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周佩,梁萍,董宝玮,等.微波消融联合过继免疫治疗肝癌的临床研究[J].同济大学学报（医学版）,2012,33(4):71-77. [点击复制]
ZHOU Pei,LIANG Ping,DONG Bao-wei,et al.Microwave ablation and combined with adoptive immunotherapy for hepatocellular carcinoma[J].同济大学学报（医学版）,2012,33(4):71-77. [点击复制]

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微波消融联合过继免疫治疗肝癌的临床研究
周佩^1,2,梁萍²,董宝玮²,于杰²,徐迎新³
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摘要:

目的观察微波消融联合树突状细胞疫苗及效应细胞过继免疫治疗肝癌的安全性,研究联合治疗对患者外周血淋巴亚群百分比的影响。方法 10例肝癌(D≤5 cm,≤3个病灶)并乙肝后肝硬化患者接受微波消融联合多种免疫细胞过继治疗纳入联合组,24例符合相同纳入标准的单纯微波治疗患者纳入微波组。免疫治疗3个疗程,分别于微波治疗日、微波治疗11 d后和第100天时开始进行,从患者外周血分离培养树突状细胞(DC)和效应细胞并经表型检测证实。在超声造影引导下,将未成熟DC、细胞因子诱导的杀伤细胞(CIK)和细胞毒性T细胞(CTL)回输到肝内消融区与充血带交界区。在超声引导下,将肿瘤抗原致敏的成熟DC回输到腹股沟淋巴结内,将DC-CIK和CTL回输到右上腹腹腔内。CIK细胞经静脉回输。治疗前及治疗后进行外周血淋巴细胞亚群及细胞因子检测。结果联合组54次细胞回输未出现Ⅱ级以上严重不良反应,随访1年临床及生化指标观察未发现心肺肝肾神经系统毒性及自身免疫反应。联合治疗后1个月,患者外周血CD8⁺CD28⁺淋巴细胞亚群百分比较治疗前升高,且显著高于微波组;CD8⁺CD28^-效应细胞亚群百分比较治疗前显著升高;CD4⁺CD25^highTreg细胞百分比较治疗前显著降低并显著低于微波组;CD4⁺/CD8⁺比值较治疗前降低并显著低于微波组。联合治疗后6个月时各指标均有回落,仅CD8⁺CD28⁺百分比及CD4⁺/CD8⁺比值较治疗前及微波组仍有显著差异。讨论微波消融联合树突状细胞和效应细胞过继免疫治疗肝癌是安全的,改善了机体免疫状态,其对临床疗效的影响尚需大样本随机试验长时间随访观察。

关键词: 肝肿瘤消融免疫治疗

DOI：10.3969/j.issn1008-0392.2012.04.016

基金项目:国家自然科学基金（30825010)；国家‘‘八六三”高技术研究发展计划（2006AA02Z4B90)；北京市自然科学基金（70820840)

Microwave ablation and combined with adoptive immunotherapy for hepatocellular carcinoma

ZHOU Pei^1,2,LIANG Ping²,DONG Bao-wei²,YU Jie²,XU Ying-xin³

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Abstract:

Objective To assess the safety and the levels of peripheral T lymphocyte subsets in patients with hepatocellular carcinoma ( HCC ) undergoing percutaneous microwave ablation ( PMWA )combined with adoptive immunotherapy. Methods Ten patients with HCC (D ≤5 cm， less than 3 tumors) were treated with radical PMWA and adoptive immunotherapy (combination group) . The immunotherapy was administrated at d0, d11 and d100 after PMWA， respectively. During the immunotherapy immature DCs, cytokine-induced killer cells (CIKs) and cytotoxic T lymphocytes (CTs) were injected into the marginal area of ablated tumors under contrast-enhanced sonographic guidance, and the tumor lysate-pulsed DCs were injected into groin lymph nodes, while DC-CIKs and CTLs were injected into the abdominal cavity, CIKs was infused intravenously. Other 24 HCC patients were treated with PMWA alone (PMWA group) . Results No adverse effects of grade M / IV were observed. The percentage of CD4⁺ CD25^high regulatory T lymphocytes decreased significantly and was significantly lower than those in PMWA group; the percentage of CD8⁺ CD28⁺ and CD8⁺ CD28^-effector cells increased significantly, the percentage of CD8⁺ CD28⁺ of combination group was significantly higher than that of PMWA group; the CD4⁺ /CD8⁺ decreased significantly and was significantly lower than that of PMWA group 1 month after therapy. Six months after therapy, only the percentage of CD8⁺ CD28⁺ and CD4⁺ /CD8⁺ of the combination group had significant difference with those of PMWA group and those before treatment. Conclusion Adoptive immunotherapy combined with PMWA is safe and can improve the immune status for patients with HCC.

Key words: hepatocellular carcinoma ablation immunotherapy