IL-12 gene therapy of leukemia with hematopoietic progenitor cells without the toxicity of systemic IL-12 treatment.
We have previously shown that the myeloid progenitor cell line 32Dc13 transduced with mIL-12 cDNAs (32DIL-12 cells) induces IFN-gamma and NK-cell-mediated cytotoxicity in vivo. Since systemic therapy with recombinant IL-12 protein has been shown to produce moderate to severe toxic side effects we examined whether IL-12 gene therapy with hematopoietic progenitor cells also induces systemic toxicities that are commonly associated with the administration of rIL-12 protein. Injection of large doses of IL-12 secreting 32DIL-12 cells (5 to 6 x 10(7) cells) significantly reduced mortality in mice injected with a lethal dose of 32Dp210 myeloid leukemia cells. More importantly, injection of similar doses of transduced cells failed to reduce body weight significantly or produce other visible signs of toxicity, i.e., fur ruffling or lethargy. There was no evidence of hematologic or hematopoietic toxicity resulting from the injection of transduced cells. In addition, microscopic examination of liver, kidney, lung, and intestine of mice injected with transduced cells revealed the absence of tissue necrosis or inflammatory response in any of these organs. Finally, 32DIL-12 cells were not found to interfere with the engraftment of syngeneic bone marrow transplant or the hematopoietic reconstitution of irradiated mice. These results demonstrate that IL-12 gene therapy with hematopoietic progenitor cells is nontoxic and provide a rationale for exploring the feasibility of treating minimal residual leukemia with IL-12 gene therapy.
Xu
Y X
YX
Division of Hematology/Oncology, Henry Ford Health System, Detroit, Michigan, 48202, USA.
Gao
X
X
Janakiraman
N
N
Chapman
R A
RA
Gautam
S C
SC
D000818:Animals; D001772:Blood Cell Count; D001855:Bone Marrow Diseases / Q000139:chemically induced / Q000517:prevention & control; D016026:Bone Marrow Transplantation; D002478:Cells, Cultured / Q000378:metabolism / Q000637:transplantation; D003114:Colony-Forming Units Assay; D005240:Feasibility Studies; D015316:Genetic Therapy; D006085:Graft Survival; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D007249:Inflammation / Q000139:chemically induced / Q000517:prevention & control; D007371:Interferon-gamma / Q000378:metabolism; D018664:Interleukin-12 / Q000235:genetics* / Q000378:metabolism / Q000627:therapeutic use / Q000633:toxicity; D007942:Leukemia, Experimental / Q000628:therapy*; D007951:Leukemia, Myeloid / Q000628:therapy; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D009336:Necrosis; D018365:Neoplasm, Residual; D011828:Radiation Chimera; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use / Q000633:toxicity; D014162:Transfection; D014781:Viscera / Q000473:pathology
D011994:Recombinant Proteins; D018664:Interleukin-12; D007371:Interferon-gamma