A Mathematical Description of the Bone Marrow Dynamics during CAR T-Cell Therapy in B-Cell Childhood Acute Lymphoblastic Leukemia
Abstract
:1. Introduction
2. Mathematical Model
2.1. Main Elements of the Model
2.2. Hematopoietic and Leukemic Compartments
2.3. CAR T-Cell Compartment
2.4. Parameter Estimation
2.5. Computational Details
3. Results
3.1. The Mathematical Model without B-Cell Development Reproduces Clinical Data
3.2. Effector and Memory CAR T-Cells Are Able to Control the Disease
3.3. Initial State Does Not Affect CAR T Expansion and Outcome
3.4. CAR T Product Characteristics Determine Therapy Success or Failure
3.5. Second Infusion in Non-Responding Patients May Improve the Therapy Outcome
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
CAR | Chimeric Antigen Receptor |
ALL | Acute Lymphoblastic Leukemia |
CD | Cluster of Differentiation |
BCA | B-Cell Aplasia |
FDA | Federal Drug Administration |
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Parameter | Meaning | Value | Units |
---|---|---|---|
Pro-B proliferation rate | /8 | day | |
Pre-BI proliferation rate | /1 | day | |
Pre-BII proliferation rate | /1.5 | day | |
Transition rate: Pro-B to Pre-BI | day | ||
Transition rate: Pre-BI to Pre-BII | day | ||
Transition rate: Pre-BII to Immature | day | ||
Blood exit rate | dayt | ||
k | Signal intensity | cell | |
Leukemic cell proliferation rate | day | ||
Leukemic cell carrying capacity | cell | ||
Leukemic cell blood exit rate | day | ||
Activated CAR T killing capacity | – | day· cell | |
Activated CAR T proliferation rate | day | ||
Activated CAR T mean lifetime | day | ||
Activated to memory transition rate | day | ||
Memory to activated transition rate | day | ||
Memory CAR T mean lifetime | 300 | day | |
h | CAR T activation threshold | – | cell |
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Martínez-Rubio, Á.; Chulián, S.; Blázquez Goñi, C.; Ramírez Orellana, M.; Pérez Martínez, A.; Navarro-Zapata, A.; Ferreras, C.; Pérez-García, V.M.; Rosa, M. A Mathematical Description of the Bone Marrow Dynamics during CAR T-Cell Therapy in B-Cell Childhood Acute Lymphoblastic Leukemia. Int. J. Mol. Sci. 2021, 22, 6371. https://doi.org/10.3390/ijms22126371
Martínez-Rubio Á, Chulián S, Blázquez Goñi C, Ramírez Orellana M, Pérez Martínez A, Navarro-Zapata A, Ferreras C, Pérez-García VM, Rosa M. 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. 2021; 22(12):6371. https://doi.org/10.3390/ijms22126371
Chicago/Turabian StyleMartínez-Rubio, Álvaro, Salvador Chulián, Cristina Blázquez Goñi, Manuel Ramírez Orellana, Antonio Pérez Martínez, Alfonso Navarro-Zapata, Cristina Ferreras, Victor M. Pérez-García, and María Rosa. 2021. "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, no. 12: 6371. https://doi.org/10.3390/ijms22126371