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A Mathematical Description of the Bone Marrow Dynamics during CAR T-Cell Therapy in B-Cell Childhood Acute Lymphoblastic Leukemia
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 c...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8232108/ https://www.ncbi.nlm.nih.gov/pubmed/34198713 http://dx.doi.org/10.3390/ijms22126371 |
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author | Martínez-Rubio, Álvaro Chulián, Salvador Blázquez Goñi, Cristina Ramírez Orellana, Manuel Pérez Martínez, Antonio Navarro-Zapata, Alfonso Ferreras, Cristina Pérez-García, Victor M. Rosa, María |
author_facet | Martínez-Rubio, Álvaro Chulián, Salvador Blázquez Goñi, Cristina Ramírez Orellana, Manuel Pérez Martínez, Antonio Navarro-Zapata, Alfonso Ferreras, Cristina Pérez-García, Victor M. Rosa, María |
author_sort | Martínez-Rubio, Álvaro |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-8232108 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-82321082021-06-26 A Mathematical Description of the Bone Marrow Dynamics during CAR T-Cell Therapy in B-Cell Childhood Acute Lymphoblastic Leukemia Martínez-Rubio, Álvaro Chulián, Salvador Blázquez Goñi, Cristina Ramírez Orellana, Manuel Pérez Martínez, Antonio Navarro-Zapata, Alfonso Ferreras, Cristina Pérez-García, Victor M. Rosa, María Int J Mol Sci Article 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. MDPI 2021-06-14 /pmc/articles/PMC8232108/ /pubmed/34198713 http://dx.doi.org/10.3390/ijms22126371 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Martínez-Rubio, Álvaro Chulián, Salvador Blázquez Goñi, Cristina Ramírez Orellana, Manuel Pérez Martínez, Antonio Navarro-Zapata, Alfonso Ferreras, Cristina Pérez-García, Victor M. Rosa, María A Mathematical Description of the Bone Marrow Dynamics during CAR T-Cell Therapy in B-Cell Childhood Acute Lymphoblastic Leukemia |
title | A Mathematical Description of the Bone Marrow Dynamics during CAR T-Cell Therapy in B-Cell Childhood Acute Lymphoblastic Leukemia |
title_full | A Mathematical Description of the Bone Marrow Dynamics during CAR T-Cell Therapy in B-Cell Childhood Acute Lymphoblastic Leukemia |
title_fullStr | A Mathematical Description of the Bone Marrow Dynamics during CAR T-Cell Therapy in B-Cell Childhood Acute Lymphoblastic Leukemia |
title_full_unstemmed | A Mathematical Description of the Bone Marrow Dynamics during CAR T-Cell Therapy in B-Cell Childhood Acute Lymphoblastic Leukemia |
title_short | A Mathematical Description of the Bone Marrow Dynamics during CAR T-Cell Therapy in B-Cell Childhood Acute Lymphoblastic Leukemia |
title_sort | mathematical description of the bone marrow dynamics during car t-cell therapy in b-cell childhood acute lymphoblastic leukemia |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8232108/ https://www.ncbi.nlm.nih.gov/pubmed/34198713 http://dx.doi.org/10.3390/ijms22126371 |
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