Administration of fusion cytokines induces tumor regression and systemic antitumor immunity

Abstract

The curative effects of cancer immunotherapy are hard to be improved in solid tumors. Cytokines, as powerful immune regulators, show potential in awaking host antitumor immunity. We have previously found that administration of certain cytokine combinations induced complete tumor clearance. Here we constructed the cognate fusion cytokines and evaluated their antitumor effects in various mouse tumor models. In situ induced expression of the fusion cytokine IL12IL2GMCSF led to tumor eradication, even those in high advanced stage. An immune memory against other irrelated syngeneic tumors was elicited. Flow cytometry analysis revealed that tumor infiltrating CD3+ cells greatly increased, accompanied with an elevation of CD8+/CD4+ ratio. The fusion protein exhibited superior immune activating capability to cytokine mixtures in vitro, and induced tumor regression in various immune competent tumor models by intratumoral injection. To improve translational potential, an immunocytokine IL12IL2DiaNFGMCSF for systemic administration was constructed by inserting tumor targeting diabody. The protein also displayed good activities in vitro. Intravenous infusion of IL12IL2DiaNFGMCSF induced a tumor infiltrating immune cell alteration like IL12IL2GMCSF, with moderate serum IFN{gamma} increment. Therapeutic effects were observed in various tumor models after systemic administration of IL12IL2DiaNFGMCSF, with slight toxicity. These results provide the feasibility of developing a versatile cancer immunotherapy remedy.