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Front Immunol. 2017 Sep 29;8:1221. doi: 10.3389/fimmu.2017.01221. eCollection 2017.

PI3Kδ Inhibition Enhances the Antitumor Fitness of Adoptively Transferred CD8+ T Cells.

Bowers JS1,2,3, Majchrzak K1,2,3,4, Nelson MH1,2,3, Aksoy BA5, Wyatt MM1,2,3, Smith AS1,2,3, Bailey SR1,2,3, Neal LR1,2,3, Hammerbacher JE1,5, Paulos CM1,2,3.

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Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, United States.
Department of Dermatology, Medical University of South Carolina, Charleston, SC, United States.
Department of Surgery, Medical University of South Carolina, Charleston, SC, United States.
Faculty of Veterinary Medicine, Department of Physiological Sciences, Warsaw University of Life Sciences, Warsaw, Poland.
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mt Sinai, New York City, NY, United States.


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. 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 phenotype (elevated CD62L/CCR7, CD127, and Tcf7). These CAL-101 T cells also persisted longer after transfer into tumor bearing mice in both the murine syngeneic and human xenograft mouse models. The less differentiated phenotype and improved engraftment of CAL-101 T cells resulted in stronger antitumor immunity compared to traditionally expanded CD8+ T cells in both tumor models. Thus, this report describes a novel direct enhancement of CD8+ T cells by a p110δ inhibitor that leads to markedly improved tumor regression. This finding has significant implications to improve outcomes from next generation cancer immunotherapies.


CAL-101; T cell; adoptive cell therapy; cancer; idelalisib; memory; phosphatidylinositol-3-kinase

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