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

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-gamma 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-gamma 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-gamma-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-gamma 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.

The treatment of established intracranial tumors by in situ retroviral IFN-γ transfer

“…The development of virus-based gene therapy techniques enabled herpes simplex virus type 1-defective virus 22 or retrovirus 23 to be engineered to express IFN-␥ and implanted into primary tumors. Enhanced tumor rejection was observed when multiple administrations of high …”

“…[17][18][19][20][21] Another strategy has been to administer purified viruses carrying the IFN-␥ gene directly into tumors. 22,23 However, multiple administrations of virus were required to induce a tumoricidal response.…”

Cell Culture Processes for the Production of Viral Vectors for Gene Therapy Purposes

“…Therefore, the actual viral dose may be 10-1000 times greater (Braas et al 1996;Lyddiat and O'Sullivan 1998). It was subsequently shown empirically that titers >5 · 10 7 IP ml À1 of infusion product can efficiently obtain in vivo gene transfer in animal models of hemophilia, arthritis, cancer, chronic HBV infection, cystic fibrosis and other diseases (Ghivizzani et al 1997;Karavodin et al 1998;Sallberg et al 1998;Wang et al 1998;Nemunaitis et al 1999;Van den Driessche et al 1999). This still leaves a gap between the number of viral particles required and the number that can be produced.…”

Induction of melanoma-associated antigen systemic immunity upon intratumoral delivery of interferon-γ retroviral vector in melanoma patients

“…These modalities include delivery to tumor cells, vaccination with tumorassociated antigen(s) (Ags), and delivery of specific cytokine(s) for immunomodulation or modulation of tumor cell growth and properties. [7][8][9][10][11] The delivery of cytostatic cytokines such as interferon-␥ (IFN-␥) has shown promising results in animal and human studies. IFN-␥ is a type II IFN, whereas IFN-␣ and IFN-␤ are type I.…”

“…or peritumoral injection of vectors expressing murine IFN-␥ has been shown to be effective in inducing systemic antitumoral immune responses and significant regional and systemic antitumoral effects. 8,9 In a phase I clinical trial involving a single injection of IFN-␥ retroviral vector every day for 5 days, no significant toxicity occurred and no replication-competent retrovirus was detected by polymerase chain reaction (PCR). 17,18 This initial study showed transgene expression, clinical safety, and suggestive clinical activity.…”