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

J Theor Biol. 2016 Apr 7;394:197-211. doi: 10.1016/j.jtbi.2016.01.026. Epub 2016 Jan 27.

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.

MeSH terms

  • Angiogenesis Inhibitors / therapeutic use*
  • Antigens, Neoplasm / immunology
  • Cell Count
  • Cell Proliferation
  • Computer Simulation
  • Dendritic Cells / immunology
  • Humans
  • Immune Evasion
  • Immunosuppression Therapy
  • Immunotherapy*
  • Models, Biological
  • Neoplasms / drug therapy
  • Neoplasms / therapy*
  • T-Lymphocytes, Cytotoxic / immunology
  • Transforming Growth Factor beta / metabolism
  • Vascular Endothelial Growth Factor A / antagonists & inhibitors

Substances

  • Angiogenesis Inhibitors
  • Antigens, Neoplasm
  • Transforming Growth Factor beta
  • Vascular Endothelial Growth Factor A