Back to Search
Start Over
Engineering CD19-specific T lymphocytes with interleukin-15 and a suicide gene to enhance their anti-lymphoma/leukemia effects and safety.
- Source :
- Leukemia (08876924); Jun2010, Vol. 24 Issue 6, p1160-1170, 11p, 3 Color Photographs, 1 Diagram, 3 Graphs
- Publication Year :
- 2010
-
Abstract
- 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. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 08876924
- Volume :
- 24
- Issue :
- 6
- Database :
- Complementary Index
- Journal :
- Leukemia (08876924)
- Publication Type :
- Academic Journal
- Accession number :
- 51313395
- Full Text :
- https://doi.org/10.1038/leu.2010.75