TNF-alpha gene therapy with myeloid progenitor cells lacks the toxicities of systemic TNF-alpha therapy

• Published in: Journal of hematotherapy Vol. 8; no. 3; p. 237
• Main Authors: Gautam, S C, Xu, Y X, Pindolia, K R, Yegappan, R, Janakiraman, N, Chapman, R A
• Format: Journal Article
• Language: English
• Published: United States 01.06.1999
• Subjects: Animals; Body Weight - drug effects; Cachexia - chemically induced; Cell Line; Genetic Therapy; Graft Survival - drug effects; Hematologic Diseases - chemically induced; Hematopoietic Stem Cells - metabolism; Humans; Immunotherapy, Adoptive; Leukemia, Myeloid - therapy; Male; Mice; Mice, Inbred C3H; Transduction, Genetic; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha - pharmacology; Tumor Necrosis Factor-alpha - toxicity
• ISSN: 1061-6128
• DOI: 10.1089/106161299320253

We examined the antileukemic activity and the toxicity of HPC transduced with human tumor necrosis factor (TNF) cDNA. Both clonal (32Dcl3) and BM-derived primary hematopoietic progenitors (BM-Prog) expressing hTNF-alpha gene (32DTNF-alpha and BMTNF-alpha cells, respectively) inhibited the development of leukemia in mice with a small dose of 32Dp210 cells, a myeloid leukemia cell line. Whether the trans-gene expressing 32DTNF-alpha cells produce toxicities commonly associated with systemic TNF-alpha therapy was determined by examining the effect of TNF-alpha-secreting progenitor cells on body weight, tissue histology, growth of HPC, and engraftment of BMT. Administration of a low or high dose of TNF-alpha-secreting 32DTNF-alpha cells to mice failed to produce loss in body weight, a measure of TNF-alpha-related cachexia. There was also no evidence of tissue necrosis or mononuclear cell (MNC) infiltration in lung, liver, kidney, or intestine of mice injected with transduced progenitor cells. Furthermore, 32DTNF-alpha cells showed no effect on the clonal growth of HPC in colony-forming assays or loss of cellularity in BM, spleen, or blood. Finally, TNF-alpha-secreting cells were found not to interfere with the engraftment of BM transplant and hematopoietic reconstitution thereafter. We conclude from these findings that unlike systemic administration of TNF-alpha, TNF-alpha gene therapy with transduced HPC is nontoxic and may have a role in eradicating residual leukemia after BMT.