Interleukin 12 gene therapy of cancer by peritumoral injection of transduced autologous fibroblasts: Outcome of a phase I study

A phase I dose-escalation clinical trial of peritumoral injections of inter leukin 12 (IL-12)-transduced autologous fibroblasts was performed in patien ts with disseminated cancer for whom effective treatment does not exist. Th e goals of this study were to assess the safety and toxicities as well as t he efficacy, and ancillarily the immunomodulatory effects, of peritumoral I L-12 gene transfer. Primary dermal fibroblasts cultured from the patients w ere transduced with retroviral vector carrying human IL-12 genes (p35 and p 40) as well as the neomycin phosphotransferase gene (TFG-hIL-12-Neo). Patie nts received four injections at intervals of 7 days. Nine patients were enr olled in this dose-escalation study, with secreted IL-12 doses ranging from 300 ng/24 hr for the first three patients to 1000, 3000, and 5000 ng/24 hr for two patients in each subsequent dosage level. Although a definite stat ement cannot be made, there appears to be perturbation of systemic immunity . Also, the locoregional effects mediated by tumor necrosis factor alpha (T NF-alpha) and CD8(+) T cells were observed with tumor regression. Treatment -related adverse events were limited to mild to moderate pain at the inject ion site; clinically significant toxicities were not encountered. Transient but clear reductions of tumor sizes were observed at the injected sites in four of nine cases, and at noninjected distant sites in one melanoma patie nt. Hemorrhagic necrosis of tumors was observed in two melanoma patients. T hese data indicate that gene therapy by peritumoral injection of IL-12-prod ucing autologous fibroblasts is feasible, and promising in patients with ad vanced cancer.