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

Abstract

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. Cancer Res; 70(3); 875-82. ©2010 AACR.

Synergistic anti-tumor effects between oncolytic vaccinia virus and paclitaxel are mediated by the IFN response and HMGB1

“…[3][4][5][6] One advantage of this approach is that viruses typically use distinct mechanisms of tumor cell killing relative to more traditional chemotherapy and radiotherapy approaches. 2 In addition, a variety of targeting mechanisms mean that different tumor phenotypic properties can be targeted with different viral strains.…”

Attenuated, Oncolytic, but Not Wild-Type Measles Virus Infection Has Pleiotropic Effects on Human Neutrophil Function

“…Measles virus (MV), a negative sense, ssRNA virus has well documented lytic activity in several in vivo models of human cancer (2)(3)(4)(5) and is already in early-phase clinical trials (6). Mechanisms of oncolytic activity, particularly in vivo, are unclear.…”

Oncolytic viruses: From bench to bedside with a focus on safety

“…70 Completed and ongoing clinical trials in patients with T cell lymphoma, ovarian cancer or glioblastoma multiforme have first used wild type MeV and later recombinant MeV expressing marker genes CEA and NIS. [72][73][74] Intratumoral, intraperitoneal and intravenous administration have been reported using doses up to 10 9 infectious viral particles without dose limiting toxicity or MeV induced immunosuppression. [72][73][74] Although wildtype MeV can cause potentially serious disease, attenuated MeV vaccine strains like Edmonston have an excellent safety record.…”

“…[72][73][74] Intratumoral, intraperitoneal and intravenous administration have been reported using doses up to 10 9 infectious viral particles without dose limiting toxicity or MeV induced immunosuppression. [72][73][74] Although wildtype MeV can cause potentially serious disease, attenuated MeV vaccine strains like Edmonston have an excellent safety record. 69 In clinical trials with rMeV-CEA, no evidence was seen of shedding in sputum and urine samples of patients who were intraperitoneally injected.…”