Antileukemic Activity of TNF-α Therapy with Myeloid Progenitor Cells Against Minimal Leukemia

Abstract

Tumor necrosis factor-α(TNF-α) has exhibited antitumor activity against a variety of tumors in rodents and human tumor xenografts in nude mice, but it has been only marginally effective in cancer patients because of dose-limiting toxicity associated with systemic TNF-α therapy. To circumvent toxicity and to test the antileukemic activity against quantitated minimal leukemia, we have cloned human TNF-α (HuTNF-α) gene in an advanced myeloid progenitor cell line. 32Dcl3 myeloid progenitor cells transfected with HuTNF-α cDNA by the retroviral supernatant infection method stably express HuTNF-α gene and secrete substantial amounts of HuTNF-α. When injected i.v. into irradiated mice, transduced cells could be detected in the marrow but not in spleen or liver 10–12 days later. Injection of 5 x 10⁶ transduced cells produced no obvious symptoms of TNF-α toxicity (i.e., weight loss, cachexia, or fever) suggesting that TNF-α producing cells are well tolerated by the recipient mice. Coinjection of 5 x 10⁶ transduced cells and 10² or 10³ 32Dp210 leukemia (BCR/ABL+) cells resulted in inhibition of leukemia development by 102 but not 10³ 32Dp210 cells. An equal dose of nontransduced 32Dcl3 cells was ineffective in inhibiting leukemia progression by 10² 32Dp210 cells. Mice that rejected leukemia were BCR/ABL oncogene negative 8 weeks after leukemia cell injection. These data demonstrate the potential for TNF-α gene therapy for destroying residual leukemia, without the toxicity of systemic TNF-α therapy, following cytoreductive therapy and bone marrow transplant.