297. Safety of Repeat Intracerebral Administration of MV-CEA in Rhesus Macaques in Support of a Phase I/II Clinical Trial for Patients with Recurrent Gliomas

Novel therapies for patients with recurrent gliomas are urgently needed, given their dismal prognosis,. Oncolytic measles virus strains derived from the Edmonston vaccine lineage are an attractive option for glioma therapy, because of their significant antitumor effect (Phuong et al, 2003). MV-CEA is an Edmonston lineage measles virus strain engineered to express the marker protein carcinoembryonic antigen (CEA), the levels of which can be monitored by a simple blood test and serve as a correlate of viral gene expression. In support of a clinical trial administering MV-CEA intracerebrally to patients with recurrent gliomas, we assessed the neurotoxicity of MV-CEA in five adult male rhesus macaques (Macaca mulatta).The animals were stereotactically administered either vehicle (n=1), 2×10 5 (n=2), or 2×106 (n=2) TCID50 MV-CEA in the right frontal lobe in two injections five days apart. Macaques were intensely monitored through clinical observations for neurotoxic effects, body weights, temperatures, CBC, CEA, clinical chemistries, coagulation, complement levels, immunoglobulin, measles antibody titers, viremia, and shedding (buccal swabs). Additionally, cisterna magna spinal taps were performed on day 9 post first article administration, and samples were analyzed for protein, glucose, cell differential, and presence of MV-CEA. After the first 3 month close follow-up period, the macaques entered a long-term observational period for an additional 9 months. MRIs were performed between 4 and 5 months post administration to assess for subclinical neurotoxicity. At the time of this abstract submission, and with a median follow up of 11 months, macaques have been remarkably tolerant of the treatment. There was no clinical or biochemical evidence of toxicity, including lack of neurological symptoms, fever, or other systemic symptoms and lack of immunosuppression. QRT- PCR analysis of blood, buccal swabs, or CSF was negative for MV- CEA at all time points. Vero cell overlays of CSF cells and supernatant have been negative for measles-related pathology. There was no CEA detection in serum or CSF at any time point. MRIs were negative for imaging abnormalities and showed no signs of encephalitis. Conclusions: Our results support the safety of CNS administration of MV-CEA. A clinical trial in patients with recurrent gliomas is planned to be activated later this year.