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

V. Hoyos, B. Savoldo, C. Quintarelli, A. Mahendravada, M. Zhang, J. Vera, H. E. Heslop, C. M. Rooney, M. K. Brenner, G. Dotti

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)1160-1170
Number of pages11
JournalLeukemia
Volume24
Issue number6
DOIs
Publication statusPublished - Jun 2010

Keywords

  • chimeric antigen receptor
  • IL-15
  • suicide gene

ASJC Scopus subject areas

  • Hematology
  • Cancer Research
  • Anesthesiology and Pain Medicine
  • Medicine(all)

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    Hoyos, V., Savoldo, B., Quintarelli, C., Mahendravada, A., Zhang, M., Vera, J., Heslop, H. E., Rooney, C. M., Brenner, M. K., & Dotti, G. (2010). Engineering CD19-specific T lymphocytes with interleukin-15 and a suicide gene to enhance their anti-lymphoma/leukemia effects and safety. Leukemia, 24(6), 1160-1170. https://doi.org/10.1038/leu.2010.75