PI3Kδ inhibition supports memory T cells with enhanced antitumor fitness

Abstract

SUMMARYPhosphatidylinositol-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.HighlightsIn vitro blockade of PI3K p110δ with CAL-101 endows antitumor T cells with a stronger memory phenotype than those treated with AKTiThe strong memory phenotype of CAL-101 treated cells translates into improved survival of mice bearing aggressive tumors after adoptive transfer of these T cellsHuman CAR engineered T cells treated with CAL-101 possess an enhanced memory phenotype and robust antitumor efficacyThe 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 phenotypeeTOC BlurbBowers 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.

Strategies to Address Chimeric Antigen Receptor Tonic Signaling

“…These cells exhibited a CD62L + early memory phenotype, suppressed glycolysis and superior anti-tumour efficacy [169]. Likewise, inhibiting the PI3Kδ catalytic subunit p110δ using the small molecule selective inhibitor Idelalisib (formerly CAL-101), can promote a strong undifferentiated memory phenotype in both murine and human CD8 + mesothelin-directed CAR T-cells (as well as pmel-1-directed transgenic TCR T-cells) characterized by the upregulation of transcription factor 7 (Tcf7) and elevated surface expression of CD62L, CCR7 and CD127 [170]. In vivo , Idelalisib-exposed CAR and transgenic TCR T-cells persisted longer following ACT and induced greater tumour regression compared to traditionally expanded CD8 + controls.…”

Fully equipped CARs to address tumor heterogeneity, enhance safety, and improve the functionality of cellular immunotherapies

“…Previous research has shown that the PI3K inhibitor idelalisib can modulate T-cell differentiation in patients with B-cell NHL (130). Idelalisib also improved the persistence and antitumor function of adoptively transferred CD8 + T cells in vivo (131,132). On this basis, investigators have explored the use of PI3K inhibitors to induce a more favorable differentiation profile and enhance the antitumor function of CAR-T cells.…”