Ex vivo blockade of PI3K gamma or delta signaling enhances the antitumor potency of adoptively transferred CD8⁺ T cells.

ABSTRACT: Adoptive T cell transfer therapy induces objective responses in patients with advanced malignancies. Despite these results, some individuals do not respond due to the generation of terminally differentiated T cells during the expansion protocol. As the gamma and delta catalytic subunits in the PI3K pathway are abundant in leukocytes and involved in cell activation, we posited that blocking both subunits ex vivo with the inhibitor IPI-145 would prevent their differentiation, thereby increasing antitumor activity in vivo. However, IPI-145 treatment generated a product with reduced antitumor activity. Instead, T cells inhibited of PI3Kγ (IPI-549) or PI3Kδ (CAL-101 or TGR-1202) alone were more potent in vivo. While T cells coinhibited of PI3Kγ and PI3Kδ were less differentiated, they were func

SUBMITTER: Dwyer CJ 

PROVIDER: S-EPMC7496332 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature