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Article

A Mathematical Description of the Bone Marrow Dynamics during CAR T-Cell Therapy in B-Cell Childhood Acute Lymphoblastic Leukemia

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Department of Mathematics, Universidad de Cádiz, Puerto Real, 11510 Cádiz, Spain
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Biomedical Research and Innovation Institute of Cádiz (INiBICA), Hospital Universitario Puerta del Mar, 11009 Cádiz, Spain
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Department of Pediatric Hematology and Oncology, Hospital de Jerez, 11407 Cádiz, Spain
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Department of Paediatric Haematology and Oncology, Instituto Investigación Sanitaria La Princesa, Hospital Infantil Universitario Niño Jesús, 28006 Madrid, Spain
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Translational Research in Pediatric Oncology, Hematopoietic Transplantation and Cell Therapy, IdiPAZ, Hospital Universitario La Paz, 28046 Madrid, Spain
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Pediatric Hemato-Oncology Department, Hospital Universitario La Paz, 28046 Madrid, Spain
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Mathematical Oncology Laboratory (MOLAB), Instituto de Matemática Aplicada a la Ciencia y la Ingeniería, Universidad de Castilla-La Mancha, 13005 Ciudad Real, Spain
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Departamento de Matemáticas, Escuela Técnica Superior de Ingenieros Industriales, Universidad de Castilla-La Mancha, 13005 Ciudad Real, Spain
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Author to whom correspondence should be addressed.
Academic Editor: Marieke F. Fransen
Int. J. Mol. Sci. 2021, 22(12), 6371; https://doi.org/10.3390/ijms22126371
Received: 11 May 2021 / Revised: 9 June 2021 / Accepted: 10 June 2021 / Published: 14 June 2021
(This article belongs to the Special Issue Immunological Responses to Cancer Therapy)
Chimeric Antigen Receptor (CAR) T-cell therapy has demonstrated high rates of response in recurrent B-cell Acute Lymphoblastic Leukemia in children and young adults. Despite this success, a fraction of patients’ experience relapse after treatment. Relapse is often preceded by recovery of healthy B cells, which suggests loss or dysfunction of CAR T-cells in bone marrow. This site is harder to access, and thus is not monitored as frequently as peripheral blood. Understanding the interplay between B cells, leukemic cells, and CAR T-cells in bone marrow is paramount in ascertaining the causes of lack of response. In this paper, we put forward a mathematical model representing the interaction between constantly renewing B cells, CAR T-cells, and leukemic cells in the bone marrow. Our model accounts for the maturation dynamics of B cells and incorporates effector and memory CAR T-cells. The model provides a plausible description of the dynamics of the various cellular compartments in bone marrow after CAR T infusion. After exploration of the parameter space, we found that the dynamics of CAR T product and disease were independent of the dose injected, initial B-cell load, and leukemia burden. We also show theoretically the importance of CAR T product attributes in determining therapy outcome, and have studied a variety of possible response scenarios, including second dosage schemes. We conclude by setting out ideas for the refinement of the model. View Full-Text
Keywords: CAR T; mathematical model; acute lymphoblastic leukemia; B cell; bone marrow CAR T; mathematical model; acute lymphoblastic leukemia; B cell; bone marrow
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MDPI and ACS Style

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

AMA Style

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 Style

Martínez-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

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