In the present paper, we address by means of mathematical modeling the following main question: How can oncolytic virus infection of some normal cells in the vicinity of tumor cells enhance oncolytic virotherapy? We formulate a mathematical model describing the interactions between the oncolytic virus, the tumor cells, the normal cells, and the antitumoral and antiviral immune responses. The model consists of a system of delay differential equations with one (discrete) delay. We derive the model’s basic reproductive number within tumor and normal cell populations and use their ratio as a metric for virus tumor-specificity. Numerical simulations are performed for different values of the basic reproduction numbers and their ratios to investigate potential trade-offs between tumor reduction and normal cells losses. A fundamental feature unravelled by the model simulations is its great sensitivity to parameters that account for most variation in the early or late stages of oncolytic virotherapy. From a clinical point of view, our findings indicate that designing an oncolytic virus that is not 100% tumor-specific can increase virus particles, which in turn, can further infect tumor cells. Moreover, our findings indicate that when infected tissues can be regenerated, oncolytic viral infection of normal cells could improve cancer treatment.

We present a novel mathematical model involving various immune cell populations and tumor cell populations. The model describes how tumor cells evolve and survive the brief encounter with the immune system mediated by natural killer (NK) cells and the activated CD8(+) cytotoxic T lymphocytes (CTLs). The model is composed of ordinary differential equations describing the interactions between these important immune lymphocytes and various tumor cell populations. Based on up-to-date knowledge of immune evasion and rational considerations, the model is designed to illustrate how tumors evade both arms of host immunity (i.e. innate and adaptive immunity). The model predicts that (a) an influx of an external source of NK cells might play a crucial role in enhancing NK-cell immune surveillance; (b) the host immune system alone is not fully effective against progression of tumor cells; (c) the development of immunoresistance by tumor cells is inevitable in tumor immune surveillance. Our model also supports the importance of infiltrating NK cells in tumor immune surveillance, which can be enhanced by NK cell-based immunotherapeutic approaches.

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.

<abstract><p>Combining chimeric antigen receptor T (CAR-T) cells with oncolytic viruses (OVs) has recently emerged as a promising treatment approach in preclinical studies that aim to alleviate some of the barriers faced by CAR-T cell therapy. In this study, we address by means of mathematical modeling the main question of whether a single dose or multiple sequential doses of CAR-T cells during the OVs therapy can have a synergetic effect on tumor reduction. To that end, we propose an ordinary differential equations-based model with virus-induced synergism to investigate potential effects of different regimes that could result in efficacious combination therapy against tumor cell populations. Model simulations show that, while the treatment with a single dose of CAR-T cells is inadequate to eliminate all tumor cells, combining the same dose with a single dose of OVs can successfully eliminate the tumor in the absence of virus-induced synergism. However, in the presence of virus-induced synergism, the same combination therapy fails to eliminate the tumor. Furthermore, it is shown that if the intensity of virus-induced synergy and/or virus oncolytic potency is high, then the induced CAR-T cell response can inhibit virus oncolysis. Additionally, the simulations show a more robust synergistic effect on tumor cell reduction when OVs and CAR-T cells are administered simultaneously compared to the combination treatment where CAR-T cells are administered first or after OV injection. Our findings suggest that the combination therapy of CAR-T cells and OVs seems unlikely to be effective if the virus-induced synergistic effects are included when genetically engineering oncolytic viral vectors.</p></abstract>