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Phase I Trial of Intratumoral Injection of an Adenovirus Encoding Interleukin-12 for Advanced Digestive Tumors

From the Liver Unit; Division of Gene Therapy; and Departments of Radiology, Gastroenterology, Pathology, Pharmacology, and Pharmacy, Clínica Universitaria and Medical School, University of Navarra, Pamplona, Spain

Address reprint requests to Bruno Sangro, MD, Liver Unit, Department of Internal Medicine, Clinica Universitaria, University of Navarra, Ap. 4209 Pamplona 31080, Spain; e-mail: bsangro{at}unav.es

PURPOSE: To evaluate the feasibility and safety of intratumoral injection of an adenoviral vector encoding human interleukin-12 genes (Ad.IL-12) and secondarily, its biologic effect for the treatment of advanced digestive tumors.

PATIENTS AND METHODS: Ad.IL-12 was administered in doses ranging from 2.5 x 10¹⁰ to 3 x 10¹² viral particles, to seven cohorts of patients with advanced pancreatic, colorectal, or primary liver malignancies. Patients were thoroughly assessed for toxicity, and antitumor response was evaluated by imaging techniques, tumor biopsy, and hypersensitivity skin tests. Patients with stable disease and no serious adverse reactions were allowed to receive up to 3 monthly doses of Ad.IL-12.

RESULTS: Twenty-one patients (nine with primary liver, five with colorectal, and seven with pancreatic cancers) received a total of 44 injections. Ad.IL-12 was well tolerated, and dose-limiting toxicity was not reached. Frequent but transient adverse reactions, including fever, malaise, sweating, and lymphopenia, seemed to be related to vector injection rather than to transgene expression. No cumulative toxicity was observed. In four of 10 assessable patients, a significant increase in tumor infiltration by effector immune cells was apparent. A partial objective remission of the injected tumor mass was observed in a patient with hepatocellular carcinoma. Stable disease was observed in 29% of patients, mainly those with primary liver cancer.

CONCLUSION: Intratumoral injection of up to 3 x 10¹² viral particles of Ad.IL-12 to patients with advanced digestive malignancies is a feasible and well-tolerated procedure that exerts only mild antitumor effects.

Supported in part by grants from Instituto de Salud Carlos III (C03/02) and Fundación Areces.

This study was presented in part at the 5th Annual Meeting of the American Society for Gene Therapy, Boston, MA, June 5-9, 2002.

Authors’ disclosures of potential conflicts of interest are found at the end of this article.

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