Phase I trial of intravesical recombinant adenovirus mediated interferon-α2b formulated in Syn3 for Bacillus Calmette-Guérin failures in nonmuscle invasive bladder cancer.
Phase I trial of intravesical recombinant adenovirus mediated interferon-α2b formulated in Syn3 for Bacillus Calmette-Guérin failures in nonmuscle invasive bladder cancer.
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DOI：
10.1016/j.juro.2013.03.030
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发表时间：
2013-09
影响因子：
6.6
通讯作者：
Benedict, William F.
中科院分区：
文献类型：
--
作者：
Dinney, Colin P. N.;Fisher, Mark B.;Navai, Neema;O'Donnell, Michael A.;Cutler, David;Abraham, Alice;Young, Sophia;Hutchins, Beth;Caceres, Maria;Kishnani, Narendra;Sode, George;Cullen, Constance;Zhang, Guangcheng;Grossman, H. Barton;Kamat, Ashish M.;Gonzales, Marshall;Kincaid, Michael;Ainslie, Nancy;Maneval, Daniel C.;Wszolek, Matthew F.;Benedict, William F.
在卡介苗（BCG）治疗后复发的非肌层浸润性膀胱癌（NMIBC）患者中进行了一项膀胱内重组腺病毒介导的干扰素-α2b基因治疗（rAd-IFNα）的I期试验，该试验采用赋形剂SCH Syn 3配制。主要目的是确定rAd-IFNα/Syn 3的安全性;次要终点是证明有效的rAd-IFNα基因表达和3个月时临床活性的初步证据。入选了17例BCG后复发的NMIBC患者。单次给予用辅料Syn 3配制的rAd-IFNα（3×109至3×1011个微粒/mL）。评价患者安全性≥12周。通过尿IFNα蛋白浓度测定基因转移的效率。在3个月时确定初步药物疗效。rAd-IFNα/Syn 3膀胱灌注耐受性良好，未出现剂量限制性毒性（DLT）。尿急是最常见的不良事件，均为1级或2级。在血液中未检测到rAd-IFNα DNA，但测量到一过性低血清IFNα和Syn 3水平。初始治疗后，尿液IFNα水平达到较高且延长的剂量相关水平。在14例接受剂量≥ 1010个微粒/mL治疗且尿IFNα可检出的患者中，6例（43%）在3个月时出现完全缓解，2例分别在29.0和39.2个月时保持无病。rAd-IFNα/Syn 3膀胱灌注耐受性良好，未发生DLT。剂量依赖性尿IFNα浓度证实了有效的基因转移和表达。膀胱内注射rAd-IFNα/Syn 3对BCG后复发的NMIBC表现出有希望的临床活性。
A Phase l trial of intravesical recombinant adenovirus-mediated interferon-α2b gene therapy (rAd-IFNα) formulated with the excipient SCH Syn3 was conducted in patients with non-muscle invasive bladder cancer (NMIBC) who recurred after Bacillus Calmette-Guerin (BCG). The primary objective was to determine the safety of rAd-IFNα/Syn3; secondary endpoints were to demonstrate effective rAd-IFNα gene expression and preliminary evidence of clinical activity at three months. Seventeen patients with recurrent NMIBC after BCG were enrolled. A single treatment of rAd-IFNα (3×109 to 3×1011 particles/mL) formulated with the excipient Syn3 was administered. Patient safety was evaluated for ≥12 weeks. Efficacy of gene transfer was determined by urine IFNα protein concentrations. Preliminary drug efficacy was determined at 3 months. Intravesical rAd-IFNα/Syn3 was well tolerated as no dose limiting toxicity (DLT) was encountered. Urgency was the most common adverse event and all were grade 1 or 2. rAd-IFNα DNA was not detected in the blood, however, transient low serum IFNα and Syn3 levels were measured. High and prolonged dose-related urine IFNα levels were achieved with the initial treatment. Of the 14 patients treated at doses ≥ 1010 particles/mL with detectable urine IFNα, 6 (43%) experienced a complete response at 3 months and 2 remained disease free at 29.0 and 39.2 months respectively. Intravesical rAd-IFNα/Syn3 was well tolerated with no DLT encountered. Dose dependent urinary IFNα concentrations confirmed efficient gene transfer and expression. Intravesical rAd-IFNα/Syn3 demonstrated promising clinical activity in NMIBC recurring after BCG.
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影响因子：
6.4
作者：
通讯作者：
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将腺病毒介导的干扰素α直接转移到人膀胱癌细胞中，但旁观者因子产生的因子诱导了内质网应激相关的细胞毒性。
影响因子：
5.1
作者：
Zhang, X-Q;Yang, Z.;Benedict, W. F.
通讯作者：
Benedict, W. F.
影响因子：
6.4
作者：
Zhang, X.;Dong, L.;Benedict, W. F.
通讯作者：
Benedict, W. F.
影响因子：
6.6
作者：
O'Donnell, MA;Lilli, K;Leopold, C
通讯作者：
Leopold, C
影响因子：
6.6
作者：
Sylvester, RJ;van der Meijden, APM;Lamm, DL
通讯作者：
Lamm, DL