Department of Pulmonary Medicine, Erasmus MC, Rotterdam, The Netherlands.
Am J Respir Crit Care Med. 2010 Jun 15;181(12):1383-90. doi: 10.1164/rccm.200909-1465OC. Epub 2010 Feb 18.
We previously demonstrated that dendritic cell-based immunotherapy induced protective antitumor immunity with a prolonged survival rate in mice. However, the clinical relevance is still in question. To examine this, we designed a clinical trial using chemotherapy followed by antigen-pulsed dendritic cell vaccination in mesothelioma patients.
The aim of this study was to assess the safety and immunological response induced by the administration of tumor lysate-pulsed dendritic cells in patients with mesothelioma.
Ten patients with malignant pleural mesothelioma received three vaccinations of clinical-grade autologous dendritic cells intradermally and intravenously at 2-week intervals after chemotherapy. Each vaccine was composed of 50 x 10(6) mature dendritic cells pulsed with autologous tumor lysate and keyhole limpet hemocyanin (KLH) as surrogate marker. Delayed-type hypersensitivity activity to tumor antigens and KLH was assessed, both in vivo and in vitro. Peripheral blood mononuclear cells during the treatment were analyzed for immunological responses.
Administration of dendritic cells pulsed with autologous tumor lysate in patients with mesothelioma was safe with moderate fever as the only side effect. There were no grade 3 or 4 toxicities associated with the vaccines or any evidence of autoimmunity. Local accumulations of infiltrating T cells were found at the site of vaccination. The vaccinations induced distinct immunological responses to KLH, both in vitro and in vivo. Importantly, after three vaccinations, cytotoxic activity against autologous tumor cells was detected in a subgroup of patients.
This study demonstrated that autologous tumor lysate-pulsed dendritic cell-based therapy is feasible, well-tolerated, and capable of inducing immunological response to tumor cells in mesothelioma patients. Clinical trial registered with www.clinicaltrials.gov (NCT00280982).
我们先前的研究表明，树突状细胞免疫疗法能够诱导小鼠产生保护性抗肿瘤免疫，延长其生存期。然而，其临床相关性仍存在争议。为了验证这一点，我们设计了一项临床试验，采用化疗联合抗原脉冲树突状细胞免疫治疗胸膜间皮瘤患者。
本研究旨在评估化疗后给予肿瘤裂解物脉冲树突状细胞治疗胸膜间皮瘤患者的安全性和免疫反应。
10 例恶性胸膜间皮瘤患者在化疗后 2 周的时间内，接受 3 次临床级自体树突状细胞皮内和静脉内接种。每次疫苗均由 50×10^6 个成熟树突状细胞组成，用自体肿瘤裂解物和蓝舌病毒血蓝蛋白（KLH）作为替代标志物脉冲。评估体内和体外肿瘤抗原和 KLH 的迟发型超敏反应活性。治疗期间分析外周血单个核细胞的免疫反应。
树突状细胞负载自体肿瘤裂解物治疗胸膜间皮瘤患者是安全的，仅出现中等程度发热作为唯一的副作用。疫苗无 3 级或 4 级毒性，也无自身免疫证据。在接种部位发现浸润 T 细胞的局部积聚。疫苗接种在体外和体内均能诱导对 KLH 的明显免疫反应。重要的是，在 3 次接种后，在部分患者中检测到针对自体肿瘤细胞的细胞毒性活性。
本研究表明，自体肿瘤裂解物脉冲树突状细胞免疫治疗是可行的，耐受性良好，能够诱导胸膜间皮瘤患者对肿瘤细胞产生免疫反应。临床试验已在 www.clinicaltrials.gov 上注册（NCT00280982）。
