Retargeted and Stealth-Modified Oncolytic Measles Viruses for Systemic Cancer Therapy in Measles Immune Patients.
Eugene S BahRebecca A NaceKah Whye PengMiguel Angel Muñoz-AlíaStephen J RussellPublished in: Molecular cancer therapeutics (2020)
Measles viruses (MV) are rapidly inactivated by anti-measles neutralizing antibodies, which has limited their clinical performance as oncolytic agents. Here, by substituting the H and F surface glycoproteins of MV with those from the homologous canine distemper virus (CDV) and engineering the CDV H attachment protein to target EGFR or CD38, we generated a fully retargeted MV capable of resisting neutralization by measles-immune human serum. The resultant recombinant MVs encoding retargeted CDV envelope glycoproteins had similar growth kinetics as the control MV, showed the expected engineered receptor specificities for cell entry, intercellular fusion, and target cell killing, and were blind to native CDV receptors. In contrast to the control MV, recombinant MVs incorporating CDV F and H glycoproteins retained full infectivity when exposed to high concentrations of pooled measles-immune human serum. Comparing viruses bearing MV or CDV glycoproteins in the SKOV3ip.1 model, only the virus bearing an EGFR-retargeted CDV envelope glycoprotein complex was capable of limiting tumor growth and extending the survival in measles immune mice. MV, "stealthed" and retargeted using engineered CDV surface glycoproteins, may be a promising platform to advance for systemic cancer therapy in measles immune patients.
Keyphrases
- cancer therapy
- end stage renal disease
- small cell lung cancer
- chronic kidney disease
- newly diagnosed
- ejection fraction
- single cell
- drug delivery
- prognostic factors
- stem cells
- peritoneal dialysis
- type diabetes
- magnetic resonance imaging
- clinical trial
- epidermal growth factor receptor
- adipose tissue
- cell therapy
- dna damage
- mesenchymal stem cells
- metabolic syndrome
- skeletal muscle
- amino acid
- patient reported outcomes
- protein protein
- insulin resistance
- contrast enhanced
- cell adhesion