Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

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

Version 1 : Received: 12 May 2021 / Approved: 14 May 2021 / Online: 14 May 2021 (11:26:20 CEST)

A peer-reviewed article of this Preprint also exists.

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. 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.

Journal reference: Int. J. Mol. Sci. 2021, 22, 6371
DOI: 10.3390/ijms22126371

Abstract

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 tumor 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.

Subject Areas

CAR T; Bone Marrow; Mathematical Model; Acute Lymphoblastic Leukemia; B cell

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