Glioblastoma multiforme, the most aggressive glioma histology, is one of the most lethal malignancies with a medial survival of less than one year despite multimodality treatment. Gliomas represent a promising target for gene transfer approaches given their limited ability to metastasize, but despite promising preclinical data, significant clinical benefit has not been materialized to date. Our group has developed a novel potent antitumor approach to attack recurrent gliomas, by utilizing an Edmonston's vaccine strain of measles virus, which we have engineered to produce the marker peptide CEA (MV-CEA). CEA serves as a trackable marker of viral gene expression and can be used to monitor viral therapy in vivo. Using MV-CEA we have demonstrated significant antitumor activity in vitro against several glioma lines and in vivo in subcutaneous and orthotopic U87 xenografts. We now propose to perform additional preclinical work in order to optimize MV-CEA-based therapy for the treatment of recurrent gliomas. In order to overcome challenges associated with the variability of expression of the measles virus receptor CD46 in gliomas and the ubiquitous, although low level, expression of CD46 in normal brain, we propose to exploit alterations of the EGFR pathway, possibly in combination with ablation of the natural binding to the CD46 and SLAM receptors to construct retargeted MV-CEA derivatives. These will be comparatively tested in vitro and in vivo in order to decide on the optimal candidate for clinical translation. This proposal brings forward two novel concepts: exploring the use of an attenuated measles virus of the Edmonston vaccine lineage to treat recurrent gliomas and use of a novel tracking system that could significantly improve our ability to monitor virotherapy trials in brain tumors. Our hypothesis is that targeted MV-CEA derivatives will be potent antitumor agents against glioblastoma multiforme with a superior efficacy/toxicity profile as compared to MV-CEA. Therefore, our proposal has the following specific aims: 1) To generate and characterize derivative attenuated vaccine strains of measles virus, expressing the marker peptide CEA by expanding the MV-CEA tropism in order to facilitate entry in glioma cells overexpressing EGFR and/or the EGFRvlII mutant with or without ablation of the tropism to the natural receptors CD46 and SLAM; 2) To compare the efficacy of MV-CEA with the EGFR targeted derivative viruses in vitro and in vivo in four different orthotopic glioblastoma models that exhibit distinct alterations of the EGFR pathway and to assess the value of serum CEA as a correlate of viral gene expression, viral replication, and antitumor activity in this setting; 3) To compare toxicity of the different engineered strains, in a susceptible primate model, and to assess the impact of preexisting measles virus immunity and steroid induced immunosuppression on the safety of the treatment; 4) To use the viral strain with the optimal safety/efficacy profile in a phase I clinical trial in patients with recurrent glioblastoma multiforme.
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