Exploring CAR-T Cell Therapy Side Effects: Mechanisms and Management Strategies

Abstract

Chimeric antigen receptor (CAR) T cell therapy has revolutionized the treatment of malignancies, especially hematological tumors, but toxicities have tempered its success. The main impediments to the development of CAR-T cell therapies are the following: cytokine release syndrome (CRS), immune-effector-cell-associated neurotoxicity syndrome (ICANS), tumor lysis syndrome (TLS), and on-target/off-tumor toxicity (OTOT). This review summarizes these side effects' underlying mechanisms and manifestations over time. It provides potential prevention and treatment according to the consensus grading, stressing the significance of establishing strategies that anticipate, reduce, and navigate the beginning of these side effects. It is essential to fully comprehend the mechanisms underlying these toxicities to create efficient treatment and preventive approaches.

Keywords: CAR-T cell; cytokine release syndrome; immune-effector-cell-associated neurotoxicity syndrome; management; mechanisms; strategies.

Figure 1

CAR-T cell therapy. The CAR-T cells are expanded before infusion into the patient’s bloodstream following lymphodepletion chemotherapy (LDC). Once in the body, the genetically modified chimeric antigen receptors (CARs) allow the T cells collected from the patient to recognize and attack cancer cells expressing specific antigens.

Figure 2

The underlying mechanisms of CRS and ICANS. CAR-T cells produce cytokine storm, which activates bystander immune cells. When CD40L on CAR-T cells interacts with CD40 on immune cells and endothelial cells, an inflammatory response occurs, with interleukin-6 (IL-6) playing a major role in the cytokine release positive feedback loop, compromising vascular integrity. The perforin produced by CAR-T cells induces tumor pyroptosis, releasing danger-associated molecular patterns (DAMPs). CAR-T cells, immune cells, and cytokines can penetrate the disrupted blood–brain barrier (BBB) and trigger inflammatory reactions in the central nervous system (CNS), resulting in neuronal injury.

Figure 3

The manifestations of CRS and ASTCT CRS consensus grading. The initial fever may progress to numerous hematologic and organ toxicities before the clinical signs of cytokine release syndrome (CRS) appear. ASTCT classified it into four grades based on its chief manifestation: hypoxia, hypotension, and fever. Continuous positive pressure airway (CPAP); bilevel positive airway pressure (BiPAP).

Figure 4

ICANS and ASTCT CRS consensus grading for adults. Immune effector cell associated neurotoxicity syndrome (ICANS) includes multiple distinct neurologic symptoms. ASTCT graded ICANS into four categories based on an immune effector cell associated encephalopathy (ICE) score: depressed level of consciousness, seizure, elevated intracranial pressure (ICP)/cerebral edema, and motor findings.