Dendritic cell-based vaccination combined with gemcitabine increases survival in a murine pancreatic carcinoma model
Dendritic cell-based vaccination combined with gemcitabine increases survival in a murine pancreatic carcinoma model
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DOI：
10.1136/gut.2006.108621
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发表时间：
2007-09-01
期刊：
影响因子：
24.5
通讯作者：
Dauer, M.
中科院分区：
文献类型：
--
作者：
Bauer, C.;Bauernfeind, F.;Dauer, M.
背景：通过接种树突状细胞 (DC) 可以在体内激活肿瘤特异性细胞毒性 T 淋巴细胞 (CTL)。然而，仅在少数实体癌患者中观察到对 DC 疫苗接种的临床反应。与化疗等其他治疗方式相结合可以克服癌细胞的免疫抵抗力。先前已表明，吉西他滨可使人胰腺癌细胞对 CTL 介导的裂解敏感。在此，使用小鼠胰腺癌模型来研究与吉西他滨组合是否会增加基于 DC 的疫苗接种的治疗效果。方法：将来自 C57BL/6 小鼠的骨髓来源的 DC 负载紫外线照射的同基因 Panc02 癌细胞，并皮下注射。对于预防性疫苗接种，在用 Panc02 细胞进行肿瘤攻击之前，小鼠每周间隔接种 3 次。当肿瘤形成可触及的结节时开始治疗性疫苗接种。吉西他滨每周腹腔注射两次。结果：基于 DC 的预防性疫苗接种完全阻止了皮下和原位肿瘤的发展，并诱导免疫记忆以及肿瘤抗原特异性 CTL。在皮下肿瘤模型中，基于 DC 的治疗性疫苗接种与吉西他滨同样有效（肿瘤攻击后第 58 天的存活率分别为 14% 和 17%；对照为 0%）。两种策略的结合显着提高了荷瘤小鼠的存活率（肿瘤攻击后第 58 天时存活率为 50%）。基于DC的疫苗接种还可以防止静脉注射Panc02细胞后因肺转移而死亡。结论：基于DC的免疫疗法不仅可以成功地与吉西他滨联合治疗晚期胰腺癌，而且还可以有效预防无肿瘤患者的局部复发或转移。
Background: Tumour-specific cytotoxic T lymphocytes (CTLs) can be activated in vivo by vaccination with dendritic cells (DCs). However, clinical responses to DC-based vaccination have only been observed in a minority of patients with solid cancer. Combination with other treatment modalities such as chemotherapy may overcome immunoresistance of cancer cells. It has been shown previously that gemcitabine sensitises human pancreatic carcinoma cells against CTL-mediated lysis. Here, a murine pancreatic carcinoma model was used to investigate whether combination with gemcitabine increases therapeutic efficacy of DC-based vaccination.Methods: Bone marrow-derived DCs from C57BL/6 mice were loaded with UV-irradiated, syngeneic Panc02 carcinoma cells and were administered subcutaneously. For prophylactic vaccination, mice were vaccinated three times at weekly intervals prior to tumour challenge with Panc02 cells. Therapeutic vaccination was started when tumours formed a palpable nodule. Gemcitabine was administered intraperitoneally twice weekly.Results: Prophylactic DC-based vaccination completely prevented subcutaneous and orthotopic tumour development and induced immunological memory as well as tumour antigen-specific CTLs. In the subcutaneous tumour model, therapeutic DC-based vaccination was equally effective as gemcitabine (14% vs 17% survival at day 58 after tumour challenge; controls, 0%). Combination of the two strategies significantly increased survival of tumour-bearing mice (50% at day 58 after tumour challenge). DC-based vaccination also prevented death from pulmonary metastatisation after intravenous injection of Panc02 cells.Conclusion: DC-based immunotherapy may not only be successfully combined with gemcitabine for the treatment of advanced pancreatic carcinoma, but may also be effective in preventing local recurrence or metastatisation in tumour-free patients.