Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota 55905, USA.
Clin Cancer Res. 2009 Dec 1;15(23):7246-55. doi: 10.1158/1078-0432.CCR-09-1292. Epub 2009 Nov 24.
Preexisting antiviral antibodies in cancer patients can quickly neutralize oncolytic measles virus (MV) and decrease its antitumor 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 that completely inactivated naked virus. Athymic mice bearing i.p. 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 i.p. 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.
癌症患者体内存在的抗病毒抗体可迅速中和溶瘤麻疹病毒（MV），降低其抗肿瘤效力。与“裸”病毒不同，细胞相关病毒可免受抗体中和。因此，我们假设如果使用感染 MV 的间充质干细胞（MSC）载体，麻疹病毒疗法治疗麻疹免疫小鼠的卵巢癌可能会更好。
测定卵巢癌患者抗麻疹抗体的效价。测定 MSC 对 MV 的保护作用、MSC 的体内生物分布特征和肿瘤浸润能力。用裸病毒或 MSC 相关病毒治疗麻疹-naïve 或免疫荷瘤小鼠，并比较小鼠的存活率。
MSC 通过细胞间异融合将 MV 感染转移至靶细胞，并在高滴度抗麻疹抗体存在下诱导合胞体形成，其水平足以使裸病毒完全失活。用麻疹免疫的人血清被动免疫的腹腔内种植人 SKOV3ip.1 卵巢肿瘤异种移植的裸鼠用生理盐水、裸 MV 或 MV 感染的 MSC 治疗。生物发光和荧光成像数据表明，腹腔内给予的 MSC 定位于腹膜肿瘤，浸润肿瘤实质，并将病毒感染转移至麻疹-naïve 和被动免疫小鼠的肿瘤。用 MV 感染的 MSC 治疗可显著提高麻疹免疫小鼠的存活率。相比之下，用裸病毒或未感染的 MSC 治疗并不能延长被动免疫小鼠的存活时间。
MSC 应作为 MV 的载体，用于麻疹免疫卵巢癌患者的腹腔内病毒治疗。
