2015, 12(4): 841-858. doi: 10.3934/mbe.2015.12.841

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

1. 

School of Mathematics and Statistics, University of Sydney, Sydney, NSW, Australia

2. 

Weill Cornell Medical College, New York, NY, United States

3. 

Department of Bioengineering, College of Engineering, Hanyang University, 222 Wangsimni-ro, Seongdong-gu, Seoul 133-791, South Korea

4. 

Department of Bioengineering, College of Engineering, Hanyang University, Seoul, South Korea

5. 

Department of Mathematics and Computer Science, University of Richmond, Richmond, VA, United States

Received  May 2014 Revised  October 2014 Published  April 2015

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.
Citation: Peter S. Kim, Joseph J. Crivelli, Il-Kyu Choi, Chae-Ok Yun, Joanna R. Wares. Quantitative impact of immunomodulation versus oncolysis with cytokine-expressing virus therapeutics. Mathematical Biosciences & Engineering, 2015, 12 (4) : 841-858. doi: 10.3934/mbe.2015.12.841
References:
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[33]

H. Veiga-Fernandes, U. Walter, C. Bourgeois, A. McLean and B. Rocha, Response of naïve and memory CD8+ T cells to antigen stimulation in vivo,, Nat. Immunol., 1 (2000), 47.   Google Scholar

[34]

Y. Wang, H. Wang, C. Y. Li and F. Yuan, Effects of rate, volume, and dose of intratumoral infusion on virus dissemination in local gene delivery,, Mol. Cancer Ther., 5 (2006), 362.  doi: 10.1158/1535-7163.MCT-05-0266.  Google Scholar

[35]

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D. Wodarz, Computational modeling approaches to studying the dynamics of oncolytic viruses,, Math. Biosci. Eng., 10 (2013), 939.  doi: 10.3934/mbe.2013.10.939.  Google Scholar

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D. Wodarz and N. Komarova, Towards predictive computational models of oncolytic virus therapy: basis for experimental validation and model selection,, PLoS ONE, 4 (2009).  doi: 10.1371/journal.pone.0004271.  Google Scholar

[38]

J. D. Wolchok, H. Kluger, M. K. Callahan, M. A. Postow, N. A. Rizvi, A. M. Lesokhin, N. H. Segal, C. E. Ariyan, R. A. Gordon, K. Reed, M. M. Burke, A. Caldwell, S. A. Kronenberg, B. U. Agunwamba, X. Zhang, I. Lowy, H. D. Inzunza, W. Feely, C. E. Horak, Q. Hong, A. J. Korman, J. M. Wigginton, A. Gupta and M. Sznol, Nivolumab plus ipilimumab in advanced melanoma,, N. Engl. J. Med., 369 (2013), 122.  doi: 10.1056/NEJMoa1302369.  Google Scholar

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[40]

J. T. Wu, D. H. Kirn and L. M. Wein, Analysis of a three-way race between tumor growth, a replication-competent virus and an immune response,, Bull. Math. Biol., 66 (2004), 605.  doi: 10.1016/j.bulm.2003.08.016.  Google Scholar

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W. Zhang, G. Fulci, H. Wakimoto, T. A. Cheema, J. S. Buhrman, D. S. Jeyaretna, A. O. Stemmer Rachamimov, S. D. Rabkin and R. L. Martuza, Combination of oncolytic herpes simplex viruses armed with angiostatin and IL-12 enhances antitumor efficacy in human glioblastoma models,, Neoplasia, 15 (2013), 591.   Google Scholar

show all references

References:
[1]

T. Alarcón, H. M. Byrne and P. K. Maini, A cellular automaton model for tumour growth in inhomogeneous environment,, J. Theor. Biol., 225 (2003), 257.  doi: 10.1016/S0022-5193(03)00244-3.  Google Scholar

[2]

N. Bagheri, M. Shiina, D. A. Lauffenburger and W. M. Korn, A dynamical systems model for combinatorial cancer therapy enhances oncolytic adenovirus efficacy by MEK-inhibition,, PLoS Comput. Biol., 7 (2011).  doi: 10.1371/journal.pcbi.1001085.  Google Scholar

[3]

Z. Bajzer, T. Carr, K. Josić, S. J. Russell and D. Dingli, Modeling of cancer virotherapy with recombinant measles viruses,, J. Theor. Biol., 252 (2008), 109.  doi: 10.1016/j.jtbi.2008.01.016.  Google Scholar

[4]

D. L. Bartlett, Z. Liu, M. Sathaiah, R. Ravindranathan, Z. Guo, Y. He and Z. S. Guo, Oncolytic viruses as therapeutic cancer vaccines,, Mol. Cancer, 12 (2013).   Google Scholar

[5]

M. Biesecker, J. H. Kimn, H. Lu, D. Dingli and Z. Bajzer, Optimization of virotherapy for cancer,, Bull. Math. Biol., 72 (2010), 469.  doi: 10.1007/s11538-009-9456-0.  Google Scholar

[6]

R. Breban, A. Bisiaux, C. Biot, C. Rentsch, P. Bousso and M. L. Albert, Mathematical model of tumor immunotherapy for bladder carcinoma identifies the limitations of the innate immune response,, Oncoimmunology, 1 (2012), 9.  doi: 10.4161/onci.1.1.17884.  Google Scholar

[7]

D. M. Catron, A. A. Itano, K. A. Pape, D. L. Mueller and M. K. Jenkins, Visualizing the first 50 hr of the primary immune response to a soluble antigen,, Immunity, 21 (2004), 341.  doi: 10.1016/j.immuni.2004.08.007.  Google Scholar

[8]

Y. Chen, T. DeWeese, J. Dilley, Y. Zhang, Y. Li, N. Ramesh, J. Lee, R. Pennathur-Das, J. Radzyminski, J. Wypych, D. Brignetti, S. Scott, J. Stephens, D. B. Karpf, D. R. Henderson and D. C. Yu, CV706, a prostate cancer-specific adenovirus variant, in combination with radiotherapy produces synergistic antitumor efficacy without increasing toxicity,, Cancer Res., 61 (2001), 5453.   Google Scholar

[9]

R. J. De Boer, M. Oprea, R. Antia, K. Murali-Krishna, R. Ahmed and A. S. Perelson, Recruitment times, proliferation, and apoptosis rates during the CD8(+) T-cell response to lymphocytic choriomeningitis virus,, J. Virol., 75 (2001), 10663.   Google Scholar

[10]

M. Del Vecchio, E. Bajetta, S. Canova, M. T. Lotze, A. Wesa, G. Parmiani and A. Anichini, Interleukin-12: biological properties and clinical application,, Clin. Cancer Res., 13 (2007), 4677.   Google Scholar

[11]

D. Dingli, C. Offord, R. Myers, K. W. Peng, T. W. Carr, K. Josic, S. J. Russell and Z. Bajzer, Dynamics of multiple myeloma tumor therapy with a recombinant measles virus,, Cancer Gene Ther., 16 (2009), 873.  doi: 10.1038/cgt.2009.40.  Google Scholar

[12]

R. Eftimie, J. L. Bramson and D. J. Earn, Interactions between the immune system and cancer: A brief review of non-spatial mathematical models,, Bull. Math. Biol., 73 (2011), 2.  doi: 10.1007/s11538-010-9526-3.  Google Scholar

[13]

N. B. Elsedawy and S. J. Russell, Oncolytic vaccines,, Expert Rev. Vaccines, 12 (2013), 1155.  doi: 10.1586/14760584.2013.836912.  Google Scholar

[14]

A. Friedman, J. P. Tian, G. Fulci, E. A. Chiocca and J. Wang, Glioma virotherapy: Effects of innate immune suppression and increased viral replication capacity,, Cancer Res., 66 (2006), 2314.  doi: 10.1158/0008-5472.CAN-05-2661.  Google Scholar

[15]

I. Ganly, V. Mautner and A. Balmain, Productive replication of human adenoviruses in mouse epidermal cells,, J. Virol., 74 (2000), 2895.  doi: 10.1128/JVI.74.6.2895-2899.2000.  Google Scholar

[16]

D. Hanahan and R. A. Weinberg, Hallmarks of cancer: The next generation,, Cell, 144 (2011), 646.  doi: 10.1016/j.cell.2011.02.013.  Google Scholar

[17]

J. H. Huang, S. N. Zhang, K. J. Choi, I. K. Choi, J. H. Kim, M. G. Lee, M. Lee, H. Kim and C. O. Yun, Therapeutic and tumor-specific immunity induced by combination of dendritic cells and oncolytic adenovirus expressing IL-12 and 4-1BBL,, Mol. Ther., 18 (2010), 264.  doi: 10.1038/mt.2009.205.  Google Scholar

[18]

C. Jogler, D. Hoffmann, D. Theegarten, T. Grunwald, K. Uberla and O. Wildner, Replication properties of human adenovirus in vivo and in cultures of primary cells from different animal species,, J. Virol., 80 (2006), 3549.  doi: 10.1128/JVI.80.7.3549-3558.2006.  Google Scholar

[19]

H. L. Kaufman and S. D. Bines, OPTIM trial: A Phase III trial of an oncolytic herpes virus encoding GM-CSF for unresectable stage III or IV melanoma,, Future Oncol., 6 (2010), 941.  doi: 10.2217/fon.10.66.  Google Scholar

[20]

N. L. Komarova and D. Wodarz, ODE models for oncolytic virus dynamics,, J. Theor. Biol., 263 (2010), 530.  doi: 10.1016/j.jtbi.2010.01.009.  Google Scholar

[21]

N. Kronik, Y. Kogan, M. Elishmereni, K. Halevi-Tobias, S. Vuk-Pavlović and A. Agur, Predicting outcomes of prostate cancer immunotherapy by personalized mathematical models,, PLoS ONE, 5 (2010).  doi: 10.1371/journal.pone.0015482.  Google Scholar

[22]

F. Le Bœuf, C. Batenchuk, M. Vähä-Koskela, S. Breton, D. Roy, C. Lemay, J. Cox, H. Abdelbary, T. Falls, G. Waghray, H. Atkins, D. Stojdl, J. S. Diallo, M. Kærn and J. C. Bell, Model-based rational design of an oncolytic virus with improved therapeutic potential,, Nat. Commun., 4 (2013).   Google Scholar

[23]

F. Le Bœuf, J. S. Diallo, J. A. McCart, S. Thorne, T. Falls, M. Stanford, F. Kanji, R. Auer, C. W. Brown, B. D. and Lichty, K. Parato, H. Atkins, D. Kirn and J. C. Bell, Synergistic interaction between oncolytic viruses augments tumor killing,, Mol. Ther., 18 (2010), 888.   Google Scholar

[24]

D. Leopardo, S. C. Cecere, M. Di Napoli, C. Cavaliere, C. Pisano, S. Striano, L. Marra, L. Menna, L. Claudio, S. Perdona, S. Setola, M. Berretta, R. Franco, R. Tambaro, S. Pignata and G. Facchini, Intravesical chemo-immunotherapy in non muscle invasive bladder cancer,, Eur. Rev. Med. Pharmacol. Sci., 17 (2013), 2145.   Google Scholar

[25]

H. L. Li, S. Li, J. Y. Shao, X. B. Lin, Y. Cao, W. Q. Jiang, R. Y. Liu, P. Zhao, X. F. Zhu, M. S. Zeng, Z. Z. Guan and W. Huang, Pharmacokinetic and pharmacodynamic study of intratumoral injection of an adenovirus encoding endostatin in patients with advanced tumors,, Gene Ther., 15 (2008), 247.  doi: 10.1038/sj.gt.3303038.  Google Scholar

[26]

D. G. Mallet and L. G. De Pillis, A cellular automata model of tumor-immune system interactions,, J. Theor. Biol., 239 (2006), 334.  doi: 10.1016/j.jtbi.2005.08.002.  Google Scholar

[27]

A. Melcher, K. Parato, C. M. Rooney and J. C. Bell, Thunder and lightning: Immunotherapy and oncolytic viruses collide,, Mol. Ther., 19 (2011), 1008.  doi: 10.1038/mt.2011.65.  Google Scholar

[28]

W. Mok, T. Stylianopoulos, Y. Boucher and R. K. Jain, Mathematical modeling of herpes simplex virus distribution in solid tumors: implications for cancer gene therapy,, Clin. Cancer Res., 15 (2009), 2352.  doi: 10.1158/1078-0432.CCR-08-2082.  Google Scholar

[29]

D. M. Rommelfanger, C. P. Offord, J. Dev, Z. Bajzer, R. G. Vile and D. Dingli, Dynamics of melanoma tumor therapy with vesicular stomatitis virus: Explaining the variability in outcomes using mathematical modeling,, Gene Ther., 19 (2012), 543.  doi: 10.1038/gt.2011.132.  Google Scholar

[30]

S. J. Russell, K. W. Peng and J. C. Bell, Oncolytic virotherapy,, Nat. Biotechnol., 30 (2012), 658.  doi: 10.1038/nbt.2287.  Google Scholar

[31]

J. R. Tysome, X. Li, S. Wang, P. Wang, D. Gao, P. Du, D. Chen, R. Gangeswaran, L. S. Chard, M. Yuan, G. Alusi, N. R. Lemoine and Y. Wang, A novel therapeutic regimen to eradicate established solid tumors with an effective induction of tumor-specific immunity,, Clin. Cancer Res., 18 (2012), 6679.  doi: 10.1158/1078-0432.CCR-12-0979.  Google Scholar

[32]

M. J. van Stipdonk, E. E. Lemmens and S. P. Schoenberger, Naïve CTLs require a single brief period of antigenic stimulation for clonal expansion and differentiation,, Nat. Immunol., 2 (2001), 423.   Google Scholar

[33]

H. Veiga-Fernandes, U. Walter, C. Bourgeois, A. McLean and B. Rocha, Response of naïve and memory CD8+ T cells to antigen stimulation in vivo,, Nat. Immunol., 1 (2000), 47.   Google Scholar

[34]

Y. Wang, H. Wang, C. Y. Li and F. Yuan, Effects of rate, volume, and dose of intratumoral infusion on virus dissemination in local gene delivery,, Mol. Cancer Ther., 5 (2006), 362.  doi: 10.1158/1535-7163.MCT-05-0266.  Google Scholar

[35]

D. Wodarz, Viruses as antitumor weapons: Defining conditions for tumor remission,, Cancer Res., 61 (2001), 3501.   Google Scholar

[36]

D. Wodarz, Computational modeling approaches to studying the dynamics of oncolytic viruses,, Math. Biosci. Eng., 10 (2013), 939.  doi: 10.3934/mbe.2013.10.939.  Google Scholar

[37]

D. Wodarz and N. Komarova, Towards predictive computational models of oncolytic virus therapy: basis for experimental validation and model selection,, PLoS ONE, 4 (2009).  doi: 10.1371/journal.pone.0004271.  Google Scholar

[38]

J. D. Wolchok, H. Kluger, M. K. Callahan, M. A. Postow, N. A. Rizvi, A. M. Lesokhin, N. H. Segal, C. E. Ariyan, R. A. Gordon, K. Reed, M. M. Burke, A. Caldwell, S. A. Kronenberg, B. U. Agunwamba, X. Zhang, I. Lowy, H. D. Inzunza, W. Feely, C. E. Horak, Q. Hong, A. J. Korman, J. M. Wigginton, A. Gupta and M. Sznol, Nivolumab plus ipilimumab in advanced melanoma,, N. Engl. J. Med., 369 (2013), 122.  doi: 10.1056/NEJMoa1302369.  Google Scholar

[39]

S. Worgall, G. Wolff, E. Falck-Pedersen and R. G. Crystal, Innate immune mechanisms dominate elimination of adenoviral vectors following in vivo administration,, Hum. Gene Ther., 8 (1997), 37.   Google Scholar

[40]

J. T. Wu, D. H. Kirn and L. M. Wein, Analysis of a three-way race between tumor growth, a replication-competent virus and an immune response,, Bull. Math. Biol., 66 (2004), 605.  doi: 10.1016/j.bulm.2003.08.016.  Google Scholar

[41]

W. Zhang, G. Fulci, H. Wakimoto, T. A. Cheema, J. S. Buhrman, D. S. Jeyaretna, A. O. Stemmer Rachamimov, S. D. Rabkin and R. L. Martuza, Combination of oncolytic herpes simplex viruses armed with angiostatin and IL-12 enhances antitumor efficacy in human glioblastoma models,, Neoplasia, 15 (2013), 591.   Google Scholar

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