Enhancing Therapeutic Efficacy of Double Negative T Cells against Acute Myeloid Leukemia Using Idelalisib

Simple Summary Persistence of infused cells is an important factor that dictates the outcome of adoptive cellular therapy (ACT). DNT therapy is a novel form of ACT with promising result in treating relapsed or refractory AML in preclinical and early clinical studies. However, in vivo kinetics of human DNTs in cancer-bearing host have not been previously investigated. This study was the first to investigate the persistence of DNTs and ways to improve it in patient-derived xenograft models. DNTs persistence was observed up to 50 days in various organs of leukemia-bearing hosts. However, the detected DNT level was low while significant level of persisting AMLs was observed. To improve the in vivo persistence and therapeutic efficacy of DNTs, we expanded DNTs in the presence of an PI3Kδ inhibitor, idelalisib (Ide). Ide treatment of healthy donor-derived DNTs promoted early memory subsets and improved overall fitness, reducing exhaustion while improving viability. These Ide-induced attributes led to prolonged persistence of DNTs, resulting in superior anti-leukemic activity in vivo. Further, Ide-treated DNTs improved the durability of the treatment response. Collectively, our study highlights the importance of DNT persistence and Ide-mediated improvements in the overall fitness of DNTs, which promote longer persistence in vivo and better treatment outcome. Abstract The double negative T cell (DNT) is a unique subset of T cells with potent anti-leukemic potential. Previously, DNT therapy has been shown to effectively target AML cells in patient-derived xenograft (PDX) models. Further, a recently completed phase I/IIa clinical study demonstrated the safety, feasibility, and potential efficacy in AML patients that relapsed after allogeneic hematopoietic stem cell transplantation. However, the persistence and durability of DNT-mediated anti-leukemic response is less well understood. In this study, we characterized the in vivo persistence of DNTs in PDX models. Further, we improved the efficacy and durability of DNT-mediated activity with phosphoinositide 3-kinase delta (PI3Kδ) inhibition. Mechanistically, DNTs treated with the PI3Kδ inhibitor, Idelalisib (Ide), exhibited early memory phenotype with superior viability and proliferative capacity but less cell exhaustion. Collectively, the findings from this study support the use of Ide-treated DNTs to improve its therapeutic outcome.