Phase I Trial of Intraperitoneal Administration of an Oncolytic Measles Virus Strain Engineered to Express Carcinoembryonic Antigen for Recurrent Ovarian Cancer

Division of Medical Oncology, Department of Molecular Medicine, Mayo Clinic, Gonda 10-141, 200 First Street Southwest, Rochester, MN 55905, USA.
Cancer Research (Impact Factor: 9.33). 02/2010; 70(3):875-82. DOI: 10.1158/0008-5472.CAN-09-2762
Source: PubMed


Edmonston vaccine strains of measles virus (MV) have shown significant antitumor activity in preclinical models of ovarian cancer. We engineered MV to express the marker peptide carcinoembryonic antigen (MV-CEA virus) to also permit real-time monitoring of viral gene expression in tumors in the clinical setting. Patients with Taxol and platinum-refractory recurrent ovarian cancer and normal CEA levels were eligible for this phase I trial. Twenty-one patients were treated with MV-CEA i.p. every 4 weeks for up to 6 cycles at seven different dose levels (10(3)-10(9) TCID(50)). We observed no dose-limiting toxicity, treatment-induced immunosuppression, development of anti-CEA antibodies, increase in anti-MV antibody titers, or virus shedding in urine or saliva. Dose-dependent CEA elevation in peritoneal fluid and serum was observed. Immunohistochemical analysis of patient tumor specimens revealed overexpression of measles receptor CD46 in 13 of 15 patients. Best objective response was dose-dependent disease stabilization in 14 of 21 patients with a median duration of 92.5 days (range, 54-277 days). Five patients had significant decreases in CA-125 levels. Median survival of patients on study was 12.15 months (range, 1.3-38.4 months), comparing favorably to an expected median survival of 6 months in this patient population. Our findings indicate that i.p. administration of MV-CEA is well tolerated and results in dose-dependent biological activity in a cohort of heavily pretreated recurrent ovarian cancer patients.

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Available from: Judith Salmon Kaur
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    • "Oncolytic virotherapy is a promising prospect to complement current therapeutic strategies in oncology, since cancers resistant to conventional treatment regimens are unlikely to be crossresistant to oncolytic viruses (OLVs). Currently, numerous OLVs, including adenovirus [1] [2] [3], reovirus [4], measles virus [5], Newcastle disease virus [6], Seneca Valley virus [7], retrovirus [8], vaccinia virus [9], herpes simplex virus [10] and Coxsackie virus A21 [10] are in or have completed clinical trials for a variety of solid malignancies with encouraging results. Given the heterogeneity associated with hematological malignancies , combination therapy is a rational option widely practiced in oncology. "
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    • "(MV- Wue) (Hummel et al., 2009). The control virus MV-Hedm will have a similar susceptibility to monoclonal anti-H antibodies and anti- MV antibodies present in human serum as oncolytic MVs tested clinically (NCT00450814; NCT00408590; US-0770; (NCT01503177; Galanis et al., 2010) as they differ from one another only by the transgene they encode. Since retargeted H glycoproteins are of a higher molecular weight their incorporation into the virons is confirmed by comparing their size to Hedm by immunoblotting for H (Fig. 2). "
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    • "The reliance of MV-Edm on CD46 receptor density allows the virus and its derivatives to discriminate between tumor and normal cells, infecting and lysing the former while sparing the latter. Phase I clinical trials have demonstrated the safety of these viruses for the treatment ovarian cancer and glioblastoma, where no dose-limiting toxicity has been observed following administration of the MV at doses up to 109 TCID50 delivered intraperiotoneally and 107 TCID50 for MV delivered through the central nervous system respectively [6,49]. "
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