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

Chimeric antigen receptor (CAR)-T cell therapy holds significant potential for cancer treatment, although disease recurrence and cytokine release syndrome (CRS) remain as frequent clinical challenges. To better understand the underlying mechanisms and temporal dynamics during CAR-T cell therapy response we developed a novel multi-layer mathematical model that accurately describes 25 patient time-courses with diverse responses and IL-6 cytokine kinetics. We successfully link the dynamic shape of the response to interpretable model parameters and study the influence of CAR-T cell dose and initial tumor burden on CRS occurrence and treatment outcome. Further accounting for three established mechanisms of macrophage activation we identified the CD40-CD40L axis as a clinically feasible target to control the activation process and modulate IL-6 peak height. Our study underscores the utility of mechanistic modeling in deciphering therapy dynamics and guiding clinical interventions, emphasizing the importance of close integration with clinical data. ### Competing Interest Statement The authors have declared no competing interest.