A Mathematical Model to Elucidate Brain Tumor Abrogation by Immunotherapy with T11 Target Structure

T11 Target structure (T11TS), a membrane glycoprotein isolated from sheep erythrocytes, reverses the immune suppressed state of brain tumor induced animals by boosting the functional status of the immune cells. This study aims at aiding in the design of more efficacious brain tumor therapies with T11 target structure. We propose a mathematical model for brain tumor (glioma) and the immune system interactions, which aims in designing efficacious brain tumor therapy. The model encompasses considerations of the interactive dynamics of glioma cells, macrophages, cytotoxic T-lymphocytes (CD8+ T-cells), TGF-β, IFN-γ and the T11TS. The system undergoes sensitivity analysis, that determines which state variables are sensitive to the given parameters and the parameters are estimated from the published data. Computer simulations were used for model verification and validation, which highlight the importance of T11 target structure in brain tumor therapy.

[1]  J. Murray,et al.  Virtual brain tumours (gliomas) enhance the reality of medical imaging and highlight inadequacies of current therapy , 2002, British Journal of Cancer.

[2]  S. Chaudhuri,et al.  Preclinical Changes in Immunoreactivity and Cellular Architecture during the Progressive Development of Intracranial Neoplasms and an Immunotherapeutic Schedule with a Novel Biological Response Modifier, the T11TS / S-LFA3. , 2002, Asian Pacific journal of cancer prevention : APJCP.

[3]  S Torquato,et al.  Simulated brain tumor growth dynamics using a three-dimensional cellular automaton. , 2000, Journal of theoretical biology.

[4]  M. Nowak,et al.  Effect of Lamivudine on Human T-Cell Leukemia Virus Type 1 (HTLV-1) DNA Copy Number, T-Cell Phenotype, and Anti-Tax Cytotoxic T-Cell Frequency in Patients with HTLV-1-Associated Myelopathy , 1999, Journal of Virology.

[5]  S. Chaudhuri,et al.  CD2-SLFA3/T11TS interaction facilitates immune activation and glioma regression by apoptosis , 2004, Cancer biology & therapy.

[6]  J. Murray,et al.  The interaction of growth rates and diffusion coefficients in a three-dimensional mathematical model of gliomas. , 1997, Journal of neuropathology and experimental neurology.

[7]  J. Murray,et al.  Quantifying Efficacy of Chemotherapy of Brain Tumors with Homogeneous and Heterogeneous Drug Delivery , 2002, Acta biotheoretica.

[8]  R. Mirimanoff,et al.  Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. , 2009, The Lancet. Oncology.

[9]  WM Kast,et al.  Effects of TGF-β on the immune system: implications for cancer immunotherapy , 1999, Leukemia.

[10]  D. Kirschner,et al.  Contribution of CD8+ T cells to control of Mycobacterium tuberculosis infection. , 2006, The Journal of Immunology.

[11]  Thorsten M. Buzug,et al.  A Validated Mathematical Model of Tumour-Immune Interactions for Glioblastoma , 2013 .

[12]  Otto O. Yang,et al.  How Many Human Immunodeficiency Virus Type 1-Infected Target Cells Can a Cytotoxic T-Lymphocyte Kill? , 2005, Journal of Virology.

[13]  C. Schaller,et al.  Cancer cell invasion of brain tissue: guided by a prepattern? , 2005 .

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

[15]  N. Laperriere,et al.  Radiotherapy for newly diagnosed malignant glioma in adults: a systematic review. , 2002, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[16]  Salvatore Torquato,et al.  A Cellular Automaton Model of Brain Tumor Treatment and Resistance , 2002 .

[17]  J. Murray,et al.  A quantitative model for differential motility of gliomas in grey and white matter , 2000, Cell proliferation.

[18]  Moritz Diehl,et al.  A Mathematical Model for the Transport of Paclitaxel (Taxol) Across the Blood-Brain Barrier , 2007 .

[19]  R. Mirimanoff,et al.  Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. , 2005, The New England journal of medicine.

[20]  D. Kirschner,et al.  Contribution of CD8+ T Cells to Control of Mycobacterium tuberculosis Infection1 , 2006, The Journal of Immunology.

[21]  R. Coffey,et al.  Hepatic processing of transforming growth factor beta in the rat. Uptake, metabolism, and biliary excretion. , 1987, The Journal of clinical investigation.

[22]  Thomas S. Deisboeck,et al.  Complex systems science in biomedicine , 2006 .

[23]  Kristin R. Swanson,et al.  Virtual resection of gliomas: Effect of extent of resection on recurrence , 2003 .

[24]  W. Hickey Basic principles of immunological surveillance of the normal central nervous system , 2001, Glia.

[25]  F. Hanson,et al.  Distributed parameters deterministic model for treatment of brain tumors using Galerkin finite element method. , 2009, Mathematical biosciences.

[26]  J. Murray,et al.  A mathematical model of glioma growth: the effect of extent of surgical resection , 1996, Cell proliferation.

[27]  Neil G Burnet,et al.  A mathematical model of the treatment and survival of patients with high-grade brain tumours. , 2007, Journal of theoretical biology.

[28]  J. Pollock,et al.  The detection of CD2+, CD4+, CD8+, and WC1+ T lymphocytes, B cells and macrophages in fixed and paraffin embedded bovine tissue using a range of antigen recovery and signal amplification techniques. , 1999, Veterinary immunology and immunopathology.

[29]  Avner Friedman,et al.  miR451 and AMPK Mutual Antagonism in Glioma Cell Migration and Proliferation: A Mathematical Model , 2011, PloS one.

[30]  C. Kruse,et al.  Cellular and Functional Characterization of Immunoresistant Human Glioma Cell Clones Selected With Alloreactive Cytotoxic T Lymphocytes Reveals Their Up-regulated Synthesis of Biologically Active TGF-β , 2007, Journal of immunotherapy.

[31]  J. Blakeley Drug delivery to brain tumors , 2008, Current neurology and neuroscience reports.

[32]  A. Chalian,et al.  CD8 positive T cells influence antigen-specific immune responses through the expression of chemokines. , 1998, The Journal of clinical investigation.

[33]  J. Murray,et al.  A mathematical model of glioma growth: the effect of chemotherapy on spatio‐temporal growth , 1995, Cell proliferation.

[34]  Yuri Kogan,et al.  Improving alloreactive CTL immunotherapy for malignant gliomas using a simulation model of their interactive dynamics , 2008, Cancer Immunology, Immunotherapy.

[35]  B. Scheithauer,et al.  Histopathology, classification, and grading of gliomas , 1995, Glia.

[36]  K. Frei,et al.  Immunosuppression and transforming growth factor-beta in glioblastoma. Preferential production of transforming growth factor-beta 2. , 1989, Journal of immunology.

[37]  Kristin R. Swanson,et al.  Dynamics of a model for brain tumors reveals a small window for therapeutic intervention , 2003 .

[38]  K. Thielen,et al.  Glioblastoma, transforming growth factor-beta, and Candida meningitis: a potential link. , 1992, The American journal of medicine.

[39]  J. Panetta,et al.  Interferon-gamma pharmacokinetics and pharmacodynamics in patients with colorectal cancer , 2004, Cancer Chemotherapy and Pharmacology.

[40]  S. Steinberg,et al.  Tumor Progression Can Occur despite the Induction of Very High Levels of Self/Tumor Antigen-Specific CD8+ T Cells in Patients with Melanoma , 2005, The Journal of Immunology.

[41]  Thomas S. Deisboeck,et al.  Modeling Tumors as Complex Biosystems: An Agent-Based Approach , 2006 .

[42]  E. Kostelich,et al.  Virtual glioblastoma: growth, migration and treatment in a three‐dimensional mathematical model , 2009, Cell proliferation.

[43]  Webster K. Cavenee,et al.  The WHO Classification of Tumors of the Nervous System , 2002 .