Chimeric antigen receptor T (CAR-T) cells represent a rapidly evolving cellular immunotherapy technology in recent years. Currently, CAR-T cell therapy has transitioned from theoretical research to clinical practice, demonstrating remarkable efficacy particularly in the treatment of hematologic malignancies and autoimmune diseases. With the increasing clinical application of CAR-T cell therapy, growing attention has been directed toward the associated adverse reactions and effective management strategies. Common severe adverse events include cytokine release syndrome, neurotoxicity, off-target effects and allergic reactions, insertional mutagenesis leading to secondary malignancies, graft-versus-host disease, and failure to effectively recognize target antigens—any of which may become life-threatening if not promptly managed. This article provides an overview of adverse reaction definitions, mechanisms, clinical manifestations, diagnostic approaches, and grading systems, while also discussing prevention strategies based on clinical case studies and treatment guidelines. Through improvements in genetic modification and clinical nursing practices, we aim to offer medical professionals and researchers insights into CAR-T cell application and optimization.

Post-Infusion Toxicity Monitoring

Following CAR-T cell infusion, close monitoring of patients' physiological parameters is essential to predict adverse reactions. According to the 2022 Chinese Society of Clinical Oncology (CSCO) guidelines for CAR-T cell therapy in hematologic malignancies and infection management related to immune-targeted therapy, as shown in Figure 1, monitoring can be categorized into five major groups: routine examinations, laboratory tests, cell-related assays, and others.

(Figure 1: Recommendations for post-infusion toxicity monitoring)

The 0-28 day period post-infusion is critical for uating therapeutic efficacy and predicting relapse. The European Society for Blood and Marrow Transplantation (EBMT) has provided hospitalization and follow-up recommendations to facilitate observation and emergency care [1].

(Figure 2: Recommended monitoring schedule for 0–28 days post-infusion)

01 Cytokine Release Syndrome (CRS)

CRS is the most common adverse event associated with CAR-T cell therapy. It is a non-antigen-specific toxicity resulting from high-level immune activation, leading to systemic inflammatory responses, hemodynamic instability, and potentially multi-organ dysfunction or death. It occurs in over 90% of patients receiving CAR-T cell therapy. CRS typically begins 2-3 days after CAR-T cell infusion and peaks at 7-10 days [2]. Common manifestations are shown in Figure 3 [3]. Researchers have modified first-generation CARs by integrating the signaling domains of CD28 or 4-1BB to provide co-stimulatory signals, enabling CAR-T cells to expand and persist longer in vivo while exerting antitumor effects. However, this approach is a double-edged sword, as it significantly increases the risk of CRS [4]. Two primary mechanisms have been proposed for CRS pathogenesis: first, dysregulated inflammation mediated primarily by IL-1 and IL-6, leading to disruption of the pro-inflammatory/anti-inflammatory balance; second, endothelial activation and dysfunction [5].

(Figure 3: Main manifestations and severe CRS-related events)

Several grading systems are used in clinical research for CRS. The Common Terminology Criteria for Adverse Events (CTCAE) version 4.0, developed by the U.S. Department of Health and Human Services, defines five grades with increasing severity, where Grade 5 indicates death. Grades 1-4 criteria are shown in Figure 4.

(Figure 4: CRS grading)

Severe CRS is positively correlated with tumor burden and is characterized by markedly elevated IL-6 levels. IL-6 elevation can reflect the proliferation level of CART cells in vivo, serving as a predictor of therapeutic efficacy [6]. Studies have also found that IL-1 is produced 24 hours earlier than IL-6 and can induce IL-6 and soluble IL-6R secretion. Administration of IL-6 or IL-1 receptor antagonists concurrently with CAR-T cell infusion can effectively prevent CRS. Tocilizumab, an IL-6 receptor inhibitor, is an FDA-approved monoclonal antibody that rapidly controls CRS symptoms [7]. Systemic corticosteroids can quickly control CRS symptoms without impairing initial antitumor efficacy; however, prolonged use (>14 days) at high doses may compromise antitumor effects. Step-up dosing regimens—administering incremental cell doses over multiple infusions—or using first- or second-generation CARs before progressing to next-generation products can help prevent massive adverse reactions. Additionally, the introduction of "suicide genes" enables selective elimination of CAR-T cells. Herpes simplex virus thymidine kinase (HSV-tk) is the most typical suicide gene, widely used in combination with ganciclovir (GCV) for treating various malignancies. HSV-tk has been incorporated into CAR-T cells targeting CD44v6. Preclinical studies have demonstrated that anti-CD44v6 CAR-T cells expressing HSV-tk exhibit potent antitumor efficacy and can be effectively eliminated upon GCV exposure. Another widely used approach is the inducible caspase 9 (iCasp9) safety switch. Administration of a dimerizing chemical inducer (AP1903) induces dimerization and activates downstream caspase molecules, leading to apoptosis of cells expressing the fusion protein. Researchers have co-expressed CD19-targeted CAR with IL-15 and iCasp9 (iCasp9/CAR-CD19/IL-15), and drug-mediated activation of iCasp9 effectively eliminated CAR-T cells, further enhancing safety and clinical applicability [8]. According to CSCO guidelines, different management strategies are recommended based on CRS grade. Additionally, various detailed nursing measures are employed in clinical practice, such as for hypotension: (1) continuous cardiac monitoring; (2) bed rest in supine or semi-recumbent position, with slow and small-range position changes; (3) the "three 30-second" rule: lie flat for 30 seconds upon waking, sit semi-recumbently for 30 seconds, and stand for 30 seconds with feet hanging before walking if no dizziness occurs [9,10].

(Figure 5: Graded management of CRS)

02 Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS)

ICANS includes CAR-T cell-related encephalopathy syndrome (CRES) and other neurological abnormalities secondary to immunotherapy. It is defined as central nervous system pathology and dysfunction resulting from T-cell infusion or activation/response of endogenous immune effector cells [11]. Its incidence ranges from 20% to 64%, with onset typically on day 4 post-infusion and duration of 5-17 days. ICANS may occur concurrently with CRS, following CRS resolution, or in the absence of CRS [12]. Gust et al. demonstrated that endothelial activation and blood-brain barrier disruption may contribute to CAR-T cell entry into the CNS and neurotoxicity, highlighting the important role of cerebrovascular pericytes [13]. Preliminary data also suggest that upregulation of α4β1 integrin—a key mediator of T-cell migration across the blood-brain barrier—may facilitate CAR-T cell entry into the brain [14]. Early ICANS manifestations include headache, inattention, tremor, aphasia, and dysgraphia. Other signs and symptoms include delirium, confusion, disorientation, and somnolence. Symptoms may progress to global aphasia, severe consciousness disturbances, motor deficits, seizures, and cerebral edema [15].

(Figure 6: Common neurological toxicities)

The American Society for Transplantation and Cellular Therapy (ASTCT) consensus recommends the ARYOX-10 screening tool for assessment, incorporating papilledema, intracranial pressure, and imaging findings into grading. The grading system proposed by Neelapu et al. (CAR-T Therapy-Related Toxicity [10 points]) defines four ICANS grades as shown in Figure 7.

(Figure 7: ICANS grading)

To further reduce treatment-related toxicities, in addition to extensive clinical and basic research and long-term follow-up providing optimal prevention strategies, more intensive preconditioning chemotherapy may be administered earlier in the disease course or prior to treatment to reduce tumor burden [16]. High serum cytokine levels and high CAR-T cell counts in patients with severe neurotoxicity support the association between CRS and neurotoxicity. Pre-existing neurological comorbidities are also associated with increased ICANS risk. Additionally, lower platelet counts at the time of CAR-T cell infusion correlate with more severe neurotoxicity [17]. Grade 1 ICANS is managed symptomatically, such as elevating the head of the bed to 30°. For ICANS ≥ Grade 1 with concurrent CRS, IL-6 or IL-6R antagonists are used. For ICANS ≥ Grade 2 without CRS, corticosteroids are administered and tapered to Grade 1 CRES improvement. Patients with ≥ Grade 3 ICANS are recommended for ICU admission, and plasmapheresis may be performed at the bedside if severe [18]. Close monitoring of consciousness is essential; for patients with difficulty closing eyes or conjunctival edema, saline-soaked gauze should cover the eyes. Sedatives such as diazepam or phenobarbital are given as ordered, and head cooling measures are implemented to protect brain tissue.

(Figure 8: Graded management of ICANS – CSCO guidelines)

References

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