Engineering CD19-specific T Lymphocytes With interleukin-15 and a Suicide Gene to Enhance Their anti-lymphoma/leukemia Effects and Safety

Leukemia. 2010 Jun;24(6):1160-70. doi: 10.1038/leu.2010.75. Epub 2010 Apr 29.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigen Presentation
  • Antigens, CD19 / genetics
  • Antigens, CD19 / immunology*
  • CD28 Antigens / genetics
  • CD28 Antigens / immunology
  • Caspase 9 / genetics
  • Caspase 9 / immunology*
  • Genetic Vectors
  • Humans
  • Immunophenotyping
  • Interleukin-15 / genetics
  • Interleukin-15 / immunology*
  • Leukemia / genetics
  • Leukemia / immunology
  • Leukemia / prevention & control*
  • Lymphocyte Activation
  • Lymphoma / genetics
  • Lymphoma / immunology
  • Lymphoma / prevention & control*
  • Mice
  • Mice, SCID
  • T-Lymphocytes / immunology*
  • Xenograft Model Antitumor Assays

Substances

  • Antigens, CD19
  • CD28 Antigens
  • Interleukin-15
  • Caspase 9