The use of lentiviral vectors in gene therapy of leukemia: Combinatorial gene delivery of immunomodulators into leukemia cells by state-of-the-art vectors

Renata Stripecke, Richard C. Koya, Huy Q. Ta, Nori Kasahara, Alexandra M. Levine

Research output: Contribution to journalArticlepeer-review

27 Scopus citations

Abstract

Our goal is to develop cell vaccines against leukemia cells, genetically modified to express molecules with potent immune-stimulatory capacities. Pre-clinical evaluation of this approach in murine models has demonstrated efficient anti-leukemic responses with the expression of immunomodulators, in particular GM-CSF and CD80, in irradiated cell vaccines. We have previously shown efficient insertion of GM-CSF and CD80 genes into primary human leukemia cells with the use of second and third generation self-inactivating (SIN) lentiviral vectors (Blood 96 (2000), 1317; Leukemia 16 (2002), 1645). The advantages of lentiviral vectors for development of autologous leukemia cell vaccines include: (1) efficient and consistent gene delivery; (2) high levels of transgene expression; (3) persistent expression of the transduced gene; (4) no viral proteins, as only the transduced gene is expressed; (5) no undesirable cytotoxic effects, and; (6) simplicity of use [leukemia cells are exposed to vector(s) only once]. In this work, we evaluated the insertion of the central polypurine tract and the central termination sequence into a SIN lentiviral vector encoding for GM-CSF and CD80, which significantly enhanced the transduction efficiency of primary leukemia cells and provided higher levels of GM-CSF and CD80 co-expression. We also demonstrate a methodology to deliver simultaneously a combination of immunomodulatory molecules (GM-CSF, CD80, IL-4, and CD40L) to activate different pathways of immune stimulation. Therefore, lentiviral vectors offer a simple, versatile, and reliable approach for engineering leukemic cells for use as cell vaccines.

Original languageEnglish (US)
Pages (from-to)28-37
Number of pages10
JournalBlood Cells, Molecules, and Diseases
Volume31
Issue number1
DOIs
StatePublished - Jan 1 2003
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Hematology
  • Cell Biology

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