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CAR-T cell therapy: improving mechanistic understanding of efficacy and safety

T. Nirnberger1, Uwe Schühly2

1) Biofi AG, Switzerland

2) Santhera Pharmaceuticals, Switzerland

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Chimeric Antigen Receptor (CAR) T cells are genetically engineered T cells designed to target and destroy cancer cells. It is a young treatment modality with promising potential to cure diseases in various indications. It is also unique in that as a cell therapy it is a living medicine that proliferates and expands within the patient body. This poses new challenges to understand its efficacy and safety profiles, and also to model and simulate it with traditional mathematical models.

Cytokine Release Syndrome is a common side effect. Resulting from generalized immune activation correlating with CAR-T expansion and marked elevations of serum inflammatory markers and cytokines.

Cytokines are released when interaction between tumor and immune effector cell occurs; and it can originate not only from the CAR-T cell but also from host immune cells such as macrophages, which respond in part to CAR-T activation.

This model was built from publicly available knowledge and includes the main mechanisms of cell kinetics and IL-6 production, a serum inflammatory marker and cytokine.

The five phase model of Morris et al. (Morris et al., 2022) is used as an overall guide of the desired kinetics and dynamics to achieve with the model.

Virtual experimentation with the models shows:

  • CAR-T cell effectiveness (how many cancer cells a CAR-T cell can attack simultaneously) is critical for survival and timing of CAR-T Cmax
  • CAR-T dose impacts levels and timing of IL-6
  • CAR-T dose impacts tumor response

    • This public model has not been algorithmically optimized towards clinical data. It serves as a foundational model to be adapted and optimized towards specific use cases.

    References
    Morris, E. C., Neelapu, S. S., Giavridis, T., & Sadelain, M. (2022). Cytokine release syndrome and associated neurotoxicity in cancer immunotherapy. Nature Reviews. Immunology, 22(2), 85–96.https://doi.org/10.1038/s41577-021-00547-6
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