American Institute of Mathematical Sciences

Advanced
June  2022, 27(6): 3261-3295. doi: 10.3934/dcdsb.2021184

On a mathematical model of tumor-immune system interactions with an oncolytic virus therapy

Sophia R-J Jang 1,, and  Hsiu-Chuan Wei 2,

1. 

Department of Mathematics and Statistics, Texas Tech University, Lubbock, TX 79409, USA
2. 

Department of Applied Mathematics, Feng Chia University, Taichung 40724, Taiwan

* Corresponding author: Sophia R-J Jang

Received  January 2021 Revised  April 2021 Published  June 2022 Early access  July 2021

We investigate a mathematical model of tumor–immune system interactions with oncolytic virus therapy (OVT). Susceptible tumor cells may become infected by viruses that are engineered specifically to kill cancer cells but not healthy cells. Once the infected cancer cells are destroyed by oncolysis, they release new infectious virus particles to help kill surrounding tumor cells. The immune system constructed includes innate and adaptive immunities while the adaptive immunity is further separated into anti-viral or anti-tumor immune cells. The model is first analyzed by studying boundary equilibria and their stability. Numerical bifurcation analysis is performed to investigate the outcomes of the oncolytic virus therapy. The model has a unique tumor remission equilibrium, which is unlikely to be stable based on the parameter values given in the literature. Multiple stable positive equilibria with tumor sizes close to the carrying capacity coexist in the system if the tumor is less antigenic. However, as the viral infection rate increases, the OVT becomes more effective in the sense that the tumor can be dormant for a longer period of time even when the tumor is weakly antigenic.

Keywords: Tumor, immune system, oncolytic virus therapy, anti-tumor immunity, anti-viral immunity, global asymptotic stability.
Mathematics Subject Classification: Primary: 92D25, 92B05.
Citation: Sophia R-J Jang, Hsiu-Chuan Wei. On a mathematical model of tumor-immune system interactions with an oncolytic virus therapy. Discrete and Continuous Dynamical Systems - B, 2022, 27 (6) : 3261-3295. doi: 10.3934/dcdsb.2021184
References:
[1]

J. Aguirre-Ghiso, Models, mechanisms and clinical evidence for cancer dormancy, Nat. Rev. Cancer, 7 (2007), 834-846.  doi: 10.1038/nrc2256.

[2]

B. K. Al-Ramadi, M. J. Fernandez-Cabezudo, H. El-Hasasna, S. Al-Salam, S. Attoub, D. Xu and S. Chouaib, Attenuated bacteria as effectors in cancer immunotherapy, N.Y. Acad. Sci, 1138 (2008), 351-357.  doi: 10.1196/annals.1414.036.

[3]

L. Allen, An Introduction to Mathematical Biology, Prentice-Hall, New Jersey, 2006.

[4]

K. S. Cheng, S. B. Hsu and S. Lin, Some results on global stability of a predator-prey system, J. Math. Biol., 12 (1981), 115-126.  doi: 10.1007/BF00275207.

[5]

M.-H. Chou, H.-C. Wei and Y.-T. Lin, Oregonator-based simulation of the Belousov-Zhabotinskii reaction, Int. J. Bifurc. Chaos Appl. Sci. Eng., 17 (2007), 4337-4353.  doi: 10.1142/S0218127407019998.

[6]

B. S. Choudhury and B. Nasipuri, Efficient virotherapy of cancer in the presence of immune response, Int. J. Dynam. Control, 2 (2014), 314-325.  doi: 10.1007/s40435-013-0035-8.

[7]

A. L. de Matos, L. S. Lranco and G. McFadden, Oncolytic viruses and the immune system: The dynamic duo, Mol. Ther. Methods Clin. Dev., 17 (2020), 349-358.  doi: 10.1016/j.omtm.2020.01.001.

[8]

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., 65 (2005), 7950-7958.  doi: 10.1158/0008-5472.CAN-05-0564.

[9]

R. Eftimie, J. Dushoff, B. W. Bridle, J. L. Bramson and D. J. D. Earn, Multi-stability and multi-instability phenomena in a mathematical model of tumor-immune-virus interactions, Bull. Math. Biol., 73 (2011), 2932-2961.  doi: 10.1007/s11538-011-9653-5.

[10]

R. Eftimie and G. Eftimie, Tumour-associated macrophages and oncolytic virotherapies: A mathematical investigation into a complex dynamics, Lett. Biomath., 5 (2018), 6-35.  doi: 10.30707/LiB5.2Eftimiea.

[11]

H. Fukuhara, Y. Ino and T. Todo, Oncolytic virus therapy: A new era of cancer treatment at dawn, Cancer Sci., 107 (2016), 1373-1379.  doi: 10.1111/cas.13027.

[12]

H. Fukuhara and T. Todo, Oncolytic herpes simplex virus type 1 and host immune responses, Curr. Cancer Drug Targets, 7 (2007), 149-155.  doi: 10.2174/156800907780058907.

[13]

T. F. Gajewski, H. Schreiber and Y.-X. Fu, Innate and adaptive immune cells in the tumor microenvironment, Nat. Immunol., 14 (2013), 1014-1022.  doi: 10.1038/ni.2703.

[14]

S. Gujar, J. G. Pol, Y. Kim, P. W. Lee and G. Kroemer, Antitumor benefits of antiviral immunity: An underappreciated aspect of oncolytic virotherapies, Trends Immunol., 39 (2018), 209-221.  doi: 10.1016/j.it.2017.11.006.

[15]

Y. Guo, B. Niu and J. Tian, Backward Hopf bifurcation in a mathematical model for oncolytic virotherapy with the infection delay and innate immune effects, J. Biol. Dyn., 13 (2019), 733-748.  doi: 10.1080/17513758.2019.1667443.

[16]

D. Haddad, Genetically engineered vaccinia viruses as agents for cancer, treatment, imaging, and transgene delivery, Front. Oncol., 7 (2017), 1-12.  doi: 10.3389/fonc.2017.00096.

[17] B. Ingalls, Mathematical Modeling in Systems Biology: An Introduction, The MIT Press, Cambridge, 2013. 
[18]

S. R.-J. Jang and H.-C. Wei, Deterministic predator-prey models with disease in the prey population, J. Biol. Syst., 28 (2020), 751-784.  doi: 10.1142/S0218339020500151.

[19]

A. L. Jenner, C.-O. Yun, P. S. Kim and A. C. F. Coster, Mathematical modelling of the interaction between cancer cells and an oncolytic virus: Insights into the effects of treatment protocols, Bull. Math. Biol., 80 (2018), 1615-1629.  doi: 10.1007/s11538-018-0424-4.

[20]

J. M. Jeschke, M. Kopp and R. Tollrian, Consumer-food systems: why type I functional responses are exclusive to filter feeders, Biol. Rev., 79 (2004), 337-349.  doi: 10.1017/S1464793103006286.

[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), 2314-2326.  doi: 10.1016/j.biomaterials.2010.10.031.

[22]

Y. Kitajima and K. Miyazaki, The critical impact of HIF-1a on gastric cancer biology, Cancers, 5 (2013), 15-26.  doi: 10.3390/cancers5010015.

[23]

N. L. Komarova and D. Wodarz, ODE models for oncolytic virus dynamics, J. Theor. Biol., 263 (2010), 530-543.  doi: 10.1016/j.jtbi.2010.01.009.

[24]

Y. Kuang and H. I. Freedman, Uniqueness of limit cycles in Gause-type models of predator-prey systems, Math. Biosci., 88 (1988), 67-84.  doi: 10.1016/0025-5564(88)90049-1.

[25]

H. -Z. Li, X. -D. Liu, R. Yan and C. Liu, Hopf bifurcation analysis of a tumor virotherapy model with two time delays, Physica A, 553 (2020), 124266. doi: 10.1016/j. physa. 2020.124266.

[26]

J. Li, J.-N. Chen, T.-T. Zeng, F. He, S.-P. Chen, S. Ma, J. Bi, X.-F. Zhu and X.-Y. Guan, CD133+ liver cancer stem cells resist interferon-gamma-induced autophagy, BMC Cancer, 16 (2016), 1-11.  doi: 10.1186/s12885-016-2050-6.

[27]

X. Li and J.-X. Xu, A mathematical prognosis model for pancreatic cancer patients receiving immunotherapy, J. Theor. Biol., 406 (2016), 42-51.  doi: 10.1016/j.jtbi.2016.06.021.

[28]

Y. Louzoun, C. Xue, G. B. Lesinski and A. Friedman, A mathematical model for pancreatic cancer growth and treatments, J. Theor. Biol., 351 (2014), 74-82.  doi: 10.1016/j.jtbi.2014.02.028.

[29]

A. Magen, J. Nie, T. Ciucci and et al., Single-cell profiling defines transcriptomic signatures specific to tumor-reactive versus virus-responsive CD4$^+$ T cells, Cell Reports, 29 (2019), 3019-3032.  doi: 10.1016/j.celrep.2019.10.131.

[30]

K. J. Mahasa, A. Eladdadi, L. de Pillis and R. Ouifki, Oncolytic potency and reduced virus tumorspecificity in oncolytic virotherapy. A mathematical modelling approach, PLoS ONE, 12 (2017), e0184347, 1–25. doi: 10.1371/journal. pone. 0184347.

[31]

K. J. Mahasa, R. Ouifki, A. Eladdadi and L. de Pillis, Mathematical model of tumor-immune surveillance, J. Theor. Biol., 404 (2016), 312-330.  doi: 10.1016/j.jtbi.2016.06.012.

[32]

G. Marelli, A. Howells, N. R. Lemoine and Y. Wang, Oncolytic viral therapy and the immune system: A double-edged sword against cancer, Front. Immunol., 9 (2018), 1-9.  doi: 10.3389/fimmu.2018.00866.

[33]

D. McDonald and O. Levy, Innate immunity, in Clinical Immunology, 5th Edn., (eds R. Rich, T. Fleisher, W. Shearer, H. Schroeder), A. Frew, and C. Weyand (London: Elsevier), 2019, 39–53.

[34]

K. W. Okamoto, P. Amarasekare and I. T. D. Petty, Modeling oncolytic virotherapy: Is complete tumor-tropism too much of a good thing?, J. Theor. Biol., 358 (2014), 166-178.  doi: 10.1016/j.jtbi.2014.04.030.

[35]

A. Reynolds, J. Rubina, G. Clermont, J. Day, Y. Vodovotz and G. B. Ermentrout, A reduced mathematical model of the acute inflammatory response: I. Derivation of model and analysis of anti-inflammation, J. Theor. Biol., 242 (2006), 220-236.  doi: 10.1016/j.jtbi.2006.02.016.

[36]

E. Sadurska, Current views on anthracycline cardiotoxicity in childhood cancer survivors, Pediatr. Cardiol., 36 (2015), 1112-1119.  doi: 10.1007/s00246-015-1176-7.

[37]

L. A. Segel and M. Slemrod, The quasi-steady-state assumption: A case study in perturbation, SIAM Rev., 31 (1989), 446-477.  doi: 10.1137/1031091.

[38]

K. M. Storey, S. E. Lawler and T. L. Jackson, Modeling oncolytic viral therapy, immune checkpoint inhibition, and the complex dynamics of innate and adaptive immunity in glioblastoma treatment, Front. Physiol., 11 (2020), 1-18.  doi: 10.3389/fphys.2020.00151.

[39]

Y. Tao and Q. Guo, The competitive dynamics between tumor cells, a replication-competent virus and an immune response, J. Math. Biol., 51 (2005), 37-74.  doi: 10.1007/s00285-004-0310-6.

[40]

H. R. Thieme, Convergence results and a Poincare-Bendixson trichotomy for asymptotically autonomous differential equations, J. Math. Biol., 30 (1992), 755-763.  doi: 10.1007/BF00173267.

[41]

A. Timalsina, J. P. Tian and J. Wang, Mathematical and computational modeling for tumor virotherapy with meated immunity, Bull. Math. Biol., 79 (2017), 1736-1758.  doi: 10.1007/s11538-017-0304-3.

[42]

H.-C. Wei, Numerical revisit to a class of one-predator, two-prey models, Int. J. Bifurc. Chaos Appl. Sci. Eng., 20 (2010), 2521-2536.  doi: 10.1142/S0218127410027143.

[43]

H.-C. Wei, A modified numerical method for bifurcations of fixed points of ODE systems with periodically pulsed inputs, Appl. Math. Comput., 236 (2014), 373-383.  doi: 10.1016/j.amc.2014.03.054.

[44]

H.-C. Wei, A mathematical model of intraguild predation with prey switching, Math. Comput. Simul., 165 (2019), 107-118.  doi: 10.1016/j.matcom.2019.03.004.

[45]

S. Wiggins, Introduction to Applied Nonlinear Dynamical Systems and Chaos, Springer, New York, 2003.

[46]

D. Wodarz, Viruses as antitumor weapons, Cancer Res., 61 (2001), 3501-3507. 

[47]

D. Wodarz and N. Komarova, Towards predictive computational models of oncolytic virus therapy: Basis for experimental validation and model selection, PLoS ONE, 4 (2009), e4217. doi: 10.1371/journal. pone. 0004271.

[48]

K. H. Wong, A. Lu, X. Chen and Z. Yang, Natural ingredient-based polymeric nanoparticles for cancer treatment, Molecules, 25 (2020), 3620. doi: 10.3390/molecules25163620.

[49]

J. T. Wu, H. M. Byrne, D. H. Kirn and L. M. Wein, Modeling and analysis of a virus that replicates selectively in tumor cells, Bull. Math. Biol., 63 (2001), 731-768.  doi: 10.1006/bulm.2001.0245.

show all references

References:
[1]

J. Aguirre-Ghiso, Models, mechanisms and clinical evidence for cancer dormancy, Nat. Rev. Cancer, 7 (2007), 834-846.  doi: 10.1038/nrc2256.

[2]

B. K. Al-Ramadi, M. J. Fernandez-Cabezudo, H. El-Hasasna, S. Al-Salam, S. Attoub, D. Xu and S. Chouaib, Attenuated bacteria as effectors in cancer immunotherapy, N.Y. Acad. Sci, 1138 (2008), 351-357.  doi: 10.1196/annals.1414.036.

[3]

L. Allen, An Introduction to Mathematical Biology, Prentice-Hall, New Jersey, 2006.

[4]

K. S. Cheng, S. B. Hsu and S. Lin, Some results on global stability of a predator-prey system, J. Math. Biol., 12 (1981), 115-126.  doi: 10.1007/BF00275207.

[5]

M.-H. Chou, H.-C. Wei and Y.-T. Lin, Oregonator-based simulation of the Belousov-Zhabotinskii reaction, Int. J. Bifurc. Chaos Appl. Sci. Eng., 17 (2007), 4337-4353.  doi: 10.1142/S0218127407019998.

[6]

B. S. Choudhury and B. Nasipuri, Efficient virotherapy of cancer in the presence of immune response, Int. J. Dynam. Control, 2 (2014), 314-325.  doi: 10.1007/s40435-013-0035-8.

[7]

A. L. de Matos, L. S. Lranco and G. McFadden, Oncolytic viruses and the immune system: The dynamic duo, Mol. Ther. Methods Clin. Dev., 17 (2020), 349-358.  doi: 10.1016/j.omtm.2020.01.001.

[8]

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., 65 (2005), 7950-7958.  doi: 10.1158/0008-5472.CAN-05-0564.

[9]

R. Eftimie, J. Dushoff, B. W. Bridle, J. L. Bramson and D. J. D. Earn, Multi-stability and multi-instability phenomena in a mathematical model of tumor-immune-virus interactions, Bull. Math. Biol., 73 (2011), 2932-2961.  doi: 10.1007/s11538-011-9653-5.

[10]

R. Eftimie and G. Eftimie, Tumour-associated macrophages and oncolytic virotherapies: A mathematical investigation into a complex dynamics, Lett. Biomath., 5 (2018), 6-35.  doi: 10.30707/LiB5.2Eftimiea.

[11]

H. Fukuhara, Y. Ino and T. Todo, Oncolytic virus therapy: A new era of cancer treatment at dawn, Cancer Sci., 107 (2016), 1373-1379.  doi: 10.1111/cas.13027.

[12]

H. Fukuhara and T. Todo, Oncolytic herpes simplex virus type 1 and host immune responses, Curr. Cancer Drug Targets, 7 (2007), 149-155.  doi: 10.2174/156800907780058907.

[13]

T. F. Gajewski, H. Schreiber and Y.-X. Fu, Innate and adaptive immune cells in the tumor microenvironment, Nat. Immunol., 14 (2013), 1014-1022.  doi: 10.1038/ni.2703.

[14]

S. Gujar, J. G. Pol, Y. Kim, P. W. Lee and G. Kroemer, Antitumor benefits of antiviral immunity: An underappreciated aspect of oncolytic virotherapies, Trends Immunol., 39 (2018), 209-221.  doi: 10.1016/j.it.2017.11.006.

[15]

Y. Guo, B. Niu and J. Tian, Backward Hopf bifurcation in a mathematical model for oncolytic virotherapy with the infection delay and innate immune effects, J. Biol. Dyn., 13 (2019), 733-748.  doi: 10.1080/17513758.2019.1667443.

[16]

D. Haddad, Genetically engineered vaccinia viruses as agents for cancer, treatment, imaging, and transgene delivery, Front. Oncol., 7 (2017), 1-12.  doi: 10.3389/fonc.2017.00096.

[17] B. Ingalls, Mathematical Modeling in Systems Biology: An Introduction, The MIT Press, Cambridge, 2013. 
[18]

S. R.-J. Jang and H.-C. Wei, Deterministic predator-prey models with disease in the prey population, J. Biol. Syst., 28 (2020), 751-784.  doi: 10.1142/S0218339020500151.

[19]

A. L. Jenner, C.-O. Yun, P. S. Kim and A. C. F. Coster, Mathematical modelling of the interaction between cancer cells and an oncolytic virus: Insights into the effects of treatment protocols, Bull. Math. Biol., 80 (2018), 1615-1629.  doi: 10.1007/s11538-018-0424-4.

[20]

J. M. Jeschke, M. Kopp and R. Tollrian, Consumer-food systems: why type I functional responses are exclusive to filter feeders, Biol. Rev., 79 (2004), 337-349.  doi: 10.1017/S1464793103006286.

[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), 2314-2326.  doi: 10.1016/j.biomaterials.2010.10.031.

[22]

Y. Kitajima and K. Miyazaki, The critical impact of HIF-1a on gastric cancer biology, Cancers, 5 (2013), 15-26.  doi: 10.3390/cancers5010015.

[23]

N. L. Komarova and D. Wodarz, ODE models for oncolytic virus dynamics, J. Theor. Biol., 263 (2010), 530-543.  doi: 10.1016/j.jtbi.2010.01.009.

[24]

Y. Kuang and H. I. Freedman, Uniqueness of limit cycles in Gause-type models of predator-prey systems, Math. Biosci., 88 (1988), 67-84.  doi: 10.1016/0025-5564(88)90049-1.

[25]

H. -Z. Li, X. -D. Liu, R. Yan and C. Liu, Hopf bifurcation analysis of a tumor virotherapy model with two time delays, Physica A, 553 (2020), 124266. doi: 10.1016/j. physa. 2020.124266.

[26]

J. Li, J.-N. Chen, T.-T. Zeng, F. He, S.-P. Chen, S. Ma, J. Bi, X.-F. Zhu and X.-Y. Guan, CD133+ liver cancer stem cells resist interferon-gamma-induced autophagy, BMC Cancer, 16 (2016), 1-11.  doi: 10.1186/s12885-016-2050-6.

[27]

X. Li and J.-X. Xu, A mathematical prognosis model for pancreatic cancer patients receiving immunotherapy, J. Theor. Biol., 406 (2016), 42-51.  doi: 10.1016/j.jtbi.2016.06.021.

[28]

Y. Louzoun, C. Xue, G. B. Lesinski and A. Friedman, A mathematical model for pancreatic cancer growth and treatments, J. Theor. Biol., 351 (2014), 74-82.  doi: 10.1016/j.jtbi.2014.02.028.

[29]

A. Magen, J. Nie, T. Ciucci and et al., Single-cell profiling defines transcriptomic signatures specific to tumor-reactive versus virus-responsive CD4$^+$ T cells, Cell Reports, 29 (2019), 3019-3032.  doi: 10.1016/j.celrep.2019.10.131.

[30]

K. J. Mahasa, A. Eladdadi, L. de Pillis and R. Ouifki, Oncolytic potency and reduced virus tumorspecificity in oncolytic virotherapy. A mathematical modelling approach, PLoS ONE, 12 (2017), e0184347, 1–25. doi: 10.1371/journal. pone. 0184347.

[31]

K. J. Mahasa, R. Ouifki, A. Eladdadi and L. de Pillis, Mathematical model of tumor-immune surveillance, J. Theor. Biol., 404 (2016), 312-330.  doi: 10.1016/j.jtbi.2016.06.012.

[32]

G. Marelli, A. Howells, N. R. Lemoine and Y. Wang, Oncolytic viral therapy and the immune system: A double-edged sword against cancer, Front. Immunol., 9 (2018), 1-9.  doi: 10.3389/fimmu.2018.00866.

[33]

D. McDonald and O. Levy, Innate immunity, in Clinical Immunology, 5th Edn., (eds R. Rich, T. Fleisher, W. Shearer, H. Schroeder), A. Frew, and C. Weyand (London: Elsevier), 2019, 39–53.

[34]

K. W. Okamoto, P. Amarasekare and I. T. D. Petty, Modeling oncolytic virotherapy: Is complete tumor-tropism too much of a good thing?, J. Theor. Biol., 358 (2014), 166-178.  doi: 10.1016/j.jtbi.2014.04.030.

[35]

A. Reynolds, J. Rubina, G. Clermont, J. Day, Y. Vodovotz and G. B. Ermentrout, A reduced mathematical model of the acute inflammatory response: I. Derivation of model and analysis of anti-inflammation, J. Theor. Biol., 242 (2006), 220-236.  doi: 10.1016/j.jtbi.2006.02.016.

[36]

E. Sadurska, Current views on anthracycline cardiotoxicity in childhood cancer survivors, Pediatr. Cardiol., 36 (2015), 1112-1119.  doi: 10.1007/s00246-015-1176-7.

[37]

L. A. Segel and M. Slemrod, The quasi-steady-state assumption: A case study in perturbation, SIAM Rev., 31 (1989), 446-477.  doi: 10.1137/1031091.

[38]

K. M. Storey, S. E. Lawler and T. L. Jackson, Modeling oncolytic viral therapy, immune checkpoint inhibition, and the complex dynamics of innate and adaptive immunity in glioblastoma treatment, Front. Physiol., 11 (2020), 1-18.  doi: 10.3389/fphys.2020.00151.

[39]

Y. Tao and Q. Guo, The competitive dynamics between tumor cells, a replication-competent virus and an immune response, J. Math. Biol., 51 (2005), 37-74.  doi: 10.1007/s00285-004-0310-6.

[40]

H. R. Thieme, Convergence results and a Poincare-Bendixson trichotomy for asymptotically autonomous differential equations, J. Math. Biol., 30 (1992), 755-763.  doi: 10.1007/BF00173267.

[41]

A. Timalsina, J. P. Tian and J. Wang, Mathematical and computational modeling for tumor virotherapy with meated immunity, Bull. Math. Biol., 79 (2017), 1736-1758.  doi: 10.1007/s11538-017-0304-3.

[42]

H.-C. Wei, Numerical revisit to a class of one-predator, two-prey models, Int. J. Bifurc. Chaos Appl. Sci. Eng., 20 (2010), 2521-2536.  doi: 10.1142/S0218127410027143.

[43]

H.-C. Wei, A modified numerical method for bifurcations of fixed points of ODE systems with periodically pulsed inputs, Appl. Math. Comput., 236 (2014), 373-383.  doi: 10.1016/j.amc.2014.03.054.

[44]

H.-C. Wei, A mathematical model of intraguild predation with prey switching, Math. Comput. Simul., 165 (2019), 107-118.  doi: 10.1016/j.matcom.2019.03.004.

[45]

S. Wiggins, Introduction to Applied Nonlinear Dynamical Systems and Chaos, Springer, New York, 2003.

[46]

D. Wodarz, Viruses as antitumor weapons, Cancer Res., 61 (2001), 3501-3507. 

[47]

D. Wodarz and N. Komarova, Towards predictive computational models of oncolytic virus therapy: Basis for experimental validation and model selection, PLoS ONE, 4 (2009), e4217. doi: 10.1371/journal. pone. 0004271.

[48]

K. H. Wong, A. Lu, X. Chen and Z. Yang, Natural ingredient-based polymeric nanoparticles for cancer treatment, Molecules, 25 (2020), 3620. doi: 10.3390/molecules25163620.

[49]

J. T. Wu, H. M. Byrne, D. H. Kirn and L. M. Wein, Modeling and analysis of a virus that replicates selectively in tumor cells, Bull. Math. Biol., 63 (2001), 731-768.  doi: 10.1006/bulm.2001.0245.

Figure 1.  A schematic diagram of model (1), depicting the interactions between different populations is presented
Figure Options

Download full-size image

Download as PowerPoint slide

Figure 3.  One solution of the immune $ ZY_TY_V $ subsystem (8) is plotted to illustrate stabilization of the model, Proposition 3.2(b). The parameter values are given in text
Figure Options

Download full-size image

Download as PowerPoint slide

Figure 2.  The parameter values are $ h_T = 2.7\times 10^4, \ \delta_{YT} = 3.75\times 10^{-4}, \ r_T = 0.0192, \ a_{AT} = 0.0016 $ and $ k_{TA} = 1/24 $ taken from the baseline values in [38] to illustrate oscillations of the $ T_SY_T $ subsystem (5), where the time unit is an hour as given in [38]
Figure Options

Download full-size image

Download as PowerPoint slide

Figure 4.  The plots demonstrate the existence of positive equilibria for system (13), which corresponds to the positive intersections of equations (11) and (12). Dimensionless parameter values in (a) are $ h_T = 0.5, \ \delta_{YT} = 1, \ \hat Z = 0.5, \ a_{TZ} = 0.3 $ and $ a_{AT} = 1.6 $ with $ T_{S_c} = 0.833 $ so that $ g(0)<f(0) $ and $ \delta_{YT}<a_{AT} $. The black vertical line segment is the line $ T_S = T_{S_c} $. In (b), $ h_T = 0.1 $, $ \delta_{YT} = 0.5, \ \hat Z = 0.6, \ a_{TZ} = 0.1 $ and $ a_{AT} = 0.15 $ so that $ g(0)> f(0) $. The curves have two positive intersections
Figure Options

Download full-size image

Download as PowerPoint slide

Figure 5.  (a) Bifurcation diagram using $ \beta $ as the bifurcation parameter, where all other parameter values are the same as in (23). The dashed lines at $ \log(T_S) = -1 $ (blue), $ \log(T_S) = 8.7124 $ (green), and $ \log(T_S) = 3.9172 $ (cyan) represent the unstable equilibria $ E_0 $, $ E_1 $, and $ E_2 $, respectively. The black dashed line between $ E_2 $ and $ E_0 $ represents an unstable positive equilibrium. (b) and (c) are the time series of cell populations for $ \beta = 6\times 10^{-8} $. The other parameter values in (b) are same as those in (a) while $ a_{TZ} = 2.4 $, $ s_{ZR} = 4.8 $, $ \delta_{ZR} = 1.658 $, and $ a_{ZZ} = 4.8 $ in (c). The tick label -1 on the vertical axis represents a population level less than 0.1
Figure Options

Download full-size image

Download as PowerPoint slide

Figure 6.  (a) Bifurcation diagram using $ \beta $ and $ a_{AT} $ as the bifurcation parameters, where all other parameter values are the same as in (23). (b) A closer look at the bifurcation curves for $ \log(\beta)\in [-10.12,-9.97] $
Figure Options

Download full-size image

Download as PowerPoint slide

Figure 7.  (a) Bifurcation diagram using $ a_{AT} = 0.005 $ and $ \beta $ as the bifurcation parameters, where all other parameter values are the same as in (23). The blue dashed curve represents unstable positive equilibria and the red curve represents stable equilibria. The light blue and green curves represent stable limit cycles. (b) A closer look at the rectangle shown in (a)
Figure Options

Download full-size image

Download as PowerPoint slide

Figure 8.  Time series of cell populations for $ a_{AT} = 0.005 $ and (a) $ \beta = 9.4\times 10^{-9} $, (b) $ \beta = 9.4\times 10^{-9} $, and (c) $ \beta = 9.5\times 10^{-9} $. The tick label -1 on the vertical axis represents a population level less than 0.1
Figure Options

Download full-size image

Download as PowerPoint slide

Figure 9.  (a) Bifurcation diagram using $ a_{AT} = 0.008 $, $ a_{AI} = 0.1 $, and $ \beta $ and $ a_{AI} $ as the bifurcation parameters, where all other parameter values are the same as in (23). (b) Bifurcation diagram using $ a_{AT} = 0.008 $, $ a_{AI} = 0.1 $, $ b_{T} = 50 $, and $ \beta $ as the bifurcation parameter. The blue dashed curve represents unstable positive equilibria and the red curve represents stable equilibria. The green curve represents stable limit cycles. (c) Bifurcation diagram using $ \beta $ and $ r_T $ as the bifurcation parameters, where all other parameter values are the same as in (23)
Figure Options

Download full-size image

Download as PowerPoint slide

Table 2.  Equilibria of $ T_SZY_TY_V $ subsystem (10) and their biological interpretations
Equilibrium Interpretation
$ E_{30}=(0,0,0,0) $ Extinction of all cell populations
$ E_{31}=(1, 0,0,0) $ Susceptible tumor only
$ E_{32}=(\bar T_S, 0, \bar Y_S,0) $ Coexistence of susceptible tumor and anti-tumor immune cells
$ E_{33}=(0,\hat Z,\hat Y_T,\hat Y_V) $ Immune cells only
$ E_{34*}=(\tilde T_S, \hat Z, \tilde T_T, \hat Y_V) $ Coexistence of susceptible tumor and immune cells
Table Options

Download as excel

Equilibrium Interpretation
$ E_{30}=(0,0,0,0) $ Extinction of all cell populations
$ E_{31}=(1, 0,0,0) $ Susceptible tumor only
$ E_{32}=(\bar T_S, 0, \bar Y_S,0) $ Coexistence of susceptible tumor and anti-tumor immune cells
$ E_{33}=(0,\hat Z,\hat Y_T,\hat Y_V) $ Immune cells only
$ E_{34*}=(\tilde T_S, \hat Z, \tilde T_T, \hat Y_V) $ Coexistence of susceptible tumor and immune cells
Table 3.  Existence and stability of boundary equilibria of system (4)
Equilibrium Existence Asymptotic stability
$ E_{0} $ always unstable
$ E_{1} $ always $ s_{ZR}a_{ZZ}<\delta_Z\delta_{ZR} $, $ a_{AT}<\delta_{YT}(h_T+1) $, $ b_T<\omega $
$ E_{2} $ $ a_{AT}>\delta_{YT}(h_T+1) $ $ s_{ZR}a_{ZZ}<\delta_Z\delta_{ZR} $, $ \bar T_S>(1-h_T)/2 $, $ \omega(\delta_T+\bar Y_T/h_I)>h_T\delta_T\bar T_S $
$ E_{3} $ $ s_{ZR}a_{ZZ}>\delta_Z\delta_{ZR} $ $ \hat Y_T>h_T $
$ E_{4*} $ $ s_{ZR}a_{ZZ}>\delta_Z\delta_{ZR} $, $ h_T\geq 1 $, $ \hat Y_T<h_T $ $\eta < 0 < \tilde \eta $
$ s_{ZR}a_{ZZ}>\delta_Z\delta_{ZR} $, $ h_T<1 $, $ \hat Y_T<h_T $, $ a_{AT}>\delta_{YT} $
Table Options

Download as excel

Equilibrium Existence Asymptotic stability
$ E_{0} $ always unstable
$ E_{1} $ always $ s_{ZR}a_{ZZ}<\delta_Z\delta_{ZR} $, $ a_{AT}<\delta_{YT}(h_T+1) $, $ b_T<\omega $
$ E_{2} $ $ a_{AT}>\delta_{YT}(h_T+1) $ $ s_{ZR}a_{ZZ}<\delta_Z\delta_{ZR} $, $ \bar T_S>(1-h_T)/2 $, $ \omega(\delta_T+\bar Y_T/h_I)>h_T\delta_T\bar T_S $
$ E_{3} $ $ s_{ZR}a_{ZZ}>\delta_Z\delta_{ZR} $ $ \hat Y_T>h_T $
$ E_{4*} $ $ s_{ZR}a_{ZZ}>\delta_Z\delta_{ZR} $, $ h_T\geq 1 $, $ \hat Y_T<h_T $ $\eta < 0 < \tilde \eta $
$ s_{ZR}a_{ZZ}>\delta_Z\delta_{ZR} $, $ h_T<1 $, $ \hat Y_T<h_T $, $ a_{AT}>\delta_{YT} $
Table 1.  Existence and stability of equilibria of $ T_SZY_TY_V $ subsystem (10)
Equilibrium Existence Asymptotic stability
$ E_{30} $ Always Unstable
$ E_{31} $ Always $ s_{ZR}a_{ZZ}<\delta_{ZR}\delta_Z $ and $ a_{AT}<\delta_{YT}(h_T+1) $
$ E_{32} $ $ a_{AT}>\delta_{YT}(h_T+1) $ $ s_{ZR}a_{ZZ}<\delta_{ZR}\delta_Z $ and $ \bar T_S>(1-h_T)/2 $
$ E_{33} $ $ s_{ZR}a_{ZZ}>\delta_{ZR}\delta_Z $ $ \hat Y_T>h_T $ (i.e., $ a_{TZ}\hat Z>\delta_{YT}h_T $)
$ E_{34*} $ $ s_{ZR}a_{ZZ}>\delta_Z\delta_{ZR} $, $ h_T\geq 1 $, $ \hat Y_T<h_T $ $\eta < 0$
$ s_{ZR}a_{ZZ}>\delta_Z\delta_{ZR} $, $ h_T<1 $, $ \hat Y_T<h_T $, $ a_{AT}>\delta_{YT} $
* This is a case for which the positive equilibrium is unique. System (10) may have more than one positive equilibrium.
Table Options

Download as excel

Equilibrium Existence Asymptotic stability
$ E_{30} $ Always Unstable
$ E_{31} $ Always $ s_{ZR}a_{ZZ}<\delta_{ZR}\delta_Z $ and $ a_{AT}<\delta_{YT}(h_T+1) $
$ E_{32} $ $ a_{AT}>\delta_{YT}(h_T+1) $ $ s_{ZR}a_{ZZ}<\delta_{ZR}\delta_Z $ and $ \bar T_S>(1-h_T)/2 $
$ E_{33} $ $ s_{ZR}a_{ZZ}>\delta_{ZR}\delta_Z $ $ \hat Y_T>h_T $ (i.e., $ a_{TZ}\hat Z>\delta_{YT}h_T $)
$ E_{34*} $ $ s_{ZR}a_{ZZ}>\delta_Z\delta_{ZR} $, $ h_T\geq 1 $, $ \hat Y_T<h_T $ $\eta < 0$
$ s_{ZR}a_{ZZ}>\delta_Z\delta_{ZR} $, $ h_T<1 $, $ \hat Y_T<h_T $, $ a_{AT}>\delta_{YT} $
* This is a case for which the positive equilibrium is unique. System (10) may have more than one positive equilibrium.
Table 4.  Biological interpretations of boundary equilibria of full system (4)
Equilibrium Biological meaning
$ E_0=(0,0, 0, 0,0,0) $ Extinction of tumor, virus and immune cells
$ E_1=(1, 0,0,0,0,0) $ Susceptible tumor only
$ E_2=(\bar T_S, 0,0,0,\bar Y_T, 0) $ Coexistence of susceptible tumor and anti-tumor immune cells
$ E_{3}=(0,0,0,\hat Z, \hat Y_T, \hat Y_V) $ Immune cells only
$ E_{4}=(\tilde T_S, 0,0,\hat Z, \tilde Y_T, \hat Y_V) $ Coexistence of susceptible tumor and immune cells
Table Options

Download as excel

Equilibrium Biological meaning
$ E_0=(0,0, 0, 0,0,0) $ Extinction of tumor, virus and immune cells
$ E_1=(1, 0,0,0,0,0) $ Susceptible tumor only
$ E_2=(\bar T_S, 0,0,0,\bar Y_T, 0) $ Coexistence of susceptible tumor and anti-tumor immune cells
$ E_{3}=(0,0,0,\hat Z, \hat Y_T, \hat Y_V) $ Immune cells only
$ E_{4}=(\tilde T_S, 0,0,\hat Z, \tilde Y_T, \hat Y_V) $ Coexistence of susceptible tumor and immune cells
[1]

Jianjun Paul Tian. The replicability of oncolytic virus: Defining conditions in tumor virotherapy. Mathematical Biosciences & Engineering, 2011, 8 (3) : 841-860. doi: 10.3934/mbe.2011.8.841
[2]

Tao Feng, Zhipeng Qiu, Xinzhu Meng. Dynamics of a stochastic hepatitis C virus system with host immunity. Discrete and Continuous Dynamical Systems - B, 2019, 24 (12) : 6367-6385. doi: 10.3934/dcdsb.2019143
[3]

Zhikun She, Xin Jiang. Threshold dynamics of a general delayed within-host viral infection model with humoral immunity and two modes of virus transmission. Discrete and Continuous Dynamical Systems - B, 2021, 26 (7) : 3835-3861. doi: 10.3934/dcdsb.2020259
[4]

Urszula Ledzewicz, Heinz Schättler. On the optimality of singular controls for a class of mathematical models for tumor anti-angiogenesis. Discrete and Continuous Dynamical Systems - B, 2009, 11 (3) : 691-715. doi: 10.3934/dcdsb.2009.11.691
[5]

Heinz Schättler, Urszula Ledzewicz, Benjamin Cardwell. Robustness of optimal controls for a class of mathematical models for tumor anti-angiogenesis. Mathematical Biosciences & Engineering, 2011, 8 (2) : 355-369. doi: 10.3934/mbe.2011.8.355
[6]

Kentarou Fujie. Global asymptotic stability in a chemotaxis-growth model for tumor invasion. Discrete and Continuous Dynamical Systems - S, 2020, 13 (2) : 203-209. doi: 10.3934/dcdss.2020011
[7]

Dan Liu, Shigui Ruan, Deming Zhu. Bifurcation analysis in models of tumor and immune system interactions. Discrete and Continuous Dynamical Systems - B, 2009, 12 (1) : 151-168. doi: 10.3934/dcdsb.2009.12.151
[8]

Shujing Shi, Jicai Huang, Yang Kuang. Global dynamics in a tumor-immune model with an immune checkpoint inhibitor. Discrete and Continuous Dynamical Systems - B, 2021, 26 (2) : 1149-1170. doi: 10.3934/dcdsb.2020157
[9]

Manuel Delgado, Cristian Morales-Rodrigo, Antonio Suárez. Anti-angiogenic therapy based on the binding to receptors. Discrete and Continuous Dynamical Systems, 2012, 32 (11) : 3871-3894. doi: 10.3934/dcds.2012.32.3871
[10]

Urszula Ledzewicz, Helmut Maurer, Heinz Schättler. Optimal and suboptimal protocols for a mathematical model for tumor anti-angiogenesis in combination with chemotherapy. Mathematical Biosciences & Engineering, 2011, 8 (2) : 307-323. doi: 10.3934/mbe.2011.8.307
[11]

Filippo Cacace, Valerio Cusimano, Alfredo Germani, Pasquale Palumbo, Federico Papa. Closed-loop control of tumor growth by means of anti-angiogenic administration. Mathematical Biosciences & Engineering, 2018, 15 (4) : 827-839. doi: 10.3934/mbe.2018037
[12]

Cristian Morales-Rodrigo. A therapy inactivating the tumor angiogenic factors. Mathematical Biosciences & Engineering, 2013, 10 (1) : 185-198. doi: 10.3934/mbe.2013.10.185
[13]

Giulio Caravagna, Alex Graudenzi, Alberto d’Onofrio. Distributed delays in a hybrid model of tumor-Immune system interplay. Mathematical Biosciences & Engineering, 2013, 10 (1) : 37-57. doi: 10.3934/mbe.2013.10.37
[14]

Yueping Dong, Rinko Miyazaki, Yasuhiro Takeuchi. Mathematical modeling on helper T cells in a tumor immune system. Discrete and Continuous Dynamical Systems - B, 2014, 19 (1) : 55-72. doi: 10.3934/dcdsb.2014.19.55
[15]

Shigui Ruan. Nonlinear dynamics in tumor-immune system interaction models with delays. Discrete and Continuous Dynamical Systems - B, 2021, 26 (1) : 541-602. doi: 10.3934/dcdsb.2020282
[16]

Gladis Torres-Espino, Claudio Vidal. Periodic solutions of a tumor-immune system interaction under a periodic immunotherapy. Discrete and Continuous Dynamical Systems - B, 2021, 26 (8) : 4523-4547. doi: 10.3934/dcdsb.2020301
[17]

A. M. Elaiw, N. H. AlShamrani. Global stability of HIV/HTLV co-infection model with CTL-mediated immunity. Discrete and Continuous Dynamical Systems - B, 2022, 27 (3) : 1725-1764. doi: 10.3934/dcdsb.2021108
[18]

Jianquan Li, Xin Xie, Dian Zhang, Jia Li, Xiaolin Lin. Qualitative analysis of a simple tumor-immune system with time delay of tumor action. Discrete and Continuous Dynamical Systems - B, 2021, 26 (10) : 5227-5249. doi: 10.3934/dcdsb.2020341
[19]

Jianquan Li, Xiangxiang Ma, Yuming Chen, Dian Zhang. Complex dynamic behaviors of a tumor-immune system with two delays in tumor actions. Discrete and Continuous Dynamical Systems - B, 2022  doi: 10.3934/dcdsb.2022033
[20]

Martina Conte, Maria Groppi, Giampiero Spiga. Qualitative analysis of kinetic-based models for tumor-immune system interaction. Discrete and Continuous Dynamical Systems - B, 2018, 23 (6) : 2393-2414. doi: 10.3934/dcdsb.2018060

2021 Impact Factor: 1.497

Tools

Metrics

  • PDF downloads (490)
  • HTML views (707)
  • Cited by (0)

Other articles
by authors

[Back to Top]

Copyright © 2022 American Institute of Mathematical Sciences | Privacy Policy