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

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