Cord blood NK cells engineered to express IL-15 and a CD19-targeted CAR show long-term persistence and potent antitumor activity

E. Liu, Y. Tong, G. Dotti, H. Shaim, B. Savoldo, M. Mukherjee, J. Orange, Xinhai Wan, X. Lu, A. Reynolds, M. Gagea, P. Banerjee, R. Cai, M. H. Bdaiwi, R. Basar, M. Muftuoglu, L. Li, D. Marin, W. Wierda, M. KeatingR. Champlin, E. Shpall, K. Rezvani

Research output: Contribution to journalArticlepeer-review

470 Scopus citations

Abstract

Chimeric antigen receptors (CARs) have been used to redirect the specificity of autologous T cells against leukemia and lymphoma with promising clinical results. Extending this approach to allogeneic T cells is problematic as they carry a significant risk of graft-versus-host disease (GVHD). Natural killer (NK) cells are highly cytotoxic effectors, killing their targets in a non-antigen-specific manner without causing GVHD. Cord blood (CB) offers an attractive, allogeneic, off-the-self source of NK cells for immunotherapy. We transduced CB-derived NK cells with a retroviral vector incorporating the genes for CAR-CD19, IL-15 and inducible caspase-9-based suicide gene (iC9), and demonstrated efficient killing of CD19-expressing cell lines and primary leukemia cells in vitro, with marked prolongation of survival in a xenograft Raji lymphoma murine model. Interleukin-15 (IL-15) production by the transduced CB-NK cells critically improved their function. Moreover, iC9/CAR.19/IL-15 CB-NK cells were readily eliminated upon pharmacologic activation of the iC9 suicide gene. In conclusion, we have developed a novel approach to immunotherapy using engineered CB-derived NK cells, which are easy to produce, exhibit striking efficacy and incorporate safety measures to limit toxicity. This approach should greatly improve the logistics of delivering this therapy to large numbers of patients, a major limitation to current CAR-T-cell therapies.

Original languageEnglish (US)
Pages (from-to)520-531
Number of pages12
JournalLeukemia
Volume32
Issue number2
DOIs
StatePublished - Feb 1 2018

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

MD Anderson CCSG core facilities

  • Advanced Technology Genomics Core
  • Flow Cytometry and Cellular Imaging Facility
  • Research Animal Support Facility
  • Cytogenetics and Cell Authentication Core

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