Intratumoral injection of bone-marrow derived dendritic cells engineered to produce interleukin-12 induces complete regression of established murine transplantable colon adenocarcinomas
Melero I. [SP], Duarte M., Ruiz J., Sangro B., Galofré J. [SP], Mazzolini G., Bustos M., Qian C., Prieto J.
Departamento de Medicina Interna, Facultad de Medicina, Universidad de Navarra, C/Irunlarrea, 1, 31008 Pamplona, Spain
Magazine: Gene Therapy
Date: Oct 1, 1999Endocrinology and Nutrition [SP] Cell Therapy Area [SP] Internal Medicine [SP]
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.
CITATION Gene Ther. 1999 Oct;6(10):1779-84
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