Originally published as JCO Early Release 10.1200/JCO.2005.00.463 on December 14 2004
Journal of Clinical Oncology, Vol 23, No 5 (February 10), 2005: pp. 999-1010
© 2005 American Society of Clinical Oncology.
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.
This article has been cited by other articles:
|
|
|
|
 
N. Eliopoulos, M. Francois, M.-N. Boivin, D. Martineau, and J. Galipeau
Neo-Organoid of Marrow Mesenchymal Stromal Cells Secreting Interleukin-12 for Breast Cancer Therapy
Cancer Res.,
June 15, 2008;
68(12):
4810 - 4818.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Wei, H. Wang, B. Lu, B. Li, S. Hou, W. Qian, K. Fan, J. Dai, J. Zhao, and Y. Guo
Cancer Immunotherapy Using In vitro Genetically Modified Targeted Dendritic Cells
Cancer Res.,
May 15, 2008;
68(10):
3854 - 3862.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Mukhopadhaya, J. Mendecki, X. Dong, L. Liu, S. Kalnicki, M. Garg, A. Alfieri, and C. Guha
Localized Hyperthermia Combined with Intratumoral Dendritic Cells Induces Systemic Antitumor Immunity
Cancer Res.,
August 15, 2007;
67(16):
7798 - 7806.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Del Vecchio, E. Bajetta, S. Canova, M. T. Lotze, A. Wesa, G. Parmiani, and A. Anichini
Interleukin-12: Biological Properties and Clinical Application
Clin. Cancer Res.,
August 15, 2007;
13(16):
4677 - 4685.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Udagawa, C. Kudo-Saito, G. Hasegawa, K. Yano, A. Yamamoto, M. Yaguchi, M. Toda, I. Azuma, T. Iwai, and Y. Kawakami
Enhancement of Immunologic Tumor Regression by Intratumoral Administration of Dendritic Cells in Combination with Cryoablative Tumor Pretreatment and Bacillus Calmette-Guerin Cell Wall Skeleton Stimulation
Clin. Cancer Res.,
December 15, 2006;
12(24):
7465 - 7475.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Akbulut, Y. Tang, K. G. Akbulut, J. Maynard, L. Zhang, and A. Deisseroth
Antitumor immune response induced by i.t. injection of vector-activated dendritic cells and chemotherapy suppresses metastatic breast cancer.
Mol. Cancer Ther.,
August 1, 2006;
5(8):
1975 - 1985.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. H. Butterfield, A. Ribas, V. B. Dissette, Y. Lee, J. Q. Yang, P. De la Rocha, S. D. Duran, J. Hernandez, E. Seja, D. M. Potter, et al.
A Phase I/II Trial Testing Immunization of Hepatocellular Carcinoma Patients with Dendritic Cells Pulsed with Four {alpha}-Fetoprotein Peptides.
Clin. Cancer Res.,
May 1, 2006;
12(9):
2817 - 2825.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
I. Melero, A. Arina, O. Murillo, J. Dubrot, C. Alfaro, J. L. Perez-Gracia, M. Bendandi, and S. Hervas-Stubbs
Immunogenic Cell Death and Cross-Priming Are Reaching the Clinical Immunotherapy Arena
Clin. Cancer Res.,
April 15, 2006;
12(8):
2385 - 2389.
[Full Text]
[PDF]
|
|
|
|
