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

骨髓来源的DC基因工程表达高水平的白细胞介素-12（IL-12）与或不与共刺激分子B7-1，离体感染重组腺病毒载体。我们使用原位转移性小鼠前列腺癌临床前模型来比较原位和皮下DC递送的两种治疗方案。在体外DC/IL-12或DC/IL-12/B7产生高水平的生物活性IL-12。与DC/β gal对照相比，DC/IL-12或DC/IL-12/B7的原位递送诱导了原发性肿瘤生长的显著抑制，以及自发性肺转移结节的数量减少。在存活实验中，原位DC/IL-12注射显示出显著的优势。与HBSS对照组相比，皮下肿瘤裂解物脉冲DC/IL-12显著降低了肿瘤大小并增加了存活率，但自发性肺转移数量的减少未达到统计学显著性。原位和皮下处理均增强了自然杀伤（NK）细胞和细胞毒性T淋巴细胞（CTL）的溶细胞活性。在该临床前模型中，基于基因修饰的DC的瘤内免疫疗法被证明是基于肿瘤生长抑制、转移抑制和生存改善的局部晚期前列腺癌的有效治疗策略。

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.