Hybrid model of tumor growth, angiogenesis and immune response yields strategies to improve antiangiogenic therapy.

Solid tumors harbor a complex and dynamic microenvironment that hinders the delivery and efficacy of therapeutic interventions. In this study, we developed and utilized a hybrid, discrete-continuous mathematical model to explore the interplay between solid tumor growth, immune response, tumor-induced angiogenesis, and antiangiogenic drugs. By integrating published data with anti-angiogenic drugs, we elucidate three primary mechanisms by which anti-angiogenesis influences tumor progression and treatment outcomes: reduction in tumor growth rate by mitigating and temporally delaying angiogenesis, normalization of blood vessel structure and function, and improving immune cell extravasation and activation. Our results indicate a significant increase in functional blood vessels and perfusion following anti-angiogenic treatment, which in turn improves the intratumoral distribution of immune cells. The normalization window, or optimal time frame for anti-angiogenic drug administration, and the dose of the drug arise naturally in the model and are highlighted as crucial factors in maximizing treatment benefits. Prolonged anti-angiogenic treatment triggers cancer cell migration into healthy tissue and induces immunosuppression due to hypoxia, potentially leading to negative effects because these cancer cells will rapidly proliferate upon treatment termination. In conclusion, the positive contribution of anti-angiogenic treatment must balance the possible negative effects by choosing a proper treatment protocol as well as combining it with proper anti-cancer treatment. Our findings provide valuable insights and a framework for the design of protocols with anti-angiogenic treatment, targeted immunotherapy, and non-targeted anti-cancer therapies.