Modeling the virus-induced tumor-specific immune response with delay in tumor virotherapy

摘要

It is urgently required to design novel cancer therapies which lead to permanent cancer eradication or cancer control. Oncolytic virotherapy is a promising cancer treatment strategy using genetically engineered viruses which can selectively infect, replicate in and kill tumor cells without harming normal cells. Due to the variable interactions between tumor cells and oncolytic viruses (OVs) as well as the accordingly immune response, the impact of tumor virotherapy on tumor control is prominent. We propose a novel mathematical modeling framework based on delay differential equation to study tumor virotherapy with mediated antitumor immunity by OVs, which incorporates complex tumor-virus-immune system interactions. We initially study the existence and local stability of equilibria, and theoretically and numerically investigate the local Hopf bifurcation from the positive equilibrium by considering the time delay as a bifurcation parameter. Further, we analyze the direction of Hopf bifurcation and the stability of bifurcating periodic solution. Main results show that the time delay can induce Hopf bifurcation and result in periodic oscillations, indicating that the delayed tumor specific CTL response induced by OVs leads to complex dynamics and may significantly influence the development process of tumor growth. Our findings also provide insight into important aspects of the virotherapy, including the dependence of the efficacy on key factors. We find that enhancing the induction of antitumor immunity by OVs can reduce the complexity of dynamics by strengthening the stability and show considerable effects on combating tumor. Further, proper choice of OVs with relative strong ability to lyse tumor cells is beneficial to ultimately control the development process of tumor growth. (c) 2021 Elsevier B.V. All rights reserved.