Abstract
In this paper we consider a combination therapy of cancer. One drug is a vaccine which activates dendritic cells so that they induce more T cells to infiltrate the tumor. The other drug is a checkpoint inhibitor, which enables the T cells to remain active against the cancer cells. The two drugs are positively correlated in the sense that an increase in the amount of each drug results in a reduction in the tumor volume. We consider the question whether a treatment with combination of the two drugs at certain levels is preferable to a treatment by one of the drugs alone at ‘roughly’ twice the dosage level; if that is the case, then we say that there is a positive ‘synergy’ for this combination of dosages. To address this question, we develop a mathematical model using a system of partial differential equations. The variables include dendritic and cancer cells, CD4+ and CD8+ T cells, IL-12 and IL-2, GM-CSF produced by the vaccine, and a T cell checkpoint inhibitor associated with PD-1. We use the model to explore the efficacy of the two drugs, separately and in combination, and compare the simulations with data from mouse experiments. We next introduce the concept of synergy between the drugs and develop a synergy map which suggests in what proportion to administer the drugs in order to achieve the maximum reduction of tumor volume under the constraint of maximum tolerated dose.
Highlights
When cancer cells undergo necrosis, they release high mobility group box-1 (HMGB-1) which activates dendritic cells [1,2,3]
It was recently suggested that the combination of a cancer vaccine and an immune checkpoint inhibitor may function synergistically to induce more effective antitumor immune responses [18, 20]
In the present paper we develop a mathematical model of treatment of cancer with a cancer vaccine combined with an immune checkpoint inhibitor; we combine GVAX and PD-1 inhibitor
Summary
When cancer cells undergo necrosis, they release high mobility group box-1 (HMGB-1) which activates dendritic cells [1,2,3]. Activated dendritic cells (DCs) mature as APC cells and play a critical role in the communication between the innate and adaptive immune responses. Th1 produces IL-2 which further promotes proliferation of the effector T cells. Both CD4+ Th1 and CD8+ T cells kill cancer cells [6,7,8]. CD8+ T cells are more effective in killing cancer cells, but the helper function of CD4+ Th1 cells improves the efficacy of tumor-reactive CD8+ T cells [9]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
