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Background <p>Chimeric antigen receptor (CAR) T-cell therapy has transformed the treatment landscape for hematologic malignancies. However, immune effector cell-associated neurotoxicity syndrome (ICANS) remains a significant and potentially lethal complication, affecting approximately 27% to 65% of patients and challenging the therapeutic risk-benefit profile.</p> Main body <p>This review synthesizes recent advances in the epidemiology, pathophysiology, diagnosis, and management of ICANS. Incidence varies significantly by product design, with anti-CD19 therapies and CD28-containing constructs demonstrating markedly higher toxicity rates compared to other targets and 4-1BB-based designs. The pathophysiological mechanism centers on blood-brain barrier disruption driven by systemic cytokine release and direct cellular injury. Monocytes and macrophages act as principal effectors, releasing interleukin-1 and granulocyte-macrophage colony-stimulating factor, which trigger endothelial activation and neuroinflammation. Clinical manifestations typically appear within the first week post-infusion, ranging from mild language disturbances to life-threatening cerebral edema. Current management has evolved from reactive symptom control to proactive strategies. Severity-based algorithms guide the use of corticosteroids and intensive care support, while emerging prophylactic approaches, particularly interleukin-1 receptor blockade with anakinra, show promise in reducing severe neurotoxicity without compromising anti-tumor efficacy. Furthermore, diagnostic precision is improving through the use of novel biomarkers, such as chimeric antigen receptor-positive extracellular vesicles, and machine-learning models that predict toxicity days before symptom onset.</p> Conclusions <p>The management of ICANS is shifting towards a precision medicine paradigm. By integrating predictive biomarkers, artificial intelligence, and novel prophylactic interventions, clinicians can better stratify risk and implement early treatments. Future research focusing on next-generation constructs with engineered safety features will be essential to decouple therapeutic efficacy from neurotoxicity, ultimately optimizing outcomes for patients with advanced hematologic cancers.</p>

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Immune effector cell-associated neurotoxicity syndrome following CAR T-cell therapy: a review of recent advances

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月26日

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  • Mahsa Fatahichegeni,
  • Mohammad Amin Ansarian,
  • Yuqi Wang,
  • Juan Ren,
  • Tongxin Zhang,
  • Xiaoning Wang

摘要

Background

Chimeric antigen receptor (CAR) T-cell therapy has transformed the treatment landscape for hematologic malignancies. However, immune effector cell-associated neurotoxicity syndrome (ICANS) remains a significant and potentially lethal complication, affecting approximately 27% to 65% of patients and challenging the therapeutic risk-benefit profile.

Main body

This review synthesizes recent advances in the epidemiology, pathophysiology, diagnosis, and management of ICANS. Incidence varies significantly by product design, with anti-CD19 therapies and CD28-containing constructs demonstrating markedly higher toxicity rates compared to other targets and 4-1BB-based designs. The pathophysiological mechanism centers on blood-brain barrier disruption driven by systemic cytokine release and direct cellular injury. Monocytes and macrophages act as principal effectors, releasing interleukin-1 and granulocyte-macrophage colony-stimulating factor, which trigger endothelial activation and neuroinflammation. Clinical manifestations typically appear within the first week post-infusion, ranging from mild language disturbances to life-threatening cerebral edema. Current management has evolved from reactive symptom control to proactive strategies. Severity-based algorithms guide the use of corticosteroids and intensive care support, while emerging prophylactic approaches, particularly interleukin-1 receptor blockade with anakinra, show promise in reducing severe neurotoxicity without compromising anti-tumor efficacy. Furthermore, diagnostic precision is improving through the use of novel biomarkers, such as chimeric antigen receptor-positive extracellular vesicles, and machine-learning models that predict toxicity days before symptom onset.

Conclusions

The management of ICANS is shifting towards a precision medicine paradigm. By integrating predictive biomarkers, artificial intelligence, and novel prophylactic interventions, clinicians can better stratify risk and implement early treatments. Future research focusing on next-generation constructs with engineered safety features will be essential to decouple therapeutic efficacy from neurotoxicity, ultimately optimizing outcomes for patients with advanced hematologic cancers.