How to schedule VEGF and PD-1 inhibitors in combination cancer therapy?

BACKGROUND: One of the questions in the design of cancer clinical trials with combination of two drugs is in which order to administer the drugs. This is an important question, especially in the case where one agent may interfere with the effectiveness of the other agent. RESULTS: In the present paper we develop a mathematical model to address this scheduling question in a specific case where one of the drugs is anti-VEGF, which is known to affect the perfusion of other drugs. As a second drug we take anti-PD-1. Both drugs are known to increase the activation of anticancer T cells. Our simulations show that in the case where anti-VEGF reduces the perfusion, a non-overlapping schedule is significantly more effective than a simultaneous injection of the two drugs, and it is somewhat more beneficial to inject anti-PD-1 first. CONCLUSION: The method and results of the paper can be extended to other combinations, and they could play an important role in the design of clinical trials with combination therapy, where scheduling strategies may significantly affect the outcome.