Cytokine Gene Therapy with Interleukin-2-Transduced Fibroblasts: Effects of IL-2 Dose on Anti-Tumor Immunity

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Abstract
We evaluated the effects of different doses of interleukin-2 (IL-2)-transduced fibroblasts in the treatment of colorectal carcinoma in the CT-26 murine tumor model. Immunization with a mixture of irradiated tumor cells and IL-2-transduced fibroblasts (100 units of IL-2/24 hr) induced significantly greater protection against a live tumor challenge compared to irradiated tumor cells alone (22/35, 65% vs. 10/30, 33%, p < 0.02). Protective effects were observed with doses of IL-2-transduced fibroblasts secreting from 5 to 100 units of IL-2/24 hr. Parallel experiments in nude mice produced no protection, indicating that the effects of immunization were mediated by a T-cell-dependent mechanism. In animals with established tumors, complete tumor remissions were observed following immunization with a mixture of irradiated tumor cells and IL-2-transduced fibroblasts secreting 100 units of IL-2/24 hr, but not after immunization with irradiated tumor cells alone (7/16 vs. 0/11 complete remissions, p < 0.02). Fibroblasts secreting higher doses of IL-2 were ineffective in generating systemic immunity, but were required to prevent tumor implantation. A statistically significant difference in the prevention of tumor implantation was observed between groups inoculated with a mixture of live tumor cells and IL-2-transduced fibroblasts (1,750 units of IL-2/24 hr) compared to control fibroblasts (6/8 vs. 0/12, p < 0.001). Similar results were observed in nude mice, suggesting that the implantation rejection response is mediated in part by cells other than thymus-derived T cells. Our data support the utility of IL-2-transduced fibroblasts and indicate that the level of IL-2 expression is an important variable in activating different effector components of antitumor immune responses in IL-2 gene therapy. Fibroblasts were transduced with IL-2 retroviral vectors to examine the paracrine effects of varying IL-2 doses on the generation of antitumor immune responses in a murine model of colon adenocarcinoma. In this study, important relationships between IL-2 expression levels and the optimization of different immune system effector mechanisms were identified. Induction of systemic antitumor immunity was T cell dependent and optimized by immunizations with transduced fibroblasts secreting 5–100 units of IL-2/24 hr. Higher doses of IL-2-secreting fibroblasts were less effective in establishing systemic antitumor immunity but were required to prevent tumor implantation by a T cell-independent mechanism. These findings indicate important relationships between IL-2 dose, immune system effector mechanisms, and antitumor efficacy that should be considered in the design of future IL-2 gene therapy trials.