Generation of a Systemic Antitumor Response with Regional Intratumoral Injections of InterferonγRetroviral Vector

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Abstract
The generation of a lasting systemic immune response is a primary goal for cancer immunotherapy. Here we examine the ability of high-titer IFN-γ retroviral vector injected into an accessible tumor to generate significant antitumor responses at a distal untreated site. CT26 or B16F10 murine tumors were inoculated subcutaneously to form solid tumors in BALB/c or C57BL/6 mice. Seven to 10 days postinoculation, high-titer IFN-γ retroviral vector was directly injected into the subcutaneous tumor nodule, and optimal dose and course of therapy were determined. As a model for disseminated disease, mice were inoculated intravenously with CT26 cells to form pulmonary lesions, at the same time as the subcutaneous injections. Regression of subcutaneous tumor correlated with a systemic response at the distal lung metastases in the IFN-γ-treated group (p < 0.0005). Splenocytes from mice with completely regressed tumors had a twofold increase in percent specific cytotoxicity in a standard CTL assay as compared with nonresponding mice. CD8+ T cells were shown to be essential for the regional and systemic antitumor response, as determined by in vivo cell depletion experiments. These data demonstrate that IFN-γ retroviral vector gene therapy delivered intralesionally can generate significant inhibition of pulmonary tumor formation distal to the treatment site. The data from these preclinical studies suggest the potential clinical value of retroviral vector-mediated cytokine gene therapy for systemic cancer. A key component of any clinically useful cancer therapy must be the ability to induce a systemic response against distant metastases. Recombinant IFN-γ has shown clinical success against certain cancers, but can cause severe systemic toxicity with the high doses needed for antitumor efficacy. In this preclinical gene therapy study, local expression of IFN-γ at the tumor site, by injection of IFN-γ retroviral vector directly into the tumor, induced both regional regression and systemic anti-tumor responses in a murine model of pulmonary metastases. The local delivery of an immunotherapeutic agent with antitumor responses at a distal site shows promise for cytokine gene therapy in the treatment of disseminated disease in patients.