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Intratumoral injection of bone-marrow derived dendritic cells engineered to produce interleukin-12 induces complete regression of established murine transplantable colon adenocarcinomas

Gene Therapy volume 6, pages 1779–1784 (1999)Cite this article

Abstract

Stimulation of the antitumor immune response by dendritic cells (DC) is critically dependent on their tightly regulated ability to produce interleukin-12 (IL-12). To enhance this effect artificially, bone marrow (BM)-derived DC were genetically engineered to produce high levels of functional IL-12 by ex vivo infection with a recombinant defective adenovirus (AdCMVIL-12). DC-expressing IL-12 injected into the malignant tissue eradicated 50–100% well established malignant nodules derived from the injection of two murine colon adenocarcinoma cell lines. Successful therapy was dependent on IL-12 transfection and was mediated only by syngeneic, but not allogeneic BM-derived DC, indicating that compatible antigen-presenting molecules were required. The antitumor effect was inhibited by in vivo depletion of CD8+ T cells and completely abrogated by simultaneous depletion with anti-CD4 and anti-CD8 mAbs. Mice which had undergone tumor regression remained immune to a rechallenge with tumor cells, showing the achievement of long-lasting systemic immunity that also was able to reject simultaneously induced concomitant untreated tumors. Tumor regression was associated with a detectable CTL response directed against tumor-specific antigens probably captured by DC artificially released inside tumor nodules. Our results open the possibility of similarly treating the corresponding human malignancies.

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Acknowledgements

We are grateful to Izaskun Gabari for her expert technical support and to Drs Lasarte and Borrás for peptide synthesis and helpful suggestions. We are grateful for the critical reading of the manuscript by Drs López-Botet, Perez-Diez and Santidrián. The first two authors have equally contributed to the experimental work. This work has been supported by grant SAF99–0039 from CICYT (Spain).

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  1. Departamento de Medicina Interna, Facultad de Medicina, Universidad de Navarra, C/Irunlarrea, 1, Pamplona, 31008, Spain

    I Melero, M Duarte, J Ruiz, B Sangro, J C Galofré, G Mazzolini, M Bustos, C Qian & J Prieto

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  1. I Melero
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Melero, I., Duarte, M., Ruiz, J. et al. Intratumoral injection of bone-marrow derived dendritic cells engineered to produce interleukin-12 induces complete regression of established murine transplantable colon adenocarcinomas. Gene Ther 6, 1779–1784 (1999). https://doi.org/10.1038/sj.gt.3301010

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