Abstract:
Mesenchymal stem cells (MSCs) loaded with oncolytic viruses are presently being investigated as a
new modality of advanced/metastatic tumors treatment and enhancement of virotherapy. MSCs can,
however, either promote or suppress tumor growth. To address the critical question of how MSCs
loaded with oncolytic viruses affect virotherapy outcomes and tumor growth patterns in a tumor
microenvironment, we developed and analyzed an integrated mathematical-experimental model. We
used the model to describe both the growth dynamics in our experiments of firefly luciferase-expressing
Hep3B tumor xenografts and the effects of the immune response during the MSCs-based virotherapy.
We further employed it to explore the conceptual clinical feasibility, particularly, in evaluating the
relative significance of potential immune promotive/suppressive mechanisms induced by MSCs loaded
with oncolytic viruses. We were able to delineate conditions which may significantly contribute to the
success or failure of MSC-based virotherapy as well as generate new hypotheses. In fact, one of the
most impactful outcomes shown by this investigation, not inferred from the experiments alone, was
the initially counter-intuitive fact that using tumor-promoting MSCs as carriers is not only helpful
but necessary in achieving tumor control. Considering the fact that it is still currently a controversial
debate whether MSCs exert a pro- or anti-tumor action, mathematical models such as this one help
to quantitatively predict the consequences of using MSCs for delivering virotherapeutic agents
in vivo. Taken together, our results show that MSC-mediated systemic delivery of oncolytic viruses is a
promising strategy for achieving synergistic anti-tumor efficacy with improved safety profiles.
