Syngeneic CAR T cells engineered for persistent delivery of desired proteins

Abstract

AbstractMouse primary T cells have been engineered as a platform using chimeric antigen receptors (CARs) to induce the synthesis of desired proteins at the disease site. This approach allows for the use of immunocompetent syngeneic tumor models to evaluate the CAR T cells' function within the context of a fully functioning immune system. Current efforts to evaluate cell-based technologies typically rely on xenograft tumor models in immunodeficient mice, which provide early feasibility data but may not fully capture the immune effects present in the tumor microenvironment. In this study, a primary T-cell-based system for site-specific protein expression has been translated from human T cells to mouse T cells, allowing for the use of an immunocompetent syngeneic tumor model. A lentivector transduction, effective in human T cells, was adapted to engineer mouse T cells. CD4 and CD8 CAR T cell subsets were engineered separately and evaluated in immunocompetent mice for site-specific expression of the desired proteins. Co-expression of membrane-bound interleukin 15 (mbIL15) on the T cells enhanced intratumoral accumulation of both CD4 and CD8 CAR T cells and supported their delivery function. Validation of this platform in syngeneic models will enable efficacy assessments beyond solid tumors and allow for the evaluation of immune-related toxicities arising from interactions between the therapeutic protein, CAR T cells, and the host immune system.”