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Mathematical modeling unveils the timeline of CAR-T cell therapy and macrophage-mediated cytokine release syndrome

Fig 4

Mapping of mechanistic parameters on response characteristics. A qualitative sensitivity analysis identified a nonlinear mapping between ten different shape features of the model response (slopes , CAR-T cell minimum, CAR-T cell peak concentration, minimum tumor load, and persistence level) to ten mechanistic parameters. This is illustrated by simulations for patient M44 (black) and alternative scenarios (blue and yellow) where one parameter is changed at a time. A-D The slopes in the distribution, expansion, and contraction phases are determined by the decay of injected CAR-T cells (), the net expansion rate of CAR-T expander cells (), their death and exhaustion (), and the decay of CAR-T persister cells (). E The minimum level of CAR-T cells observed at the end of the distribution phase is determined by the activation rate of injected CAR-T cells (η). F,G The CAR-T cell peak depends on the saturation constants for the antigen binding (A) and tumor killing (B) functions. H The persistence level is mainly determined by the memory pool formation rate ϵ. I,J The slopes in the shrinkage and response phases of tumor dynamics are determined by CAR-T cell cytotoxicity (γ) and tumor growth rate (ρ), respectively. K,L The minimum tumor load is negatively correlated with the CAR-T cell peak and therefore is also determined by A and B. Although most of the response characteristics appear to have a first-order dependence on only one mechanistic parameter, this is not the case for the CAR-T cell peak and the minimum tumor burden, which also strongly depend on κ, , γ and ρ. See also S5 and S6 Figs.

doi: https://doi.org/10.1371/journal.pcbi.1012908.g004