A Mathematical Description of the Bone Marrow Dynamics during CAR T-Cell Therapy in B-Cell Childhood Acute Lymphoblastic Leukemia.
Álvaro MartínezSalvador ChuliánCristina Blázquez GoñiManuel RamírezPérez-Martínez AntonioAlfonso Navarro-ZapataCristina Ferreras Bárbara PascualVictor M Pérez-GarcíaMaría RosaPublished in: International journal of molecular sciences (2021)
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.
Keyphrases
- bone marrow
- cell therapy
- mesenchymal stem cells
- acute lymphoblastic leukemia
- young adults
- induced apoptosis
- stem cells
- peripheral blood
- acute myeloid leukemia
- end stage renal disease
- cell cycle arrest
- allogeneic hematopoietic stem cell transplantation
- chronic kidney disease
- newly diagnosed
- oxidative stress
- ejection fraction
- low dose
- working memory
- endoplasmic reticulum stress
- dendritic cells
- peritoneal dialysis
- risk factors
- patient reported outcomes
- solid state