Development of cell and gene therapy for prostate cancer with dendritic cells engineered to produce interleukin-12

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Bone marrow-derived DC were genetically engineered to express high levels of interleukin-12 (IL-12) with or without the costimulatory molecule B7-1, by ex vivo infection with recombinant adenoviral vectors. We used an orthotopic metastatic mouse prostate cancer preclinical model to compare two therapeutic protocols for DC delivery, in situ and subcutaneous. In vitro DC/IL-12 or DC/IL-12/B7 produced high levels of biologically active IL-12. In situ delivery of DC/IL-12 or DC/IL-12/B7 induced a significant suppression of primary tumor growth compared to DC/beta gal controls, as well as reduced numbers of spontaneous lung metastatic nodules. In survival experiments, in situ DC/IL-12 injection demonstrated a significant advantage. Subcutaneous, tumor lysate pulsed DC/IL-12 significantly decreased tumor size and increased survival compared to HBSS controls but the decrease in the number of spontaneous lung metastases did not achieve statistical significance. Both in situ and subcutaneous treatments enhanced cytolytic activities of natural killer (NK) cells and cytotoxic T lymphocytes (CTL). In this preclinical model, gene-modified DC-based intratumoral immunotherapy was shown to be an effective therapeutic strategy for locally advanced prostate cancer based on tumor growth suppression, inhibition of metastasis and survival improvement.