ANTILEUKEMIC ACTIVITY OF TNF-ALPHA GENE-THERAPY WITH MYELOID PROGENITOR CELLS AGAINST MINIMAL LEUKEMIA

Tumor necrosis factor-alpha (TNF-alpha) has exhibited antitumor activi ty against a variety of tumors in rodents and human tumor xenografts i n nude mice, but it has been only marginally effective in cancer patie nts because of dose-limiting toxicity associated with systemic TNF-alp ha therapy, To circumvent toxicity and to test the antileukemic activi ty against quantitated minimal leukemia, we have cloned human TNF-alph a (HuTNF-alpha) gene in an advanced myeloid progenitor cell line, 32Dc l3 myeloid progenitor cells transfected with HuTNF-alpha cDNA by the r etroviral supernatant infection method stably express HuTNF-alpha gene and secrete substantial amounts of HuTNF-alpha. When injected i.v. in to irradiated mice, transduced cells could be detected in the marrow b ut not in spleen or liver 10-12 days later, Injection of 5 x 10(6) tra nsduced cells produced no obvious symptoms of TNF-alpha toxicity (i.e. , weight loss, cachexia, or fever) suggesting that TNF-alpha producing cells are well tolerated by the recipient mice, Coinjection of 5 x 10 (6) transduced cells and 10(2) or 10(3) 32Dp210 leukemia (BCR/ABL+) ce lls resulted in inhibition of leukemia development by 10(2) but not 10 (3) 32Dp210 cells, An equal dose of nontransduced 32Dcl3 cells was ine ffective in inhibiting leukemia progression by 10(2) 32Dp210 cells, Mi ce that rejected leukemia were BCR/ABL oncogene negative 8 weeks after leukemia cell injection. These data demonstrate the potential for TNF -alpha gene therapy for destroying residual leukemia, without the toxi city of systemic TNF-alpha, therapy, following cytoreductive therapy a nd bone marrow transplant.