968. Next Generation Measles Virus Vectors for Oncolytic Therapy: Targeted, Armed and Stealth

Abstract

Top of pageAbstract Infection with wild-type measles virus (MV), a negative-stranded RNA virus of the family Paramyxoviridae, has been associated with spontaneous remissions in patients with lymphoma and leukaemia. In addition, studies with lymphoma, myeloma, glioma and ovarian cancer xenografts have documented oncolytic effects of an Edmonston lineage virus (MV-Edm) on a wide array of cancer types. Recombinant MV with targeted cell entry have been produced: specifity domains displayed on the viral attachment protein H mediate entry into normally non-permissive cells via designated receptors. Moreover, viruses that are |[ldquo]|blind|[rdquo]| for their natural receptors have been generated by mutating residues responsible for entry through CD46 and SLAM. To engineer the most efficient and safe vectors for clinical trials we pursue three independent approaches to be eventually combined: i) Vector retargeting at the cell entry level. ii) Vector arming with suicide genes. iii) Production of vectors with a stealth envelope that is not recognized by measles-specific antibodies. RESULTS. We have produced viruses expressing suicide genes: thymidine kinase (TK), cytosine deaminase (CD) and the E. coli purine nucleoside phosphorylase (PNP), that kills infected and bystander cells very effectively and have combined arming with receptor-targeting. We have begun to analyse these new viruses. First, the ability of retargeted MV to retard the growth of tumor xenografts was demonstrated in an immunocompetent mouse model based on murine MC38cea cells expressing the designated receptor human CEA. Second, the efficacy of recombinant viruses with combined oncolytic specificities in entering and killing target cells was demonstrated in vitro. The efficacy of these viruses is currently under investigation in a CD20/lymphoma xenograft model. Third, we are producing vectors with the glycoproteins F and H from the Tupaia paramyxovirus (TPMV) in place of the homologous MV proteins. We have previously shown that the TPMV H protein can be retargeted to support fusion of cells expressing a designated receptor. Now we show that a chimeric virus with the MV proteins N, P, L, M and the TPMV F and H protein can be rescued but does not spread efficiently. DISCUSSION. The success of oncolytic virotherapy depends on the specificity of viral replication in cancer cells, the efficacy of the oncolytic agent in eliminating those cells, and their ability of spreading without being neutralized by antibodies. We have obtained targeted and armed viruses, and have made good progress toward the production of stealth particles.