Mathematical Biosciences and Engineering (MBE)

Quantitative impact of immunomodulation versus oncolysis with cytokine-expressing virus therapeutics

Pages: 841 - 858, Volume 12, Issue 4, August 2015      doi:10.3934/mbe.2015.12.841

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Peter S. Kim - School of Mathematics and Statistics, University of Sydney, Sydney, NSW, Australia (email)
Joseph J. Crivelli - Weill Cornell Medical College, New York, NY, United States (email)
Il-Kyu Choi - Department of Bioengineering, College of Engineering, Hanyang University, 222 Wangsimni-ro, Seongdong-gu, Seoul 133-791, South Korea (email)
Chae-Ok Yun - Department of Bioengineering, College of Engineering, Hanyang University, Seoul, South Korea (email)
Joanna R. Wares - Department of Mathematics and Computer Science, University of Richmond, Richmond, VA, United States (email)

Abstract: The past century's description of oncolytic virotherapy as a cancer treatment involving specially-engineered viruses that exploit immune deficiencies to selectively lyse cancer cells is no longer adequate. Some of the most promising therapeutic candidates are now being engineered to produce immunostimulatory factors, such as cytokines and co-stimulatory molecules, which, in addition to viral oncolysis, initiate a cytotoxic immune attack against the tumor.
    This study addresses the combined effects of viral oncolysis and T-cell-mediated oncolysis. We employ a mathematical model of virotherapy that induces release of cytokine IL-12 and co-stimulatory molecule 4-1BB ligand. We found that the model closely matches previously published data, and while viral oncolysis is fundamental in reducing tumor burden, increased stimulation of cytotoxic T cells leads to a short-term reduction in tumor size, but a faster relapse.
    In addition, we found that combinations of specialist viruses that express either IL-12 or 4-1BBL might initially act more potently against tumors than a generalist virus that simultaneously expresses both, but the advantage is likely not large enough to replace treatment using the generalist virus. Finally, according to our model and its current assumptions, virotherapy appears to be optimizable through targeted design and treatment combinations to substantially improve therapeutic outcomes.

Keywords:  Oncolytic virotherapy, adenovirus, cytokines, co-stimulatory molecules, mathematical model, ordinary differential equations model.
Mathematics Subject Classification:  Primary: 92C50, 92B05; Secondary: 37N25.

Received: May 2014;      Accepted: October 2014;      Available Online: April 2015.