2015, 12(6): 1237-1256. doi: 10.3934/mbe.2015.12.1237

Treatment strategies for combining immunostimulatory oncolytic virus therapeutics with dendritic cell injections

1. 

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

2. 

Weill Cornell Medical College, New York, NY

3. 

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

4. 

Department of Mathematics and Statistics, The College of New Jersey, Ewing, NJ, United States

5. 

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

Received  October 2014 Revised  March 2015 Published  August 2015

Oncolytic viruses (OVs) are used to treat cancer, as they selectively replicate inside of and lyse tumor cells. The efficacy of this process is limited and new OVs are being designed to mediate tumor cell release of cytokines and co-stimulatory molecules, which attract cytotoxic T cells to target tumor cells, thus increasing the tumor-killing effects of OVs. To further promote treatment efficacy, OVs can be combined with other treatments, such as was done by Huang et al., who showed that combining OV injections with dendritic cell (DC) injections was a more effective treatment than either treatment alone. To further investigate this combination, we built a mathematical model consisting of a system of ordinary differential equations and fit the model to the hierarchical data provided from Huang et al. We used the model to determine the effect of varying doses of OV and DC injections and to test alternative treatment strategies. We found that the DC dose given in Huang et al. was near a bifurcation point and that a slightly larger dose could cause complete eradication of the tumor. Further, the model results suggest that it is more effective to treat a tumor with immunostimulatory oncolytic viruses first and then follow-up with a sequence of DCs than to alternate OV and DC injections. This protocol, which was not considered in the experiments of Huang et al., allows the infection to initially thrive before the immune response is enhanced. Taken together, our work shows how the ordering, temporal spacing, and dosage of OV and DC can be chosen to maximize efficacy and to potentially eliminate tumors altogether.
Citation: Joanna R. Wares, Joseph J. Crivelli, Chae-Ok Yun, Il-Kyu Choi, Jana L. Gevertz, Peter S. Kim. Treatment strategies for combining immunostimulatory oncolytic virus therapeutics with dendritic cell injections. Mathematical Biosciences & Engineering, 2015, 12 (6) : 1237-1256. doi: 10.3934/mbe.2015.12.1237
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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.

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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.

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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.

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show all references

References:
[1]

J. W. Ady, J. Heffner, K. Mojica, C. Johnsen, L. J. Belin, D. Love, C. T. Chen, A. Pugalenthi, E. Klein, N. G. Chen, Y. A. Yu, A. A. Szalay and Y. Fong, Oncolytic immunotherapy using recombinant vaccinia virus GLV-1h68 kills sorafenib-resistant hepatocellular carcinoma efficiently,, Surgery, 156 (2014), 263. doi: 10.1016/j.surg.2014.03.031.

[2]

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.

[3]

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.

[4]

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.

[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.

[6]

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.

[7]

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.

[8]

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.

[9]

L. de Pillis, A. Gallegos and A. Radunskaya, A model of dendritic cell therapy for melanoma,, Front Oncol, 3 (2013).

[10]

L. G. de Pillis, A. E. Radunskaya and C. L. Wiseman, A validated mathematical model of cell-mediated immune response to tumor growth,, Cancer Res., 67 (2007). doi: 10.1158/0008-5472.CAN-07-1403.

[11]

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. doi: 10.1158/1078-0432.CCR-07-0776.

[12]

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.

[13]

R. M. Eager and J. Nemunaitis, Clinical development directions in oncolytic viral therapy,, Cancer Gene Ther., 18 (2011), 305. doi: 10.1038/cgt.2011.7.

[14]

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.

[15]

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

[16]

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.

[17]

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.

[18]

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.

[19]

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.

[20]

P. H. Kim, T. I. Kim, J. W. Yockman, S. W. Kim and C. O. Yun, The effect of surface modification of adenovirus with an arginine-grafted bioreducible polymer on transduction efficiency and immunogenicity in cancer gene therapy,, Biomaterials, 31 (2010), 1865. doi: 10.1016/j.biomaterials.2009.11.043.

[21]

P. H. Kim, J. H. Sohn, J. W. Choi, Y. Jung, S. W. Kim, S. Haam and C. O. Yun, Active targeting and safety profile of PEG-modified adenovirus conjugated with herceptin,, Biomaterials, 32 (2011), 2314. doi: 10.1016/j.biomaterials.2010.10.031.

[22]

P. S. Kim, J. J. Crivelli, I. K. Choi, C. O. Yun and J. R. Wares, Quantitative impact of immunomodulation versus oncolysis with cytokine-expressing virus therapeutics,, (submitted)., ().

[23]

D. Kirn, R. L. Martuza and J. Zwiebel, Replication-selective virotherapy for cancer: Biological principles, risk management and future directions,, Nat. Med., 7 (2001), 781.

[24]

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.

[25]

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

[26]

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).

[27]

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

[28]

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.

[29]

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.

[30]

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.

[31]

T. S. Miest and R. Cattaneo, New viruses for cancer therapy: Meeting clinical needs,, Nat. Rev. Microbiol., 12 (2014), 23. doi: 10.1038/nrmicro3140.

[32]

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.

[33]

F. Pappalardo, M. Pennisi, A. Ricupito, F. Topputo and M. Bellone, Induction of T-cell memory by a dendritic cell vaccine: A computational model,, Bioinformatics, 30 (2014), 1884. doi: 10.1093/bioinformatics/btu059.

[34]

M. Robertson-Tessi, A. El-Kareh and A. Goriely, A mathematical model of tumor-immune interactions,, J. Theor. Biol., 294 (2012), 56. doi: 10.1016/j.jtbi.2011.10.027.

[35]

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.

[36]

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

[37]

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.

[38]

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.

[39]

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.

[40]

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.

[41]

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

[42]

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.

[43]

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.

[44]

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.

[45]

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.

[46]

M. Zeyaullah, M. Patro, I. Ahmad, K. Ibraheem, P. Sultan, M. Nehal and A. Ali, Oncolytic viruses in the treatment of cancer: A review of current strategies,, Pathol. Oncol. Res., 18 (2012), 771. doi: 10.1007/s12253-012-9548-2.

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