Ibrutinib enhances chimeric antigen receptor T-cell engraftment and efficacy in leukemia
Menée in vitro et in vivo, cette étude met en évidence des mécanismes suggérant que l'ibrutinib améliore l'efficacité d'une immunothérapie à base de lymphocytes CAR-T pour le traitement de patients atteints d'une leucémie lymphocytaire chronique
Ibrutinib treatment of CLL enhances the generation of CAR T-cells for adoptive immunotherapy. Concurrent ibrutinib therapy improves the engraftment and therapeutic efficacy of anti-CD19 CAR T-cells in mouse models. 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 five or more cycles of ibrutinib therapy improved the expansion of CD19-directed CAR T-cells (CTL019), in association with decreased expression of the immunosuppressive molecules PD1 on T-cells and CD200 on B-CLL cells. In support of these findings, we observed that three CLL patients who had been treated with ibrutinib for at least one 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. Finally, we show that ibrutinib exposure does not impair CAR T-cell function in vitro and in fact improves CAR T-cell engraftment, tumor clearance and survival in human xenograft models of resistant acute lymphocytic leukemia (ALL) 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. Finally, our studies demonstrate that improved T-cell function may also contribute to the efficacy of ibrutinib in CLL. NCT01747486 - www.ClinicalTrials.gov; NCT01105247 - www.ClinicalTrials.gov; NCT01217749 - www.ClinicalTrials.gov
Blood 2016