Marshall D Behrens, Robert J Stiles, Gennett M Pike, Laura A Sikkink, Yongxian Zhuang, Jia Yu, Liewei Wang, Judy C Boughey, Matthew P Goetz, Mark J Federspiel
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引用次数: 4
Abstract
Historically, the clinical utility of oncolytic virotherapy as a treatment for a wide range of cancer types was first demonstrated by three pilot human clinical trials conducted in Japan in the 1970s and 1980s using a wild-type Urabe mumps virus (MuV) clinical isolate. Using a sample of the actual original oncolytic Urabe MuV clinical trial virus stock (MuV-U-Japan) used in these Japanese clinical trials, we found that MuV-U-Japan consisted of a wide variety of very closely related Urabe MuVs that differed by an average of only three amino acids. Two MuV-U-Japan isolates, MuV-UA and MuV-UC, potently killed a panel of established human breast cancer cell lines in vitro, significantly extended survival of nude mice with human triple-negative breast cancer (TNBC) MDA-MB-231 tumor xenografts in vivo, and demonstrated significant killing activity against breast cancer patient-derived xenograft (PDX) cell lines grown as 3D organoids, including PDXs from patients resistant to anthracycline- and taxane-based chemotherapy. We also report success in developing a large-scale MuV-U production and purification process suitable for supporting Investigational New Drug applications for clinical trials. This study demonstrates the suitability of the MuV-UC virus for translation to modern clinical trials for treating patients with TNBC.
从历史上看,溶瘤病毒疗法作为一种治疗多种癌症类型的临床应用,最早是在20世纪70年代和80年代在日本使用野型Urabe腮腺炎病毒(MuV)临床分离物进行的三次试点人体临床试验中得到证实的。使用这些日本临床试验中使用的实际原始溶瘤性Urabe MuV临床试验病毒库存(MuV- u - japan)的样本,我们发现MuV- u - japan由各种非常密切相关的Urabe MuV组成,平均只有三个氨基酸不同。两株MuV-U-Japan分离株MuV-UA和MuV-UC在体外有效地杀死了一组已建立的人乳腺癌细胞系,在体内显著延长了人三阴性乳腺癌(TNBC) MDA-MB-231肿瘤异种移植物裸鼠的存活时间,并对生长为3D类器官的乳腺癌患者来源的异种移植物(PDX)细胞系显示出显著的杀伤活性,包括对蒽环类和紫杉烷类化疗耐药的患者的PDX。我们还成功开发了大规模的MuV-U生产和纯化工艺,适用于支持临床试验新药申请。这项研究证明了MuV-UC病毒用于治疗TNBC患者的现代临床试验的适用性。
期刊介绍:
Molecular Therapy — Oncolytics is an international, online-only, open access journal focusing on the development and clinical testing of viral, cellular, and other biological therapies targeting cancer.