Interleukin-12 (IL-12) gene therapy of leukemia: Immune and anti-leukemic effects of IL-12-transduced hematopoietic progenitor cells.

Gautam, Subhash C; Xu, Yong X; Dumaguin, Mariquit; Janakiraman, Nalini; Chapman, Robert A

Recombinant interleukin-12 (rIL-12) is a potent immunomodulatory cytokine that has been shown to exert strong antitumoral and antimetastatic activity against several mouse tumors grown as solid lesions. The therapeutic efficacy of rlL-12 against hematological tumors and the transfer of IL-12 genes into hematopoietic progenitor cells to deliver IL-12 to the bone marrow (BM) to treat residual leukemia has not been studied adequately. We have investigated the retroviral-mediated transduction of hematopoietic progenitor cells with IL-12 genes and the in vivo anti-leukemic activity of transduced cells against the murine myeloid leukemia cell line 32Dp210. We were able to efficiently transduce the IL-3-dependent 32Dc13 myeloid progenitor cell line and primary hematopoietic progenitor cells using an MFG-based polycistronic retroviral vector containing the cDNAs of p35 and p40 murine IL-12 genes. 32Dc13 myeloid progenitor cells expressing IL-12 genes (32DIL-12 cells) have stably secreted biologically active murine IL-12 for > 9 months. Mice transplanted with 32DIL-12 cells transiently express the transgene in the BM and spleen, which is associated with a rapid elevation of interferon-γ (IFN-γ) in the circulation and with secretion of IFN-γ by spleen cells in vitro. In addition, spleen and BM cells of mice injected with 32DIL-12 cells readily acquire the capacity to lyse natural killer cell-sensitive YAC-1 target cells and 32Dp210 myeloid leukemia cells. Furthermore, whereas mice challenged with leukemia cells suffered 100% mortality within 14 days, ∼40% of mice coinjected with 32Dp210 leukemia cells and 32DIL-12 progenitor cells exhibited long-term, leukemia-free survival (> 60 days). This study demonstrates that IL-12 can be stably expressed in hematopoietic cells; in addition, when transplanted, transduced cells induce IFN-γ production and activation of natural killer cells, both of which may be involved in inhibiting the progression of...

INTERLEUKIN-12; GENE therapy; LEUKEMIA treatment

Cancer Gene Therapy, 2000, Vol 7, Issue 7, p1060

0929-1903

Academic Journal

10.1038/sj.cgt.7700201