PI3Kδ inhibition supports memory T cells with enhanced antitumor fitness

SUMMARY Phosphatidylinositol-3-kinase p110δ (PI3Kδ) inhibition by Idelalisib (CAL-101) in hematological malignancies directly induces apoptosis in cancer cells and disrupts immunological tolerance by depleting regulatory T cells (Tregs). Yet, little is known about the direct impact of PI3Kδ blockade on effector T cells from CAL-101 therapy. Herein, we demonstrate a direct effect of p110δ inactivation via CAL-101 on murine and human CD8 + T cells that promotes a strong undifferentiated memory phenotype (elevated CD62L/CCR7, CD127 and Tcf7). These CAL-101 T cells also persisted longer after transfer and exerted stronger antitumor immunity compared to traditionally expanded CD8 + T cells in two solid tumor models. Thus, this report describes a novel direct enhancement of CD8 + T cell memory by a p110δ inhibitor that leads to markedly improved tumor regression. This finding has significant implications to improve outcomes from next generation cancer immunotherapies. Highlights In vitro blockade of PI3K p110δ with CAL-101 endows antitumor T cells with a stronger memory phenotype than those treated with AKTi The strong memory phenotype of CAL-101 treated cells translates into improved survival of mice bearing aggressive tumors after adoptive transfer of these T cells Human CAR engineered T cells treated with CAL-101 possess an enhanced memory phenotype and robust antitumor efficacy The antitumor efficacy of CAL-101 primed T cells is not mediated by high CD62L or CD127 expression, but is likely driven by their stem memory phenotype eTOC Blurb Bowers et al report a novel function of PI3K blockade using the p110δ subunit inhibitor CAL-101 to induce memory and antitumor potency in CD8 + T cells. Ex vivo treatment of T cells with CAL-101 leads to improved antitumor control and subject survival in both murine transgenic T cell and human CAR T cell models.