When, Where, and How Much: Toward Smarter Design and Delivery of CAR T-Cell Therapy

Abstract Chimeric antigen receptor (CAR) T-cell therapies have fundamentally reshaped clinical oncology by achieving durable remissions in refractory hematologic malignancies. However, their broader translation remains bottlenecked by severe, treatment-associated hyperinflammatory toxicities, including cytokine release syndrome (CRS), immune effector cell–associated neurotoxicity syndrome (ICANS), and immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS). Current management strategies are reactive and rely on systemic immunosuppressants, such as corticosteroids and the anti-IL-6 receptor antibody tocilizumab. While these interventions blunt acute inflammation, they can exert systemic effects that have the possibility to impair CAR-T cell persistence, prolong cytopenias, and compromise long-term antitumor efficacy. In this review, we challenge the conventional paradigm that treats toxicity as a uniform, unavoidable consequence of systemic immune activation. Instead, we present emerging evidence demonstrating that CAR-T-associated toxicities possess discrete spatial, temporal, and kinetic organization across distinct tissue compartments and biological phases. We propose a cohesive engineering framework that leverages advanced drug delivery technologies to convert toxicity management from a reactive clinical hurdle into a systems-level design problem. By organizing future therapeutic strategies around three core pillars: temporal control (gating interventions to specific phases of immune escalation), dosing and kinetic control (flattening proliferation slopes via fractionated delivery, dynamic feedback loops, and mathematical modeling), and spatial control (anatomical targeting of inflamed vasculature, lymphoid organs, and the central nervous system), it may be possible to selectively decouple localized toxic inflammatory cascades from therapeutic CAR-T cell expansion. Ultimately, integrating these spatiotemporal and kinetic parameters provides a blueprint for engineering the next generation of safer, scalable, and highly efficacious cellular immunotherapies.