Introduction
Chimeric antigen receptor T-cell (CAR-T) therapy has revolutionized the treatment landscape for hematological malignancies such as leukemia and lymphoma, offering unprecedented remission rates. However, the clinical application of CAR-T therapy is limited by a spectrum of potentially severe adverse events, collectively termed CAR-T cell-associated toxicities. These toxicities include cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), cytopenias, and on-target off-tumor effects. Addressing these complications is critical for maximizing therapeutic benefit and ensuring patient safety. This article comprehensively reviews the major toxicities related to CAR-T therapy, explores underlying mechanisms, and discusses current and emerging strategies for toxicity management.
Cytokine Release Syndrome (CRS)
CRS is the most common and well-characterized toxicity associated with CAR-T therapy. It is an acute systemic inflammatory response caused by rapid and massive proliferation of CAR-T cells and subsequent release of proinflammatory cytokines such as interleukin-6 (IL-6), interferon-gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α), and granulocyte-macrophage colony-stimulating factor (GM-CSF). The activation of monocytes and macrophages further amplifies the cytokine cascade.
Clinically, CRS symptoms range from mild flu-like manifestations including fever, fatigue, and myalgias to severe, life-threatening complications such as hypotension, hypoxia, coagulopathy, and multiorgan failure. CRS typically develops within days of CAR-T cell infusion and its severity correlates with tumor burden, CAR-T dose, and the specific target antigen.
Management of CRS
Management of CRS requires prompt recognition and grading of severity, commonly using standardized scales such as the ASTCT consensus grading system. Mild cases often respond to supportive care including antipyretics and intravenous fluids. For moderate to severe CRS, targeted immunomodulatory therapy is necessary.
Tocilizumab, an IL-6 receptor antagonist, is FDA-approved for treating CRS and has demonstrated efficacy in reducing symptoms and cytokine levels without impairing CAR-T cell function. For severe or refractory CRS, corticosteroids are employed to dampen the hyperinflammatory response. Emerging agents such as the TNF-α inhibitor etanercept and the IL-1 receptor antagonist anakinra are under clinical investigation as adjunctive or alternative therapies.
Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS)
ICANS is a neurotoxic complication often occurring concurrently with or following CRS. Patients may present with symptoms ranging from mild confusion, aphasia, and tremors to seizures, cerebral edema, and coma. Pathophysiologically, ICANS is associated with elevated cytokines in cerebrospinal fluid (CSF), disruption of the blood–brain barrier (BBB), and infiltration of activated myeloid cells into the central nervous system.
Unlike CRS, IL-6 inhibition with tocilizumab has limited efficacy in ICANS due to poor penetration across the BBB. Corticosteroids remain the mainstay treatment, especially for moderate to severe neurotoxicity. Intrathecal administration of tocilizumab is being explored for refractory cases.
Novel approaches targeting monocyte and macrophage activation through GM-CSF inhibition, such as with lenzilumab, have shown promise in preclinical and early clinical studies by reducing both CRS and neurotoxicity.
Cytopenias and On-Target Off-Tumor Toxicities
Persistent cytopenias are frequently observed following CAR-T therapy due to lymphodepleting chemotherapy, CAR-T cell activity, and immune-mediated mechanisms. These cytopenias increase infection risk and require supportive management with growth factors and transfusions.
On-target off-tumor toxicity (OTOT) arises when CAR-T cells target antigens expressed on both malignant and normal tissues, leading to unintended tissue damage. For example, CD19-directed CAR-T cells can attack normal B cells causing hypogammaglobulinemia. Similarly, CAR-T therapies targeting antigens such as HER2 or Claudin18.2 have been associated with damage to normal epithelial tissues expressing these antigens.
Strategies to Mitigate CAR-T Toxicities
CAR Structure Modification
Engineering CAR constructs to reduce toxicity risk is a promising approach. Incorporating 4–1BB costimulatory domains rather than CD28 reduces cytokine production and toxicity risk. Modifying the hinge region to decrease flexibility has shown to lower inflammatory cytokine secretion.
Suicide Gene Systems
Incorporation of suicide genes such as herpes simplex virus thymidine kinase (HSV-TK) or inducible caspase 9 (iCasp9) enables controlled elimination of CAR-T cells in cases of severe toxicity, providing a safety switch.
Split CAR Systems
Split or dual CAR systems require co-recognition of two tumor antigens to activate cytotoxicity, enhancing specificity and reducing off-tumor effects. Examples include AND gate CARs targeting ALK and B7H3 or GD2, which minimize damage to normal tissues.
Pharmacologic Interventions
Targeted therapies such as JAK inhibitors (ruxolitinib) and BTK inhibitors (ibrutinib) are emerging as adjuncts to manage toxicity by modulating cytokine signaling pathways without compromising antitumor activity.
Monitoring and Early Intervention
Routine clinical monitoring and early identification of toxicities using standardized grading systems are essential for timely management and improved outcomes.
Emerging Applications of CAR-T Therapy Beyond Oncology
Beyond cancer, CAR-T cells are being explored for autoimmune diseases such as systemic lupus erythematosus and immune-mediated necrotizing myopathy, with encouraging early safety and efficacy data. These applications highlight the expanding potential of CAR-T therapies and underscore the importance of understanding and managing associated toxicities.
Conclusion and Future Perspectives
CAR-T cell therapy represents a major advancement in immunotherapy, offering durable remissions for hematological malignancies. However, toxicity management remains a critical challenge. Advances in genetic engineering, pharmacological modulation, and clinical monitoring are progressively enhancing the safety profile of CAR-T therapies.
Future research should focus on refining CAR design, developing effective combination therapies, and expanding universal CAR-T approaches to improve accessibility and reduce costs. A multidisciplinary approach integrating molecular insights with clinical management will be essential to maximize patient benefit and safely extend CAR-T therapies to broader indications.
