LOCAL IL-4 DELIVERY ENHANCES IMMUNE REACTIVITY TO MURINE TUMORS - GENE-THERAPY IN COMBINATION WITH IL-2

Tumor cells transduced with the IL-4 gene demonstrate reduction of gro wth associated with macrophage and eosinophilic infiltrates, generatio n of cytotoxic T-cells, and protective immunity. Using murine IL-4 ret roviral vectors, murine fibroblasts and tumors that produce from 50 to 5000 U of IL-4/10(6) cells per 24 hours as determined by ELISA and bi oassay were successfully transduced. in blinded studies using C57BL/6 and BALB/c mice, we have shown that tumor growth can be inhibited (mea n delay of 10 days compared with controls; P < .05) and in some cases, completely suppressed by the coinjection of viable tumor with IL-4-pr oducing fibroblasts (tumor free > 100 days; P < .001). Animals that ar e able to reject an initial tumor inoculate can also completely reject subsequent parental tumor challenge of 10(5) cells (P < .001) while c hallenge of 10(6) parental tumor cells results in a significant delay of tumor induction (P < .05). in addition, immunization with IL-4 tran sduced fibroblasts and irradiated tumor cells resulted in complete sup pression of parental tumor challenge in animals that received the high -dose IL-4 delivered by fibroblasts (P < .001) acid in a mean of 8 day s delay (P < .05) of tumor growth in animals receiving low-dose IL-4 d elivery. Finally coadministration of systemic IL-2 led to enhancement of IL-4 gene therapy resulting in a 20-day delay of preestablished tum or growth compared with controls (P < .05).