期刊
BLOOD
卷 127, 期 9, 页码 1117-1127出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2015-11-679134
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资金
- National Institutes of Health National Cancer Institute [T32 CA009140, K08 CA166039, P01 CA095426, K23 CA178183, R35 CA198183, R01 CA177292, R01 CA165206]
- D. Warren Brown Foundation
- Four Winds Foundation
- Lymphoma Research Foundation
- Novartis
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 vivoexpansionand response to CART cells. To evaluate the effect of ibrutinib treatment on the T-cell compartment in CLL as it relates to CART-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 CART 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.
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