A phase I clinical trial of single-dose intrapleural IFN-β gene transfer for malignant pleural mesothelioma and metastatic pleural effusions:: High rate of antitumor immune responses
A phase I clinical trial of single-dose intrapleural IFN-β gene transfer for malignant pleural mesothelioma and metastatic pleural effusions:: High rate of antitumor immune responses
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DOI：
10.1158/1078-0432.ccr-07-0403
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发表时间：
2007-08-01
影响因子：
11.5
通讯作者：
Albelda, Steven M.
中科院分区：
文献类型：
--
作者：
Sterman, Daniel H.;Recio, Adri;Albelda, Steven M.
目的：这项1期剂量递增研究评估了使用腺病毒载体（Ad.实验设计：通过留置的胸膜导管以9 × 10（11）至3 × 10（12）病毒颗粒（vp）的剂量向患有恶性胸膜间皮瘤（MPM）（7名患者）和转移性胸腔积液（MPE）（3名患者）的两个患者组群中施用Ad. IFN-β。通过18 -fluorocleoxyglucose-正电子发射断层扫描和胸部计算机断层扫描，评价受试者的（a）毒性，（B）基因转移，（c）体液、细胞和精氨酸介导的免疫应答，和（d）肿瘤应答。达到的最大耐受剂量为9 × 10（11）vp，2例患者接受3 × 10（12）vp治疗，继发于特异质剂量限制性毒性（缺氧和肝功能异常）。载体的存在未在胸膜腔中引起显著的细胞浸润。胸膜内细胞因子水平在基线和对基因转移应答后高度可变。10名患者中有7名通过IFN-β信息或蛋白质的证明记录了基因转移。在10名患者中的7名中引发了抗肿瘤免疫应答，包括检测到细胞毒性T细胞（1名患者）、激活循环自然杀伤细胞（2名患者）以及对已知（猿猴病毒40大T抗原和间皮素）和未知肿瘤抗原的体液应答（7名患者）。10例患者中有4例表现出有意义的临床反应，定义为疾病的稳定性和/或18-fluorodeoxyglucosepositron发射断层扫描和计算机断层扫描在第60天vector infusation.Conclusions后消退：胸腔内滴注的广告。IFN-β是一种潜在的有用的方法，为MPM和MPE患者的抗肿瘤免疫反应的产生，并应进一步研究的整体临床疗效。
Purpose: This phase 1 dose escalation study evaluated the safety and feasibility of single-dose intrapleural IFN-beta gene transfer using an adenoviral vector (Ad. IFN-beta) in patients with malignant pleural mesotheliorna (MPM) and metastatic pleural effusions (MPE).Experimental Design: Ad.IFN-beta was administered through an indwelling pleural catheter in doses ranging from 9 x 10(11) to 3 x 10(12) viral particles (vp) in two cohorts of patients with MPM (7 patients) and MPE (3 patients). Subjects were evaluated for (a) toxicity, (b) gene transfer, (c) humoral, cellular, and cytokine-mediated immune responses, and (d) tumor responses via 18 -fluorocleoxyglucose- positron emission tomography scans and chest computed tomography scans.Results: Intrapleural Ad.IFN-beta was generally well tolerated with transient lymphopenia as the most common side effect. The maximally tolerated dose achieved was 9 x 10(11) vp secondary to idiosyncratic dose-limiting toxicities (hypoxia and liver function abnormalities) in two patients treated at 3 X 10(12) vp. The presence of the vector did not elicit a marked cellular infiltrate in the pleural space. Intrapleural levels of cytokines were highly variable at baseline and after response to gene transfer. Gene transfer was documented in 7 of the 10 patients by demonstration of IFN-beta message or protein. Antitumor immune responses were elicited in 7 of the 10 patients and included the detection of cytotoxic T cells (1 patient), activation of circulating natural killer cells (2 patients), and humoral responses to known (Simian virus 40 large Tantigen and mesothelin) and unknown tumor antigens (7 patients). Four of 10 patients showed meaningful clinical responses defined as disease stability and/or regression on 18-fluorodeoxyglucosepositron emission tomography and computed tomography scans at day 60 after vector infusion.Conclusions: Intrapleural instillation of Ad.IFN-beta is a potentially useful approach for the generation of antitumor immune responses in MPM and MPE patients and should be investigated further for overall clinical efficacy.