Papers
Topics
Authors
Recent
Gemini 2.5 Flash
Gemini 2.5 Flash
173 tokens/sec
GPT-4o
7 tokens/sec
Gemini 2.5 Pro Pro
46 tokens/sec
o3 Pro
4 tokens/sec
GPT-4.1 Pro
38 tokens/sec
DeepSeek R1 via Azure Pro
28 tokens/sec
2000 character limit reached

Understanding the role of B-cells in CAR T-cell therapy in leukemia through a mathematical model (2403.00340v1)

Published 1 Mar 2024 in math.DS and q-bio.QM

Abstract: Chimeric Antigen Receptor T (CAR-T) cell therapy has been proven to be successful against different leukaemias and lymphomas. This paper makes an analytical and numerical study of a mathematical model describing the competition of CAR-T, leukaemias tumor and B cells. Considering its significance in sustaining anti-CD19 CAR T-cell stimulation, we integrate a B-cell source term into the model. Through stability and bifurcation analyses, we reveal the potential for tumor eradication contingent on the continuous influx of B-cells, uncovering a transcritical bifurcation at a critical B-cell input. Additionally, we identify an almost heteroclinic cycle between equilibrium points, providing a theoretical basis for understanding disease relapse. Analyzing the oscillatory behavior of the system, we approximate the time-dependent dynamics of CAR T-cells and leukemic cells, shedding light on the impact of initial tumor burden on therapeutic outcomes. In conclusion, our study provides insights into CAR T-cell therapy dynamics for acute lymphoblastic leukemias, offering a theoretical foundation for clinical observations and suggesting avenues for future immunotherapy modeling research.

Definition Search Book Streamline Icon: https://streamlinehq.com
References (41)
  1. J. Koury, M. Lucero, C. Cato, L. Chang, J. Geiger, D. Henry, J. Hernandez, F. Hung, P. Kaur, G. Teskey,  and T. A, “Immunotherapies: Exploiting the immune system for cancer treatment,” Journal of Immunology Research 2018 (2018), 10.1155/2018/9585614.
  2. G. D’Errico, H. L. Machado,  and B. Sainz Jr., “A current perspective on cancer immune therapy: step-by-step approach to constructing the magic bullet,” Clinical and Translational Medicine 6, e3 (2017).
  3. S. Feins, W. Kong, E. F. Williams, M. C. Milone,  and J. A. Fraietta, “An introduction to Chimeric Antigen Receptor (CAR) T-cell immunotherapy for human cancer,” American Journal of Hematology 94, S3–S9 (2019).
  4. S. L. Maude, T. W. Laetsch, J. Buechner, S. Rives, M. Boyer, H. Bittencourt, P. Bader, M. R. Verneris, H. E. Stefanski, G. D. Myers, M. Qayed, B. De Moerloose, H. Hiramatsu, K. Schlis, K. L. Davis, P. L. Martin, E. R. Nemecek, G. A. Yanik, C. Peters, A. Baruchel, N. Boissel, F. Mechinaud, A. Balduzzi, J. Krueger, C. H. June, B. L. Levine, P. Wood, T. Taran, M. Leung, K. T. Mueller, Y. Zhang, K. Sen, D. Lebwohl, M. A. Pulsipher,  and S. A. Grupp, “Tisagenlecleucel in children and young adults with B-Cell lymphoblastic leukemia,” New England Journal of Medicine 378, 439–448 (2018).
  5. S. J. Schuster, M. R. Bishop, C. S. Tam, E. K. Waller, P. Borchmann, J. P. McGuirk, U. Jäger, S. Jaglowski, C. Andreadis, J. R. Westin, I. Fleury, V. Bachanova, S. R. Foley, P. J. Ho, S. Mielke, J. M. Magenau, H. Holte, S. Pantano, L. B. Pacaud, R. Awasthi, J. Chu, O. Anak, G. Salles,  and R. T. Maziarz, “Tisagenlecleucel in adult relapsed or refractory diffuse large B-Cell lymphoma,” New England Journal of Medicine 380, 45–56 (2019).
  6. M. Sadelain, “CAR therapy: the CD19 paradigm,” The Journal of Clinical Investigation 125, 3392–3400 (2015).
  7. A. Chaudhury, X. Zhu, L. Chu, A. Goliaei, C. H. June, J. D. Kearns,  and A. M. Stein, “Chimeric Antigen Receptor T Cell Therapies: A Review of Cellular Kinetic-Pharmacodynamic Modeling Approaches,” The Journal of Clinical Pharmacology 60, S147–S159 (2020).
  8. R. Mostolizadeh, Z. Afsharnezhad,  and A. Marciniak-Czochra, “Mathematical model of Chimeric Anti-gene Receptor (CAR) T cell therapy with presence of cytokine,” Numerical Algebra, Control & Optimization 8, 63–80 (2018).
  9. A. M. Stein, S. A. Grupp, J. E. Levine, T. W. Laetsch, M. A. Pulsipher, M. W. Boyer, K. J. August, B. L. Levine, L. Tomassian, S. Shah, et al., “Tisagenlecleucel model-based cellular kinetic analysis of Chimeric Antigen Receptor–T cells,” CPT: Pharmacometrics & Systems Pharmacology 8, 285–295 (2019).
  10. E. Khailov, E. Grigorieva,  and A. Klimenkova, “Optimal CAR T-cell Immunotherapy Strategies for a Leukemia Treatment Model,” Games 11, 53 (2020).
  11. L. R. C. Barros, B. d. J. Rodrigues,  and R. C. Almeida, “CAR-T cell Goes on a Mathematical Model,” Journal of Cellular Immunology 2, 31–37 (2020).
  12. L. R. C. Barros, E. A. Paixão, A. M. P. Valli, G. T. Naozuka, A. C. Fassoni,  and R. C. Almeida, “CARTmath—A Mathematical Model of CAR-T Immunotherapy in Preclinical Studies of Hematological Cancers,” Cancers 13, 2941 (2021).
  13. P. A. Valle, L. N. Coria, C. Plata,  and Y. Salazar, “CAR-T Cell Therapy for the Treatment of ALL: Eradication Conditions and In Silico Experimentation,” Hemato 2, 441–462 (2021).
  14. O. León-Triana, S. Sabir, G. F. Calvo, J. Belmonte-Beitia, S. Chulián, A. Martínez-Rubio, M. Rosa, A. Pérez-Martínez, M. Ramirez-Orellana,  and V. M. Pérez-García, “CAR T cell therapy in B-cell acute lymphoblastic leukaemia: Insights from mathematical models,” Communications in Nonlinear Science and Numerical Simulation 94, 105570 (2021).
  15. V. M. Pérez-García, O. León-Triana, M. Rosa,  and A. Pérez-Martínez, “CAR T cells for T-cell leukemias: Insights from mathematical models,” Communications in Nonlinear Science and Numerical Simulation 96, 105684 (2021).
  16. Á. Martínez-Rubio, S. Chulián, C. Blázquez Goñi, M. Ramírez Orellana, A. Pérez Martínez, A. Navarro-Zapata, C. Ferreras, V. M. Pérez-García,  and M. Rosa, “A mathematical description of the bone marrow dynamics during CAR T-cell therapy in B-cell childhood acute lymphoblastic leukemia,” International Journal of Molecular Sciences 22, 6371 (2021).
  17. T. Derippe, S. Fouliard, I. Marchiq, S. Dupouy, M. Almena-Carrasco, J. Geronimi, X. Declèves, M. Chenel,  and D. E. Mager, “Mechanistic modeling of the interplay between host immune system, IL-7 and UCART19 allogeneic CAR-T cells in adult B-cell Acute Lymphoblastic Leukemia,” Cancer Research Communications 2, 1532–1544 (2022).
  18. A. Mueller-Schoell, N. Puebla-Osorio, R. Michelet, M. R. Green, A. Künkele, W. Huisinga, P. Strati, B. Chasen, S. S. Neelapu, C. Yee,  and C. Kloft, “Early Survival Prediction Framework in CD19-Specific CAR-T Cell Immunotherapy Using a Quantitative Systems Pharmacology Model,” Cancers 13, 2782 (2021).
  19. K. Owens and I. Bozic, “Modeling CAR T-cell therapy with patient preconditioning,” Bulletin of Mathematical Biology 83, 1–36 (2021).
  20. G. J. Kimmel, F. L. Locke,  and P. M. Altrock, “The roles of T cell competition and stochastic extinction events in Chimeric Antigen Receptor T cell therapy,” Proceedings of the Royal Society B 288, 20210229 (2021).
  21. M. Bodnar, U. Foryś, M. J. Piotrowska, M. Bodzioch, J. A. Romero-Rosales,  and J. Belmonte-Beitia, “On the analysis of a mathematical model of CAR–T cell therapy for glioblastoma: Insights from a mathematical model,” International Journal of Applied Mathematics and Computer Science 33, 379–394 (2023).
  22. N. Semenova and V. V. Tuchin, “3D models of the dynamics of cancer cells under external pressure,” Chaos: An Interdisciplinary Journal of Nonlinear Science 31, 083122 (2021).
  23. P. Bi, S. Ruan,  and X. Zhang, “Periodic and chaotic oscillations in a tumor and immune system interaction model with three delays,” Chaos: An Interdisciplinary Journal of Nonlinear Science 24, 023101 (2014).
  24. L. R. Dickman and Y. Kuang, “Analysis of tumor-immune dynamics in a delayed dendritic cell therapy model,” Chaos: An Interdisciplinary Journal of Nonlinear Science 30, 113108 (2020).
  25. D. Kasakovski, L. Xu,  and Y. Li, “T cell senescence and CAR-T cell exhaustion in hematological malignancies,” Journal of Hematology and Oncology 11 (2018).
  26. S. Ghorashian, A. Kramer, S. Onuoha,  and et al, “Enhanced CAR T cell expansion and prolonged persistence in pediatric patients with ALL treated with a low-affinity CD19 CAR,” Nature Medicine 25, 1408–1414 (2019).
  27. D. W. Lee, J. N. Kochenderfer, M. Stetler-Stevenson, Y. K. Cui, C. Delbrook, S. A. Feldman, T. J. Fry, R. Orentas, M. Sabatino, N. N. Shah, S. M. Steinberg, D. Stroncek, N. Tschernia, C. Yuan, H. Zhang, L. Zhang, S. A. Rosenberg, A. S. Wayne,  and C. L. Mackall, “T cells expressing CD19 Chimeric Antigen Receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial,” The Lancet 385, 517–528 (2015).
  28. S. Chulián, Á. Martínez-Rubio, A. Marciniak-Czochra, T. Stiehl, C. B. Goñi, J. F. R. Gutiérrez, M. R. Orellana, A. C. Robleda, V. M. Pérez-García,  and M. Rosa, “Dynamical properties of feedback signalling in B lymphopoiesis: A mathematical modelling approach,” Journal of Theoretical Biology 522, 110685 (2021).
  29. G. Shahaf, S. Zisman-Rozen, D. Benhamou, D. Melamed,  and R. Mehr, “B cell development in the bone marrow is regulated by homeostatic feedback exerted by mature B cells,” Frontiers in Immunology 7, 77 (2016).
  30. H. E. Skipper and S. Perry, “Kinetics of normal and leukemic leukocyte populations and relevance to chemotherapy,” Cancer Research 30, 1883 – 1897 (1970).
  31. D. Fulcher and A. Basten, “B cell life span: A review,” Immunology & Cell Biology 75, 446–455 (1997).
  32. F. Pianosi and T. Wagener, “A simple and efficient method for global sensitivity analysis based on cumulative distribution functions,” Environmental Modelling & Software 67, 1–11 (2015).
  33. M. Heiblig, G. Salles,  and X. Thomas, “Allogeneic anti-CD19 CAR T cells: new perspectives in the treatment of B-cell malignancies that progress after allogeneic stem cell transplantation,” Translational Cancer Research 5, S5–S8 (2016).
  34. J. N. Brudno, R. P. Somerville, V. Shi, J. J. Rose, D. C. Halverson, D. H. Fowler, J. C. Gea-Banacloche, S. Z. Pavletic, D. D. Hickstein, T. L. Lu, et al., “Allogeneic T cells that express an anti-CD19 Chimeric Antigen Receptor induce remissions of B-cell malignancies that progress after allogeneic hematopoietic stem-cell transplantation without causing graft-versus-host disease,” Journal of Clinical Oncology 34, 1112 (2016).
  35. M. L. Davila and M. Sadelain, “Biology and clinical application of CAR T cells for B cell malignancies,” International Journal of Hematology 104, 6–17 (2016).
  36. C. Annesley, R. Gardner, A. Wilson, C. Summers, A. J. Lamble, J. Rivers, Q. V. Wu, A. Brand, A. Johnson, K. Spratt, et al., “Novel CD19t T-Antigen Presenting Cells expand CD19 CAR T cells in vivo,” Blood 134, 223 (2019).
  37. R. C. Larson and M. V. Maus, “Recent advances and discoveries in the mechanisms and functions of CAR T cells,” Nature Reviews Cancer 21, 145–161 (2021).
  38. K. M. Cappell and J. N. Kochenderfer, “Long-term outcomes following CAR T cell therapy: What we know so far,” Nature Reviews Clinical Oncology , 1–13 (2023).
  39. L. Liu, C. Ma, Z. Zhang, M. T. Witkowski, I. Aifantis, S. Ghassemi,  and W. Chen, “Computational model of CAR T-cell immunotherapy dissects and predicts leukemia patient responses at remission, resistance, and relapse,” Journal for ImmunoTherapy of Cancer 10, e005360 (2022).
  40. D. S. Santurio, E. A. Paixão, L. R. Barros, R. C. Almeida,  and A. C. Fassoni, “Mechanisms of resistance to CAR-T cell immunotherapy: Insights from a mathematical model,” Applied Mathematical Modelling 125, 1–15 (2024).
  41. F. Pianosi, F. Sarrazin,  and T. Wagener, “A matlab toolbox for global sensitivity analysis,” Environmental Modelling & Software 70, 80–85 (2015).
Citations (2)
View on Semantic Scholar

Summary

We haven't generated a summary for this paper yet.

Ai Sparkles Streamline Icon: https://streamlinehq.com Summarize Now
X Twitter Logo Streamline Icon: https://streamlinehq.com

Tweets