Latest updates on pathogenesis mechanisms and management strategies for cytokine release syndrome, neurotoxicity, and hemophagocytic lymphohistiocytosis related to CAR-T cell therapies

Abstract

Nowadays, chimeric antigen receptor (CAR) -T cell therapy has shown significant efficacy in treating hematological tumors, with an obvious increase in patient survival rates. However, with the widespread application of CAR-T, the incidence of CAR-T related adverse events has gradually increased, including cytokine release syndrome (CRS), immune effector cell associated neurotoxicity syndrome (ICANS), and hemophagocytic lymphohistiocytosis (HLH). These complications may be life-threatening, so early diagnosis and intervention treatment are crucial for the prognosis of patients. In this review, we first comprehensively summarize the latest insights into the pathogenesis and clinical manifestations of CRS, ICANS, and HLH after CAR-T, with a focus on elaborating on the specific mechanisms and related pathways of the inflammatory storm caused by a large number of cytokines after CAR-T. We also discussed the established prevention and management strategies for the three complications mentioned above, and demonstrated the effectiveness of the treatment by introducing the therapeutic effects of various treatment methods in current clinical or preclinical trials. In addition, we provide a prospective perspective on the measures and modifications currently being studied to mitigate the toxicity associated with CAR-T cell therapy.

Keywords: Chimeric antigen receptor (CAR)-T cell therapies; Cytokine release syndrome; Hemophagocytic lymphohistiocytosis; Immune effector cell-associated neurotoxicity syndrome.

Fig. 1

Schematic diagram of cytokines (such as IL-6, IL-1, GM-CSF) and immune cells (CAR-T cells, macrophages) involved in the pathogenesis of CRS. The blue arrows indicate the secretion of various cytokines and catecholamines, as well as the pyroptosis process of target tumor cells, which collectively contribute to the occurrence and development of CRS

Fig. 2

CAR-T cell-induced pyroptosis in target cells and subsequent macrophage activation. CAR-T cells release granzyme B, which activates caspase-3 in target cells (e.g., leukemia cells). Caspase-3 cleaves gasdermin E (GSDME) into GSDME-NT and triggers pyroptosis. Pyroptotic cells release DAMPs and cytokines which activate macrophages. Inflammasome-mediated caspase-1 activation in macrophages cleaves gasdermin D (GSDMD) into GSDMD-NT, amplifying pyroptosis and cytokine release (e.g., IL-1β, IL-6). This cascade contributes to cytokine release syndrome (CRS) and CAR-T-related toxicity. Key molecules involved are labeled in the diagram

Fig. 3

The mechanism of endothelial activation through Ang-2/Ang-1 imbalance and the release of cytokines (IL-6, VEGF) leads to blood-brain barrier disruption. Potential therapeutic interventions targeting MCP-1 or VEGF were identified

Fig. 4

This figure illustrates the mechanism of blood-brain barrier integrity disruption in CAR-T associated neurotoxicity (ICANS). The dysfunction of astrocytes (affected by IL-1, IL-6, IFN - γ, TNF - α) and pericytes (affected by endothelial cell activation) leads to the invasion of inflammatory cells and cytokines into the central nervous system, causing neuroinflammation and neuronal damage

Fig. 5

This figure provides a comprehensive overview of therapeutic interventions for CAR-T cell therapy-associated toxicities. The schematic highlights three principal therapeutic approaches targeting different pathological mechanisms. Cytokine-directed therapies form the cornerstone of management, with agents such as tocilizumab (IL-6 receptor antagonist), anakinra (IL-1 receptor antagonist), lenzilumab (GM-CSF neutralizing antibody), and specific cytokine blockers including etanercept (TNF-α inhibitor) and emapalumab (IFN-γ monoclonal antibody). Small molecule inhibitors like ruxolitinib (JAK1/2 inhibitor) and dasatinib (SRC kinase inhibitor) modulate downstream inflammatory signaling pathways. Supportive measures including therapeutic plasma exchange, etoposide (VP-16) for HLH, and intrathecal corticosteroids for neurotoxicity management complete the multidimensional treatment strategy

Fig. 6

This flowchart outlines the assessment and treatment strategies for three major CAR-T therapy-related toxicities: CRS, ICANS, and HLH. CRS grading and intervention: Grade 1: supportive care (such as prophylactic antibiotics). Grade 2: tocilizumab. Grade 3/4: tocilizumab + methylprednisolone. For refractory cases, steroid dosage gradually increases. ICANS grading and intervention: Grade 1/2: dexamethasone. Grade 3/4: high dose steroids, intrathecal injection of methotrexate and dexamethasone