Mesenchymal stem cell carriers protect oncolytic measles viruses from antibody neutralization in an orthotopic ovarian cancer therapy model.
Mesenchymal stem cell carriers protect oncolytic measles viruses from antibody neutralization in an orthotopic ovarian cancer therapy model.
复制标题
DOI：
10.1158/1078-0432.ccr-09-1292
复制
发表时间：
2009-12-01
期刊：
影响因子：
--
通讯作者：
Peng KW
中科院分区：
文献类型：
--
作者：
Mader EK;Maeyama Y;Lin Y;Butler GW;Russell HM;Galanis E;Russell SJ;Dietz AB;Peng KW
癌症患者体内预先存在的抗病毒抗体可以迅速中和溶瘤麻疹病毒（MV）并降低其抗肿瘤效力。与“裸”病毒相反，细胞相关病毒受到保护，不受抗体中和。因此，我们假设，麻疹病毒治疗卵巢癌的麻疹免疫小鼠可能是上级，如果MV感染的间充质干细胞（MSC）载体使用。测定卵巢癌患者抗麻疹抗体滴度。观察MSC对MV的免疫保护作用、体内分布及肿瘤浸润能力。用裸病毒或MSC相关病毒治疗麻疹初治或免疫荷瘤小鼠，并比较小鼠存活率。MSC通过细胞间异源融合将MV感染转移到靶细胞，并在高滴度抗麻疹抗体存在下诱导合胞体形成;在完全灭活裸病毒的水平。用盐水、裸MV或MV感染的MSC处理携带用麻疹免疫人血清被动免疫的腹膜内人SKOV3ip.1卵巢肿瘤异种移植物的无胸腺小鼠。生物发光和荧光成像数据表明，腹腔内注射MSC定位于腹膜肿瘤，浸润到肿瘤实质中，并将病毒感染转移到麻疹初治和被动免疫小鼠的肿瘤中。麻疹免疫小鼠的存活率通过MV感染的MSC治疗显著提高。与此相反，被动免疫小鼠的生存期没有延长治疗与裸病毒或未感染的MSC。MSC可作为MV的载体用于麻疹免疫性卵巢癌患者的腹腔内病毒治疗。
Pre-existing antiviral antibodies in cancer patients can quickly neutralize oncolytic measles virus (MV) and decrease its anti-tumor potency. In contrast to `naked' viruses, cell-associated viruses are protected from antibody neutralization. Hence, we hypothesized that measles virotherapy of ovarian cancer in measles immune mice might be superior if MV infected mesenchymal stem cell (MSC) carriers are used. Antimeasles antibodies titers in ovarian cancer patients were determined. The protection of MV by MSC from antimeasles antibodies, the in vivo biodistribution profiles and tumor infiltration capability of MSC were determined. Measles naïve or immune tumor-bearing mice were treated with naked virus or MSC-associated virus and mice survivals were compared. MSC transferred MV infection to target cells via cell-to-cell heterofusion and induced syncytia formation in the presence of high titers of antimeasles antibody; at levels which completely inactivated naked virus. Athymic mice bearing intraperitoneal human SKOV3ip.1 ovarian tumor xenografts passively immunized with measles immune human serum were treated with saline, naked MV or MV infected MSC. Bioluminescent and fluorescent imaging data indicated that intraperitoneally administered MSC localized to peritoneal tumors, infiltrated into the tumor parenchyma and transferred virus infection to tumors in measles naïve and passively immunized mice. Survival of the measles immune mice was significantly enhanced by treatment with MV-infected MSC. In contrast, survivals of passively immunized mice were not prolonged by treatment with naked virus or uninfected MSC. MSC should be used as carriers of MV for intraperitoneal virotherapy in measles-immune ovarian cancer patients.