A phase I trial of immunotherapy with intratumoral adenovirus-interferon-gamma (TG1041) in patients with malignant melanoma

Aims: Interferon-gamma (IFN-γ) has been shown to upregulate MHC class I and II expression, and to promote generation of specific antitumor immune responses. We hypothesized that intratumoral administration of an IFN-γ gene transfer vector facilitates its enhanced local production and may activate effector cells locally. We conducted a phase I dose-escalation study of a replication-deficient adenovirus-interferon-gamma construct (TG1041) to determine safety and tolerability of intratumoral administration, in advanced or locally recurrent melanoma. Methods: Patients were enrolled at four successive dose levels: 10⁷ infectious units (iu) (n = 3), 10⁸iu (n = 3), 10⁹iu (n = 3), and 10¹⁰iu (n = 2) per injection per week for 3 weeks. TG1041 was injected in the same tumor nodule weekly in each patient. Safety, toxicity, local and distant tumor responses and biologic correlates were evaluated. Results: A total of 11 patients were enrolled and received the planned three injections per cycle. One patient with stable disease received a second cycle of treatment. A maximum tolerated dose was not reached in this study. No grade 4 toxicities were observed. Two grade 3 toxicities, fever and deep venous thrombosis were observed in one patient. The most frequently reported toxicities were grade 1 pain and redness at the injected site (n = 8), and grade 1 fatigue (n = 5) patients. Clinical changes observed at the local injected tumor site included erythema (nc = 5), a minor decrease in size of the injected lesion (n = 5) and significant central necrosis by histopathology (n = 1). Systemic effects included stable disease in one patient. Correlative studies did not reveal evidence of immunologic activity. Conclusion: Weekly intratumoral administration of TG1041 appears to be safe and well tolerated in patients with advanced melanoma.