In situ administration of cytokine combinations induces tumor regression

Recent advances in cancer immunotherapy suggest a possibility of harnessing the immune system to defeat malignant tumors, but complex immunosuppressive microenvironment confined the therapeutic benefits to a minority of patients with solid tumors. Here we constructed a lentivector based inducible system to evaluate the therapeutic effect of cytokines in established tumors. Doxycycline (Dox) induced local expression of cytokine combinations exhibited strong synergistic effect, leading to complete regression of tumors. Notably, IL12+GMCSF+IL2 expression induced eradication of tumors in all mice tolerated with this treatment, including those bearing large tumors of ~15mm in diameter, and generated an intensive systemic antitumor immunity. Other combinations with similar immune regulatory roles also induced tumor elimination in a majority of mice. Moreover, intratumoral injection of chitosan/IL12+GMCSF+IL2 solution induced complete response in all tested syngeneic tumor models, regardless of various tumor immunograms. These results provide a versatile method for the immunotherapy of intractable malignant neoplasm.