Route of administration influences the antitumor effects of bone marrow-derived dendritic cells engineered to produce interleukin-12 in a metastatic mouse prostate cancer model
Route of administration influences the antitumor effects of bone marrow-derived dendritic cells engineered to produce interleukin-12 in a metastatic mouse prostate cancer model
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DOI：
10.1038/sj.cgt.7700709
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发表时间：
2004-05
影响因子：
6.4
通讯作者：
T. Saika;T. Satoh;N. Kusaka;S. Ebara;V. Mouraviev;T. Timme;T. Thompson
中科院分区：
文献类型：
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作者：
T. Saika;T. Satoh;N. Kusaka;S. Ebara;V. Mouraviev;T. Timme;T. Thompson
基因修饰的树突状细胞(DC)为前列腺癌提供了独特的治疗策略；然而，使用适当的临床前模型对特定给药方案的比较评估尚未被描述。在本研究中，利用重组腺病毒载体体外感染骨髓来源的DC，使其在共刺激分子B7-1作用下表达高水平的白介素12(IL-12)。我们使用一种原位转移性小鼠前列腺癌临床前模型(178-2BMA)来比较DC的两种治疗方案，即原位和皮下注射。将同基因129/Sv小鼠的骨髓在GM-CSF和IL-4的共同作用下培养成DC。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半乳糖对照组相比，原位注射DC/IL-12或DC/IL-12/B7可显著抑制原发肿瘤的生长(P=。0328和P=.0019)，以及自发性肺转移结节的数量减少(P=.1404和P=。0335)。在生存实验中，原位注射DC/IL-12显示出微小但有统计学意义的优势(P=。0041)。皮下注射肿瘤裂解物致敏的DC/IL-12显著减小肿瘤大小(P=.与HBSS对照组相比，存活率增加(P=0.0433)，但自发性肺转移数目的减少没有统计学意义。原位和皮下治疗均增强自然杀伤(NK)细胞和细胞毒性T淋巴细胞(CTL)的杀伤活性。在这个临床前模型中，基于DC的基因修饰的肿瘤内免疫治疗被证明是一种基于抑制肿瘤生长、抑制转移和提高生存的局部晚期前列腺癌的有效治疗策略。
Gene-modified dendritic cells (DC) provide unique therapeutic strategies for prostate cancer; however, the comparative evaluation of specific delivery options using appropriate preclinical models has not been described. In this study, 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 (178-2 BMA) to compare two therapeutic protocols for DC delivery, in situ and subcutaneous. DC were generated from bone marrow of syngeneic 129/Sv mice by culturing in the presence of GM-CSF and IL-4. 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/βgal controls (P=. 0328 and P=. 0019, respectively), as well as reduced numbers of spontaneous lung metastatic nodules (P=. 1404 and P=. 0335, respectively). In survival experiments, in situ DC/IL-12 injection demonstrated a small but statistically significant advantage (P=. 0041). Subcutaneous, tumor lysate pulsed DC/IL-12 significantly decreased tumor size (P=. 0152) and increased survival (P= 0.0433) 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.