Ibrutinib enhances chimeric antigen receptor T-cell engraftment and efficacy in leukemia

JA Fraietta, KA Beckwith, PR Patel… - Blood, The Journal …, 2016 - ashpublications.org
JA Fraietta, KA Beckwith, PR Patel, M Ruella, Z Zheng, DM Barrett, SF Lacey, JJ Melenhorst…
Blood, The Journal of the American Society of Hematology, 2016ashpublications.org
Anti-CD19 chimeric antigen receptor (CAR) T-cell therapy is highly promising but requires
robust T-cell expansion and engraftment. A T-cell defect in chronic lymphocytic leukemia
(CLL) due to disease and/or therapy impairs ex vivo expansion and response to CAR T
cells. To evaluate the effect of ibrutinib treatment on the T-cell compartment in CLL as it
relates to CAR T-cell generation, we examined the phenotype and function of T cells in a
cohort of CLL patients during their course of treatment with ibrutinib. We found that≥ 5 …
Abstract
Anti-CD19 chimeric antigen receptor (CAR) T-cell therapy is highly promising but requires robust T-cell expansion and engraftment. A T-cell defect in chronic lymphocytic leukemia (CLL) due to disease and/or therapy impairs ex vivo expansion and response to CAR T cells. To evaluate the effect of ibrutinib treatment on the T-cell compartment in CLL as it relates to CAR T-cell generation, we examined the phenotype and function of T cells in a cohort of CLL patients during their course of treatment with ibrutinib. We found that ≥5 cycles of ibrutinib therapy improved the expansion of CD19-directed CAR T cells (CTL019), in association with decreased expression of the immunosuppressive molecule programmed cell death 1 on T cells and of CD200 on B-CLL cells. In support of these findings, we observed that 3 CLL patients who had been treated with ibrutinib for ≥1 year at the time of T-cell collection had improved ex vivo and in vivo CTL019 expansion, which correlated positively together and with clinical response. Lastly, we show that ibrutinib exposure does not impair CAR T-cell function in vitro but does improve CAR T-cell engraftment, tumor clearance, and survival in human xenograft models of resistant acute lymphocytic leukemia and CLL when administered concurrently. Our collective findings indicate that ibrutinib enhances CAR T-cell function and suggest that clinical trials with combination therapy are warranted. Our studies demonstrate that improved T-cell function may also contribute to the efficacy of ibrutinib in CLL. These trials were registered at www.clinicaltrials.gov as #NCT01747486, #NCT01105247, and #NCT01217749.
ashpublications.org