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- Title
Engineering CD19-specific T lymphocytes with interleukin-15 and a suicide gene to enhance their anti-lymphoma/leukemia effects and safety.
- Authors
Hoyos, V.; Savoldo, B.; Quintarelli, C.; Mahendravada, A.; Zhang, M.; Vera, J.; Heslop, H. E.; Rooney, C. M.; Brenner, M. K.; Dotti, G.
- 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.
- Subjects
T cells; CELL death; B cells; LYMPHOMAS; T-cell lymphoma; ANIMAL experimentation; ANTIGENS; CELLULAR immunity; GENES; IMMUNOLOGY technique; IMMUNOPHENOTYPING; INTERLEUKINS; LEUKEMIA; MICE; PROTEINS; RESEARCH funding; PREVENTION
- Publication
Leukemia (08876924), 2010, Vol 24, Issue 6, p1160
- ISSN
0887-6924
- Publication type
journal article
- DOI
10.1038/leu.2010.75