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Blood. 2016 Mar 3;127(9):1117-27. doi: 10.1182/blood-2015-11-679134. Epub 2016 Jan 26.

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

Author information

1
Center for Cellular Immunotherapies and Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA;
2
Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH;
3
Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA;
4
Center for Cellular Immunotherapies and Division of Hematology-Oncology, Department of Internal Medicine and.
5
Center for Cellular Immunotherapies and Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA; Division of Hematology-Oncology, Department of Internal Medicine and.
6
Center for Cellular Immunotherapies and Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA; Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA; and.
7
Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA.

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.

PMID:
26813675
PMCID:
PMC4778162
[Available on 2017-03-03]
DOI:
10.1182/blood-2015-11-679134
[Indexed for MEDLINE]
Free PMC Article

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