Originally published as JCO Early Release 10.1200/JCO.2005.00.463 on December 14 2004

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Intratumoral Injection of Dendritic Cells Engineered to Secrete Interleukin-12 by Recombinant Adenovirus in Patients With Metastatic Gastrointestinal Carcinomas

Guillermo Mazzolini, Carlos Alfaro, Bruno Sangro, Esperanza Feijoó, Juan Ruiz, Alberto Benito, Iñigo Tirapu, Ainhoa Arina, Josu Sola, Maite Herraiz, Felipe Lucena, Cristina Olagüe, José Subtil, Jorge Quiroga, Ignacio Herrero, Belén Sádaba, Maurizio Bendandi, Cheng Qian, Jesús Prieto, Ignacio Melero

From the Division of Hepatology and Gene Therapy and Departments of Radiology, Pathology, Gastroenterology, Pharmacology, Hematology, Clínica Universitaria/School of Medicine, Foundation for Applied Medical Research, University of Navarra, Pamplona, Spain

Address reprint requests to Guillermo Mazzolini MD, PhD, Clínica Universitaria/School of Medicine, University of Navarra, c/Irunlarrea, s/n, 31008 Pamplona, Spain; e-mail: gmazzolini{at}unav.es.

PURPOSE: To evaluate the feasibility and safety of intratumoral injection of autologous dendritic cells (DCs) transfected with an adenovirus encoding interleukin-12 genes (AFIL-12) for patients with metastatic gastrointestinal carcinomas. Secondarily, we have evaluated biologic effects and antitumoral activity.

PATIENTS AND METHODS: Seventeen patients with metastatic pancreatic (n = 3), colorectal (n = 5), or primary liver (n = 9) malignancies entered the study. DCs were generated from CD14+ monocytes from leukapheresis, cultured and transfected with AFIL-12 before administration. Doses from 10 x 10⁶ to 50 x 10⁶ cells were escalated in three cohorts of patients. Patients received up to three doses at 21-day intervals.

RESULTS: Fifteen (88%) and 11 of 17 (65%) patients were assessable for toxicity and response, respectively. Intratumoral DC injections were mainly guided by ultrasound. Treatment was well tolerated. The most common side effects were lymphopenia, fever, and malaise. Interferon gamma and interleukin-6 serum concentrations were increased in 15 patients after each treatment, as well as peripheral blood natural killer activity in five patients. DC transfected with AFIL-12 stimulated a potent antibody response against adenoviral capsides. DC treatment induced a marked increase of infiltrating CD8+ T lymphocytes in three of 11 tumor biopsies analyzed. A partial response was observed in one patient with pancreatic carcinoma. Stable disease was observed in two patients and progression in eight patients, with two of the cases fast-progressing during treatment.

CONCLUSION: Intratumoral injection of DC transfected with an adenovirus encoding interleukin-12 to patients with metastatic gastrointestinal malignancies is feasible and well tolerated. Further studies are necessary to define and increase clinical efficacy.

Supported by grants from Ministerio de Ciencia y Tecnologia (SAF 02/0373), Fondo de Investigaciones Sanitarias (PI031253), Redes Temáticas de Investigación Cooperativa (C03/10 and C03/02), Departamento de Salud y Departamento de Educación del Gobierno de Navarra and "UTE-project CIMA".

Terms in blue are defined in the glossary, found at the end of this issue and online at www.jco.org.

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

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