The Edmonston-B derived vaccine strain of measles virus (MV) is oncolytic in various tumor models in vivo and is currently being tested in several phase 1 trials. Our data suggest that a “one-size-fits-all” model of immune response to viral oncolysis is not appropriate, and each tumor target will need full characterization for the potential of both direct and indirect, innate immune responses to generate benefit. MVhGCSF replicated within an MV-infectable CD46 transgenic mouse model with detectable serum levels of hGCSF but no toxicity. This finding was recapitulated by exogenously administered hGCSF. MVhGCSF enhanced the oncolytic capacity of MV in the Raji model in vivo, whereas in the Nalm-6 model, the opposite was unexpectedly the case. Next, we compared MVhGCSF with the unmodified backbone virus MVNSe. Evaluating the effects in two different models of B-cell malignancy, we showed that depletion of neutrophils abrogated the MV therapeutic effect in an in vivo Raji-but not Nalm-6 tumor model. In the present study, we attempted to enhance the neutrophil response toward MV-infected tumor targets by generating an oncolytic MV-expressing human granulocyte colony-stimulating factor (MVhGCSF). We previously showed that neutrophils are involved in MV-mediated tumor regressions and become activated, upon MV infection. The mechanism by which oncolytic measles virus (MV) kills cancer cells remains obscure.
0 Comments
Leave a Reply. |