A cancer treatment based on synergy between anti-angiogenic and immune cell therapies

Abstract

A mathematical model integrating tumor angiogenesis and tumor-targeted cytotoxicity by immune cells was developed to identify the therapeutic window of two distinct modes to treat cancer: (1) an anti-angiogenesis treatment based on the monoclonal antibody bevacizumab that targets tumor vasculature, and (2) immunotherapy involving the injection of unlicensed dendritic cells to boost the anti-tumor adaptive response. The angiogenic cytokine Vascular Endothelial Growth Factor (VEGF) contributes to the immunosuppressive tumor microenvironment, which is responsible for the short-lived therapeutic effect of cancer-targeted immunotherapy. The effect of immunosuppression on the width of the therapeutic window of each treatment was quantified. Experimental evidence has shown that neutralizing immunosuppressive cytokines results in an enhanced immune response against infections and chronic diseases. The model was used to determine treatment protocols involving the combination of anti-VEGF and unlicensed dendritic cell injections that enhance tumor regression. The model simulations predicted that the most effective method to treat tumors involves administering a series of biweekly anti-VEGF injections to disrupt angiogenic processes and limit tumor growth. The simulations also verified the hypothesis that reducing the concentration of the immunosuppressive factor VEGF prior to an injection of unlicensed dendritic cells enhances the cytotoxicity of CD8+ T cells and results in complete tumor elimination. Feasible treatment protocols for tumors that are diagnosed late and have grown to a relatively large size were identified.

Keywords: Immunosuppression; Immunotherapy; Mathematical modeling; Monoclonal antibody; Tumor angiogenesis; VEGF.

Conflict of interest statement

Conflict of interest statement

The author discloses that there are no potential conflicts of interest.

Copyright © 2016 Elsevier Ltd. All rights reserved.

Figures

Fig. 1.

Tumor escape when a standard anti-angiogenesis treatment is not continued, and is not combined with a treatment of unlicensed dendritic cells. Although tumor size is reduced significantly by a standard anti-VEGF treatment started on day 600, the tumor will eventually grow if the anti-VEGF treatment is not expanded, or if no follow-up DC immunotherapy is administered. (A) number of tumor cells, (B) concentration of free VEGF, (C) number of endothelial cells, and (D) total tumor vasculature.

Fig. 2.

Tumor elimination via synergy between an anti-angiogenic treatment and a DC treatment. A standard anti-VEGF treatment started on day 600 decreases tumor size, and the concentration of free VEGF, low enough to make a standard DC treatment started on day 710 effective at eliminating the remaining tumor cells. (A) number of tumor cells, (B) concentration of free VEGF, (C) number of endothelial cells, and (D) total tumor vasculature.

Fig. 3.

Dynamics of tumor-targeted dendritic cells and CTL when synergy between an anti-angiogenic treatment and a DC treatment is achieved. A standard anti-VEGF treatment was started on day 600 and was followed by a standard DC treatment started on day 710. This treatment combination was effective at eliminating the tumor. (A) number of unlicensed dendritic cells, (B) number of licensed dendritic cells, (C) number of inactive CTL, and (D) number of active CTL.

Fig. 4.

Dynamics of anti-tumor CD4+ helper T cells and of pro-tumor regulatory T cells when synergy between an anti-angiogenic treatment and a DC treatment is achieved. A standard anti-VEGF treatment was started on day 600 and was followed by a standard DC treatment started on day 710. Since regulatory T cells are stimulated by licensed DC, the number of Tregs initially increases following unlicensed DC treatment. However, this type of immunotherapy also activates helper T cells and CTL that target the tumor. The activation of anti-tumor cells outweighs the activation of pro-tumor cells. Hence, the end result is complete tumor elimination. (A) number of inactive helper T cells, (B) number of active helper T cells, (C) number of inactive Tregs, and (D) number of active Tregs.