Neurotoxicity associated with chimeric antigen receptor T-cell therapy

Area of Science:

• Oncology
• Immunology
• Neuroscience

Background:

• Chimeric antigen receptor T cell (CAR-T) therapy has revolutionized hematological malignancy treatment, with FDA-approved products targeting CD19 or BCMA.
• Despite efficacy, CAR-T therapy is associated with significant toxicities, including cytokine release syndrome (CRS) and immune-effector cell associated neurotoxicity syndrome (ICANS).
• Emerging toxicities, such as delayed parkinsonism with BCMA-directed therapies, highlight the need for better understanding and management.

Purpose of the Study:

• To provide a comprehensive analysis of CAR-T cell-associated neurotoxicity.
• To explore novel pathophysiological insights, clinical manifestations, and diagnostic evaluations for ICANS.
• To identify candidate biomarkers and review current therapeutic strategies for ICANS management.

Main Methods:

• Literature review focusing on CAR-T therapy, neurotoxicity, ICANS, and related biomarkers.
• Analysis of clinical data, preclinical studies, and ongoing clinical trials.
• Synthesis of information on disease mechanisms, diagnostic approaches, and treatment options.

Main Results:

• CAR-T associated neurotoxicity presents with diverse neurological and cognitive symptoms, ranging from tremors to seizures and cerebral edema.
• Understanding of ICANS mechanisms, clinical correlates, and predictive biomarkers remains limited, hindering prophylactic interventions.
• Delayed-onset neurotoxicity, including parkinsonism, has been observed with specific CAR-T constructs like BCMA-directed therapies.

Conclusions:

• CAR-T cell-associated neurotoxicity, particularly ICANS, represents a significant challenge requiring further investigation.
• Development of predictive biomarkers and targeted therapies for ICANS is a critical unmet need.
• This review consolidates current knowledge and highlights key areas for future research in managing CAR-T therapy-related neurotoxicity.