Human scFv based, ALPPL2-specific CAR expressing T cells induce potent antitumor activity in an IL15-dependent manner

Chimeric antigen receptor (CAR) T cells have robust antitumor activity against hematologic malignancies and have the potential to benefit patients with solid tumors. Immune recognition of murine proteins expressed in adoptively transferred T cells and lack of homeostatic in the tumor microenvironment can limit expansion and persistence of CAR T cells. CARs generated only from human sequences reduce the risk of immune mediated rejection and Interleukin-15, which promotes T cell survival and fitness can improve the expansion and persistence of T cells. In this study, we report a CAR T construct (ABBz) assembled from only human sequences including an scFv specific to ALPPL2 selected through an unbiased, high-throughput screen of human antibody-based, phage-displayed scFv library based on binding specificity, stringency, and low dissociation constant. We demonstrate specificity to the antigen, effective cytolytic function, and cytokine production induction in ABBz T cells. We detail key transcriptomic, phenotypic and functional changes specific to IL15 coexpression in ABBz T cells. Lastly, we demonstrate that ABBz CAR T cells have robust anti-tumor activity which is further enhanced through IL15 co-expression resulting in increased cytolytic capacity and superior expansion secondary to reduced apoptosis of CAR T cells.