Dynamics of Immune Checkpoints, Immune System, and BCG in the Treatment of Superficial Bladder Cancer

This paper aims to study the dynamics of immune suppressors/checkpoints, immune system, and BCG in the treatment of superficial bladder cancer. Programmed cell death protein-1 (PD-1), cytotoxic T-lymphocyte-associated antigen 4 (CTLA4), and transforming growth factor-beta (TGF-β) are some of the examples of immune suppressors/checkpoints. They are responsible for deactivating the immune system and enhancing immunological tolerance. Moreover, they categorically downregulate and suppress the immune system by preventing and blocking the activation of T-cells, which in turn decreases autoimmunity and enhances self-tolerance. In cancer immunotherapy, the immune checkpoints/suppressors prevent and block the immune cells from attacking, spreading, and killing the cancer cells, which leads to cancer growth and development. We formulate a mathematical model that studies three possible dynamics of the treatment and establish the effects of the immune checkpoints on the immune system and the treatment at large. Although the effect cannot be seen explicitly in the analysis of the model, we show it by numerical simulations.

[1]  J. Chaskalovic,et al.  A mathematical model of combined bacillus Calmette-Guerin (BCG) and interleukin (IL)-2 immunotherapy of superficial bladder cancer. , 2011, Journal of theoretical biology.

[2]  Yu Yao,et al.  Human cancer immunotherapy with antibodies to the PD-1 and PD-L1 pathway. , 2015, Trends in molecular medicine.

[3]  D. Lamm,et al.  Bacillus Calmette-Guerin immunotherapy of superficial bladder cancer. , 1980, The Journal of urology.

[4]  K. Starkov,et al.  Dynamical properties and tumor clearance conditions for a nine-dimensional model of bladder cancer immunotherapy. , 2016, Mathematical biosciences and engineering : MBE.

[5]  D. Kirschner,et al.  Modeling immunotherapy of the tumor – immune interaction , 1998, Journal of mathematical biology.

[6]  A. Böhle,et al.  Immune mechanisms in bacillus Calmette-Guerin immunotherapy for superficial bladder cancer. , 2003, The Journal of urology.

[7]  X. Zang,et al.  The PD-1/PD-L1 (B7-H1) Pathway in Chronic Infection-Induced Cytotoxic T Lymphocyte Exhaustion , 2011, Journal of biomedicine & biotechnology.

[8]  H. Niu,et al.  Effect of TLR4 and B7-H1 on immune escape of urothelial bladder cancer and its clinical significance. , 2014, Asian Pacific journal of cancer prevention : APJCP.

[9]  J. Wolchok,et al.  Immune Checkpoint Blockade in Cancer Therapy. , 2015, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[10]  CorrigendumCorrigendum to “A mathematical model of combined bacillus Calmette-Guerin (BCG) and interleukin(IL)-2immunotherapy of superficial bladder cancer” [J. Theor. Biol. 277(1) (2011) 27–40] , 2011 .

[11]  Subhas Khajanchi,et al.  A Mathematical Model to Elucidate Brain Tumor Abrogation by Immunotherapy with T11 Target Structure , 2014, PloS one.

[12]  Yoshimasa Tanaka,et al.  Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[13]  M. Glickman,et al.  The mechanism of action of BCG therapy for bladder cancer—a current perspective , 2014, Nature Reviews Urology.

[14]  M. Newton,et al.  Bladder Cancer Immunotherapy: BCG and Beyond , 2012, Advances in urology.

[15]  R. Kapoor,et al.  Bacillus Calmette-Guérin in the management of superficial bladder cancer , 2008, Indian journal of urology : IJU : journal of the Urological Society of India.

[16]  A. Yoshimura,et al.  TGF-β function in immune suppression. , 2010, Current topics in microbiology and immunology.

[17]  Svetlana Bunimovich-Mendrazitsky,et al.  Mathematical Model of BCG Immunotherapy in Superficial Bladder Cancer , 2007, Bulletin of mathematical biology.

[18]  S. Holmäng,et al.  Bacillus Calmette‐Guérin therapy in stage Ta/T1 bladder cancer: prognostic factors for time to recurrence and progression , 2004, BJU international.

[19]  Drew M. Pardoll,et al.  The blockade of immune checkpoints in cancer immunotherapy , 2012, Nature Reviews Cancer.

[20]  S. Halachmi,et al.  Improving Bacillus Calmette-Guérin (BCG) immunotherapy for bladder cancer by adding interleukin 2 (IL-2): a mathematical model. , 2016, Mathematical medicine and biology : a journal of the IMA.

[21]  H. Nishiyama,et al.  Bacillus Calmette–Guerin (BCG) immunotherapy for bladder cancer: Current understanding and perspectives on engineered BCG vaccine , 2013, Cancer science.

[22]  N. Vasdev,et al.  Immunotherapy for bladder cancer , 2015, Research and Reports in Urology.

[23]  G. Freeman,et al.  PD-1 and its ligands in tolerance and immunity. , 2008, Annual review of immunology.

[24]  G. Freeman,et al.  PD-L2 is a second ligand for PD-1 and inhibits T cell activation , 2001, Nature Immunology.

[25]  F. Paillard Immunosuppression mediated by tumor cells: a challenge for immunotherapeutic approaches. , 2000, Human gene therapy.

[26]  Svetlana Bunimovich-Mendrazitsky,et al.  Mathematical Model of Pulsed Immunotherapy for Superficial Bladder Cancer , 2008, Bulletin of mathematical biology.

[27]  L. Xerri,et al.  PD-1 is a novel regulator of human B-cell activation. , 2013, International Immunology.