In situ administration of cytokine combinations induces tumor regression in mice

Background: Recent advances in cancer immunotherapy suggest a possibility of harnessing the immune system to defeat malignant tumors, but the complex immunosuppressive microenvironment confines the therapeutic benefits to a minority of patients with solid tumors. Methods: A lentivector-based inducible system was established to evaluate the therapeutic effect of cytokines in established tumors. Intratumoral injection of certain cytokine combination in syngeneic tumor models was conducted to assess the therapeutic potentials. Findings: Doxycycline (Dox)-induced local expression of cytokine combinations exhibites a strong synergistic effect. leading to complete regression of tumors. Notably, IL12 + GMCSF+IL2 expression induces eradication of tumors in all mice tolerated with this treatment, including those bearing large tumors of similar to 15 mm in diameter, and generates intensive systemic antitumor immunity. Other combinations with similar immune regulatory roles also induce tumor elimination in most of mice. Moreover, intratumoral injection of chitosan/ IL12 + GMCSF+IL2 solution induces a complete response in all the tested syngeneic tumor models, regardless of various tumor immunograms. Intetpretation: Administration of certain cytokine combinations in tumor microenvironment induces a strong synergistic antitumor response, including the recruitment of large amount of immune cells and the generation of systemic antitumor immunity. It provides a versatile method for the immunotherapy of intractable malignant neoplasms. (C) 2018 The Authors. Published by Elsevier B.V.