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Ibrutinib enhances chimeric antigen receptor T-cell engraftment and efficacy in leukemia.
- Source :
-
Blood [Blood] 2016 Mar 03; Vol. 127 (9), pp. 1117-27. Date of Electronic Publication: 2016 Jan 26. - Publication Year :
- 2016
-
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.<br /> (© 2016 by The American Society of Hematology.)
- Subjects :
- Adenine analogs & derivatives
Administration, Oral
Aged
Animals
Antigens, CD metabolism
Cell Line, Tumor
Cell Proliferation drug effects
Cytotoxicity, Immunologic drug effects
Demography
Disease Models, Animal
Drug Resistance, Neoplasm drug effects
Gene Transfer Techniques
Humans
Immunosuppression Therapy
K562 Cells
Leukemia, Lymphocytic, Chronic, B-Cell pathology
Male
Mice
Middle Aged
Piperidines
Programmed Cell Death 1 Receptor metabolism
Pyrazoles administration & dosage
Pyrazoles pharmacology
Pyrimidines administration & dosage
Pyrimidines pharmacology
T-Lymphocytes drug effects
Time Factors
Treatment Outcome
Leukemia, Lymphocytic, Chronic, B-Cell drug therapy
Leukemia, Lymphocytic, Chronic, B-Cell immunology
Pyrazoles therapeutic use
Pyrimidines therapeutic use
Receptors, Antigen, T-Cell metabolism
T-Lymphocytes immunology
Subjects
Details
- Language :
- English
- ISSN :
- 1528-0020
- Volume :
- 127
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- Blood
- Publication Type :
- Academic Journal
- Accession number :
- 26813675
- Full Text :
- https://doi.org/10.1182/blood-2015-11-679134