Oncolytic efficacy and enhanced safety of measles virus activated by tumor-secreted matrix metalloproteinases.
Cancer cells secrete matrix metalloproteinases (MMP) that degrade the extracellular matrix and are responsible for some hallmarks of malignant cancer. Many viruses, including a few currently used in oncolytic virotherapy clinical trials, depend on intracellular proteases to process their proteins and activate their particles. We show here for measles virus (MV) that particle activation can be made dependent of proteases secreted by cancer cells. The MV depends on the intracellular protease furin to process and activate its envelope fusion (F) protein. To make F protein activation cancer cell specific, we introduced hexameric sequences recognized by an MMP and identified the mutant proteins most effective in fusing MMP-expressing human fibrosarcoma cells (HT1080). We showed that an MMP inhibitor interferes with syncytia formation elicited by mutant F proteins and confirmed MMP-dependent cleavage by Edman degradation sequence analysis. We generated recombinant MVs expressing the modified F proteins in place of furin-activated F. These viruses spread only in cells secreting MMP. In nude mice, an MMP-activated MV retarded HT1080 xenograft growth as efficiently as the furin-activated MV vaccine strain. In MV-susceptible mice, the furin-activated virus caused lethal encephalitis upon intracerebral inoculation, whereas the MMP-activated did not. Thus, MV particle activation can be made dependent of proteases secreted by cancer cells, enhancing safety. This study opens the perspective of combining targeting at the particle activation, receptor recognition, and selective replication levels to improve the therapeutic index of MV and other viruses in ongoing clinical trials of oncolysis.
Springfeld
Christoph
C
Molecular Medicine Program and Virology and Gene Therapy Track, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55902, USA.
von Messling
Veronika
V
Frenzke
Marie
M
Ungerechts
Guy
G
Buchholz
Christian J
CJ
Cattaneo
Roberto
R
D000595:Amino Acid Sequence; D000818:Animals; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D005354:Fibrosarcoma / Q000201:enzymology / Q000628:therapy / Q000821:virology; D045683:Furin / Q000378:metabolism; D006801:Humans; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D008459:Measles virus / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008819:Mice, Nude; D008969:Molecular Sequence Data; D050130:Oncolytic Virotherapy / Q000009:adverse effects / Q000379:methods*; D014709:Vero Cells; D014760:Viral Fusion Proteins / Q000235:genetics / Q000378:metabolism; D014775:Virus Activation
D061965:Matrix Metalloproteinase Inhibitors; D014760:Viral Fusion Proteins; D045683:Furin; D020782:Matrix Metalloproteinases