Mathematical modeling unveils the timeline of CAR-T cell therapy and macrophage-mediated cytokine release syndrome
Fig 7
Dynamics of macrophage activation and IL-6 release. A Time course of patient M44, selectively activating DAMPs release, antigen-binding, and CD40 contact mechanisms one at a time. DAMPs-only activation leads to an IL-6 peak around day 3 during tumor shrinkage. Antigen-biding activation results in IL-6 increasing with CAR-T expansion, peaking around day 8. CD40-mediated activation alone maintains IL-6 at baseline, but when combined with small values for DAMPs and antigen-binding parameters, it produces an IL-6 peak around day 13, four days after the CAR-T cell peak. B Splitting the active macrophage population according to their source, i.e., activation mechanisms (see Methods), and reconstructing the timeline for each patient, we found that the peak of DAMP-activated macrophages takes place early, during the tumor shrinkage phase. The second subpopulation to present a peak is the antigen-binding-activated macrophages, which expand in parallel with CAR-T expansion. The last sub-population to peak are CD40-activated macrophages, which require the presence of previously activated macrophages. For 8 out of the 15 patients, the major source of activated macrophages was CD40 contact (pie charts), which was also the source of 62% of all activated macrophages when all patients are combined.