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 growth associated with macrophage and eosinophilic infiltrates, generation of cytotoxic T-cells, and protective immunity. Using murine IL-4 retroviral 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 bioassay were successfully transduced. In blinded studies using C57BL/6 and BALB/c mice, we have shown that tumor growth can be inhibited (mean delay of 10 days compared with controls; P < .05) and in some cases, completely suppressed by the coinjection of viable tumor with IL-4-producing fibroblasts (tumor free > 100 days; P < .001). Animals that are able to reject an initial tumor inoculate can also completely reject subsequent parental tumor challenge of 10(5) cells (P < .001) while challenge of 10(6) parental tumor cells results in a significant delay of tumor induction (P < .05). In addition, immunization with IL-4 transduced fibroblasts and irradiated tumor cells resulted in complete suppression of parental tumor challenge in animals that received the high-dose IL-4 delivery. Finally coadministration of systemic IL-2 led to enhancement of IL-4 gene therapy resulting in a 20-day delay of preestablished tumor growth compared with controls (P < .05).