Periodically Pulsed Immunotherapy in a Mathematical Model of Tumor, CD4+ T Cells, and Antitumor Cytokine Interactions

Immunotherapy is one of the most recent approaches for controlling and curing malignant tumors. In this paper, we consider a mathematical model of periodically pulsed immunotherapy using CD4+ T cells and an antitumor cytokine. Mathematical analyses are performed to determine the threshold of a successful treatment. The interindividual variability is explored by one-, two-, and three-parameter bifurcation diagrams for a nontreatment case. Numerical simulation conducted in this paper shows that (i) the tumor can be regulated by administering CD4+ T cells alone in a patient with a strong immune system or who has been diagnosed at an early stage, (ii) immunotherapy with a large amount of an antitumor cytokine can boost the immune system to remit or even to suppress tumor cells completely, and (iii) through polytherapy the tumor can be kept at a smaller size with reduced dosages.

[1]  J. Peterson,et al.  Inhibition of Angiogenesis by Interleukin 4 , 1998, The Journal of experimental medicine.

[2]  P. Foster,et al.  Immunotherapy of Cytotoxic T Cell–resistant Tumors by T Helper 2 Cells , 2003, The Journal of experimental medicine.

[3]  W. Heath,et al.  Induction of a CD8+ Cytotoxic T Lymphocyte Response by Cross-priming Requires Cognate CD4+ T Cell Help , 1997, The Journal of experimental medicine.

[4]  Hsiu-Chuan Wei,et al.  A modified numerical method for bifurcations of fixed points of ODE systems with periodically pulsed inputs , 2014, Appl. Math. Comput..

[5]  S. Rosenberg,et al.  Adoptive cell transfer as personalized immunotherapy for human cancer , 2015, Science.

[6]  M. Atkins Immunotherapy and experimental approaches for metastatic melanoma. , 1998, Hematology/oncology clinics of North America.

[7]  B. Fazekas de St. Groth,et al.  Tumour‐specific CD4 T cells eradicate melanoma via indirect recognition of tumour‐derived antigen , 2016, Immunology and cell biology.

[8]  A. Perelson,et al.  Nonlinear dynamics of immunogenic tumors: parameter estimation and global bifurcation analysis. , 1994, Bulletin of mathematical biology.

[9]  J. Wolchok,et al.  The mechanism of anti-CTLA-4 activity and the negative regulation of T-cell activation. , 2008, The oncologist.

[10]  P. Muranski,et al.  Naive tumor-specific CD4+ T cells differentiated in vivo eradicate established melanoma , 2010, The Journal of experimental medicine.

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

[12]  M. Raffeld,et al.  Cancer Regression and Autoimmunity in Patients After Clonal Repopulation with Antitumor Lymphocytes , 2002, Science.

[13]  T. Olencki,et al.  T-cell adoptive immunotherapy of metastatic renal cell carcinoma. , 1999, Urology.

[15]  C. Lowenstein,et al.  The Central Role of CD4+ T Cells in the Antitumor Immune Response , 1998, The Journal of experimental medicine.

[16]  P. Morrissey,et al.  Interleukin-4 (B-cell stimulatory factor-1) augments the in vivo generation of cytotoxic cells in immunosuppressed animals. , 1989, Biotechnology therapeutics.

[17]  Y. Kogan,et al.  Improving T-cell Immunotherapy for Melanoma Through a Mathematically Motivated Strategy: Efficacy in Numbers? , 2012, Journal of immunotherapy.

[18]  E. Bastiaannet,et al.  Radiation therapy following lymph node dissection in melanoma patients: treatment, outcome and complications. , 2005, Cancer treatment reviews.

[19]  H. Okada,et al.  Cytokine gene therapy of gliomas: effective induction of therapeutic immunity to intracranial tumors by peripheral immunization with interleukin-4 transduced glioma cells , 2001, Gene Therapy.

[20]  D. Morton,et al.  Peripheral Blood CD4+ T-Cell Response Before Postoperative Active Immunotherapy Correlates with Clinical Outcome in Metastatic Melanoma , 2004, Annals of Surgical Oncology.

[21]  Olivier Lantz,et al.  CD4 cells can be more efficient at tumor rejection than CD8 cells. , 2007 .

[22]  W. Marsden I and J , 2012 .

[23]  R. Blasberg,et al.  Tumor-reactive CD4+ T cells develop cytotoxic activity and eradicate large established melanoma after transfer into lymphopenic hosts , 2010, The Journal of experimental medicine.

[24]  Dirk Schadendorf,et al.  Vaccination of melanoma patients with peptide- or tumorlysate-pulsed dendritic cells , 1998, Nature Medicine.

[25]  J. A. Kuznecov Elements of applied bifurcation theory , 1998 .

[26]  H. P. de Vladar,et al.  Dynamic response of cancer under the influence of immunological activity and therapy. , 2004, Journal of theoretical biology.

[27]  M. Kaplan,et al.  CD4+ T‐cell‐mediated anti‐tumor immunity can be uncoupled from autoimmunity via the STAT4/STAT6 signaling axis , 2009, European journal of immunology.

[28]  B. Neyns,et al.  Optimized dendritic cell-based immunotherapy for melanoma: the TriMix-formula , 2014, Cancer Immunology, Immunotherapy.

[29]  G. G. Stokes "J." , 1890, The New Yale Book of Quotations.

[30]  J. Wolchok,et al.  Anti-CTLA-4 antibody therapy: immune monitoring during clinical development of a novel immunotherapy. , 2010, Seminars in oncology.

[31]  M. Griffioen,et al.  CD4+ Th2 Cell Recognition of HLA-DR-Restricted Epitopes Derived from CAMEL: A Tumor Antigen Translated in an Alternative Open Reading Frame , 2003, The Journal of Immunology.

[32]  J. Thompson,et al.  Adoptive T cell therapy using antigen-specific CD8+ T cell clones for the treatment of patients with metastatic melanoma: In vivo persistence, migration, and antitumor effect of transferred T cells , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[33]  Jui-Ling Yu,et al.  Qualitative behavior of systems of tumor–CD4+–cytokine interactions with treatments , 2015 .

[34]  D. Earn,et al.  Interactions Between the Immune System and Cancer: A Brief Review of Non-spatial Mathematical Models , 2011, Bulletin of mathematical biology.

[35]  P ? ? ? ? ? ? ? % ? ? ? ? , 1991 .

[36]  D. K. Shakir,et al.  Chemotherapy Induced Cardiomyopathy: Pathogenesis, Monitoring and Management , 2009, Journal of clinical medicine research.

[37]  Hsiu-Chuan Wei,et al.  Periodically Pulsed immunotherapy in a Mathematical Model of Tumor-Immune Interaction , 2013, Int. J. Bifurc. Chaos.

[38]  J. Wolchok,et al.  Genetic basis for clinical response to CTLA-4 blockade in melanoma. , 2014, The New England journal of medicine.

[39]  D. Earn,et al.  Modeling anti-tumor Th1 and Th2 immunity in the rejection of melanoma. , 2010, Journal of theoretical biology.

[40]  S. Plesničar,et al.  Actual doubling time values of pulmonary metastases from malignant melanoma. , 1978, The Australian and New Zealand journal of surgery.

[41]  D. Kondziolka,et al.  Autologous glioma cell vaccine admixed with interleukin-4 gene transfected fibroblasts in the treatment of patients with malignant gliomas , 2007, Journal of Translational Medicine.