期刊
LEUKEMIA
卷 24, 期 6, 页码 1160-1170出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/leu.2010.75
关键词
chimeric antigen receptor; IL-15; suicide gene
资金
- Leukemia and Lymphoma Society Specialized Center of Research (SCOR) [7018]
- NIH [PO1CA94237, P50CA126752, RO1CA131027]
- Leukemia and Lymphoma Society
- Doris Duke Charitable Foundation
- CLL Global Research
T lymphocytes expressing a chimeric antigen receptor (CAR) targeting the CD19 antigen (CAR. 19) may be of value for the therapy of B-cell malignancies. Because the in vivo survival, expansion and anti-lymphoma activity of CAR.19(+) T cells remain suboptimal even when the CAR contains a CD28 costimulatory endodomain, we generated a novel construct that also incorporates the interleukin-15 (IL-15) gene and an inducible caspase-9-based suicide gene (iC9/CAR.19/IL-15). We found that compared with CAR.19(+) T cells, iC9/CAR.19/IL-15(+) T cells had: (1) greater numeric expansion upon antigen stimulation (10-fold greater expansion in vitro, and 3- to 15-fold greater expansion in vivo) and reduced cell death rate (Annexin-V+/7-AAD(+) cells 10 +/- 6% for iC9/CAR.19/IL-15(+) T cells and 32 +/- 19% for CAR.19(+) T cells); (2) reduced expression of the programmed death 1 (PD-1) receptor upon antigen stimulation (PD-1(+) cells <15% for iC9/CAR.19/IL-15(+) T cells versus >40% for CAR.19(+) T cells); and (3) improved antitumor effects in vivo (from 4.7- to 5.4-fold reduced tumor growth). In addition, iC9/CAR.19/IL-15(+) T cells were efficiently eliminated upon pharmacologic activation of the suicide gene. In summary, this strategy safely increases the anti-lymphoma/leukemia effects of CAR.19-redirected T lymphocytes and may be a useful approach for treatment of patients with B-cell malignancies. Leukemia (2010) 24, 1160-1170; doi:10.1038/leu.2010.75; published online 29 April 2010
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