. In vivo animal studies will then demonstrate the ability of DACART cells to control CRC or LUAD tumors through both direct killing and activation of endogenous T cells. Following these in vitro and in vivo efficacy studies, this project will conduct safety studies to demonstrate the specificity of this treatment and develop clinical-scale production process and safety specifications to prepare this treatment for translation to the clinic. Matching the effectiveness of CAR-T for blood cancers by combining cytotoxic CAR-T cell therapy and cancer vaccination in a single cell therapy that effectively kills solid tumors while also stimulating an endogenous anti-tumor immune response would be a breakthrough in the treatment of many of the deadliest cancers. If this approach is successful with CRC or LUAD, the approach can be applied to other solid tumors, including other prevalent and deadly cancers like prostate, and breast.
