Cancer Therapy: Preclinical Mesenchymal Stem Cell Carriers Protect Oncolytic Measles Viruses from Antibody Neutralization in an Orthotopic Ovarian Cancer Therapy Model

Purpose: 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. Experimental Design: 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. Results: 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 treatedwith saline, nakedMV, orMV-infectedMSC. Bioluminescent and fluorescent imaging data indicated that i.p. administeredMSC localized to peritoneal tumors, infiltrated into the tumor parenchyma, and transferred virus infection to tumors inmeasles 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. Conclusions: MSC should be used as carriers of MV for intraperitoneal virotherapy in measles-immune ovarian cancer patients. (Clin Cancer Res 2009;15(23):7246–55) Epithelial ovarian cancer is the most lethal of all gynecologic malignancies, killing >15,000 women in the United States each year (1). Due to the lack of effective screening modalities, the majority of patients present with advanced stage III disease at the time of diagnosis where the cancer still remains confined within the peritoneal cavity (2). Primary treatment is maximal debulking surgery followed by chemotherapy using carboplatin and paclitaxel or carboplatin alone (3). More than 75% of patients will eventually relapse, and salvage therapies for recurrent disease are not curative. Various novel biological therapeutics are being developed for the treatment of ovarian cancer; these include immunotherapy using tumor vaccines, monoclonal antibody (Ab) therapy, gene transfer of cytotoxic and antiangiogenic transgenes, and virotherapy using replication-competent tumor selective viruses (4–8). We have been developing the Edmonston vaccine lineage of MVas a tumor selective oncolytic agent for cancer therapy (9).OncolyticMVuses the hemagglutinin envelope glycoprotein to infect cancer cells via the cellular CD46 receptor and the fusion envelope glycoprotein to trigger fusion of the viral cell membranes for virus entry (10). Expression of these fusogenic hemagglutinin and fusion proteins on surfaces of virus-infected cells results in massive intercellular fusion with uninfected neighboring CD46-positive cells to generate the characteristic measles virus (MV)–induced cytopathic effects (CPE) of syncytia formation (11). We recently showed that overexpression of CD46 on cell surfaces results in the preferential killing of tumor cells (12, 13). Indeed, human ovarian cancer cells overexpress CD46 (14) and are highly susceptible to measles-induced CPE and cell killing (10, 12). A phase I dose escalation clinical trial testing the safety of i.p. administration of 10 to 10 TCID50 of MV-CEA, a recombinant MV genetically modified to express a soluble marker Authors' Affiliations: Department of Molecular Medicine and Divisions of Transfusion Medicine and Laboratory Medicine, Mayo Clinic, Rochester, Minnesota Received 5/20/09; revised 8/19/09; accepted 9/8/09; published OnlineFirst 11/24/09. Grant support: TheMinnesotaOvarianCancerAlliance, Andersen Foundation, Alliance for Cancer Gene Therapy, and the National Cancer Institute (CA136547 and CA129966). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Requests for reprints: Kah-Whye Peng, Guggenheim 18, Mayo Clinic, 200 First Street Southwest, Rochester, MN 55905. Phone: 507-284-8357; Fax: 507-284-8388; E-mail: [email protected]. F 2009 American Association for Cancer Research. doi:10.1158/1078-0432.CCR-09-1292 7246 Clin Cancer Res 2009;15(23) December 1, 2009 www.aacrjournals.org Research. on April 14, 2017. © 2009 American Association for Cancer clincancerres.aacrjournals.org Downloaded from Published OnlineFirst November 24, 2009; DOI: 10.1158/1078-0432.CCR-09-1292