Engineering CD19-specific T lymphocytes with interleukin-15 and a suicide gene to enhance their anti-lymphoma/leukemia effects and safety

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 106% for iC9/CAR.19/IL-15 T + cells and 3219% 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.