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...
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MDPI AG
2021-06-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/22/12/6371 |
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| author | Álvaro Martínez-Rubio Salvador Chulián Cristina Blázquez Goñi Manuel Ramírez Orellana Antonio Pérez Martínez Alfonso Navarro-Zapata Cristina Ferreras Victor M. Pérez-García María Rosa |
| author_facet | Álvaro Martínez-Rubio Salvador Chulián Cristina Blázquez Goñi Manuel Ramírez Orellana Antonio Pérez Martínez Alfonso Navarro-Zapata Cristina Ferreras Victor M. Pérez-García María Rosa |
| author_sort | Álvaro Martínez-Rubio |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-03-10T10:25:47Z |
| format | Article |
| id | doaj.art-d5c69ebbce874e56a60e7b255843df4a |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T10:25:47Z |
| publishDate | 2021-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-d5c69ebbce874e56a60e7b255843df4a2023-11-22T00:05:50ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-06-012212637110.3390/ijms22126371A Mathematical Description of the Bone Marrow Dynamics during CAR T-Cell Therapy in B-Cell Childhood Acute Lymphoblastic LeukemiaÁlvaro Martínez-Rubio0Salvador Chulián1Cristina Blázquez Goñi2Manuel Ramírez Orellana3Antonio Pérez Martínez4Alfonso Navarro-Zapata5Cristina Ferreras6Victor M. Pérez-García7María Rosa8Department of Mathematics, Universidad de Cádiz, Puerto Real, 11510 Cádiz, SpainDepartment of Mathematics, Universidad de Cádiz, Puerto Real, 11510 Cádiz, SpainBiomedical Research and Innovation Institute of Cádiz (INiBICA), Hospital Universitario Puerta del Mar, 11009 Cádiz, SpainDepartment of Paediatric Haematology and Oncology, Instituto Investigación Sanitaria La Princesa, Hospital Infantil Universitario Niño Jesús, 28006 Madrid, SpainTranslational Research in Pediatric Oncology, Hematopoietic Transplantation and Cell Therapy, IdiPAZ, Hospital Universitario La Paz, 28046 Madrid, SpainTranslational Research in Pediatric Oncology, Hematopoietic Transplantation and Cell Therapy, IdiPAZ, Hospital Universitario La Paz, 28046 Madrid, SpainTranslational Research in Pediatric Oncology, Hematopoietic Transplantation and Cell Therapy, IdiPAZ, Hospital Universitario La Paz, 28046 Madrid, SpainMathematical Oncology Laboratory (MOLAB), Instituto de Matemática Aplicada a la Ciencia y la Ingeniería, Universidad de Castilla-La Mancha, 13005 Ciudad Real, SpainDepartment of Mathematics, Universidad de Cádiz, Puerto Real, 11510 Cádiz, SpainChimeric 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.https://www.mdpi.com/1422-0067/22/12/6371CAR Tmathematical modelacute lymphoblastic leukemiaB cellbone marrow |
| spellingShingle | Álvaro Martínez-Rubio Salvador Chulián Cristina Blázquez Goñi Manuel Ramírez Orellana Antonio Pérez Martínez Alfonso Navarro-Zapata Cristina Ferreras Victor M. Pérez-García María 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 CAR T mathematical model acute lymphoblastic leukemia B cell bone marrow |
| 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 | CAR T mathematical model acute lymphoblastic leukemia B cell bone marrow |
| url | https://www.mdpi.com/1422-0067/22/12/6371 |
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