Poster Abstract
Background and Aim
Chimeric antigen receptor T (CAR-T) cell therapy has shown remarkable success in treating various leukemias and lymphomas. CARs are engineered to redirect T cells to specific antigens. [1]
CAR-T PK behavior is distinct from other therapies due to its "living" nature; it is characterized by an exponential expansion, fast initial decline (contraction), and slow long-term decline (persistence). [2]
Much is still unknown about the workings of CAR-T cells in the body, and there is not a standard monitoring process. Modeling can shed light on CAR-T cell PK/PD and inform future studies.
Our aim is to reproduce typical CAR-T PK using a mechanistic modeling approach, validate our model with PD results, and understand system variability.
Methodology
Our model of CAR-T cell therapy for B cell lymphoma contains the following components:
- Bolus dose administered as part CD8+, part CD4+ drug product
- CAR-T cells become activated when they bind to CD19 on malignant B cells
- Activated CAR-T cells proliferate and eventually become effector cells
- Effector cells kill B cells, which otherwise exhibit logistic growth
- A fraction of effector cells become memory cells; the rest die
- Model also tracks other lymphocytes which are not affected by CAR-T cells
- Both receptors and cells are modeled explicitly
- Receptors are synthesized and degraded
Conclusions and Future Directions
- We were able to capture CAR-T cell PK using a mechanistic modeling approach
- Our model can reproduce PD and provide information on characteristics of CAR-T and tumor cells that drive system dynamics
Future directions
- More PD data will be helpful in improving model accuracy
- The model can be used to explore and optimize properties of CAR-T cells such as expansion, CD4:CD8 ratio, and killing capacity
- Additional model components can be included, e.g. other cell types, distribution to other tissues, and toxicity considerations
References
[1] Sterner, Robert C, and Rosalie M Sterner. “CAR-T cell therapy: current limitations and potential strategies.” Blood cancer journal vol. 11,4 69. 6 Apr. 2021, doi:10.1038/s41408-021-00459-7
[2] Chaudhury, Anwesha et al. “Chimeric Antigen Receptor T Cell Therapies: A Review of Cellular Kinetic-Pharmacodynamic Modeling Approaches.” Journal of clinical pharmacology vol. 60 Suppl 1 (2020): S147-S159. doi:10.1002/jcph.1691
[3] Ying, Zhitao et al. “Distribution of chimeric antigen receptor-modifed T cells against CD19 in B-cell malignancies.” BMC cancer vol. 21,1 198. 25 Feb. 2021, doi:10.1186/s12885-021-07934-1