This study found that 141 patients (11.67%) had immune system SAEs, and the incidence of SAEs from high to low was the CRS (137 cases), graft versus host disease (2 cases), etc ( Table 2 ). As a result of the high production of cytokines during CAR-T cells therapy, CRS is the most common SAEs of immune system (28). It was found that 128 cytokines may be closely related to CRS, among which IL6, IFN-γ, TNF-α, ICAM-1, VCAM-1, VEGFA and other important factors may be the key factors to predict CRS (29). Additionally, it causes SAEs throughout the body in a variety of systems (30). Cytokines are a double-edged sword in the process of CAR-T cells therapy, which can stimulate immune cells to kill tumor cells while also causing damage to normal organs of the body (31, 32).

Z. Ying et al. (33)conducted a meta-analysis involving 27 studies (1687 patients) to evaluate the safety of CD19-targeted CAR-T cells in patients with diffuse large B-cell lymphoma (DLBCL). Severe CRS and severe neurotoxicity were found in 6% (95%CI: 3-10%) and 16% (95%CI: 10-24%), respectively. Moreover, studies have shown that neurological SAEs are associated with CRS (34, 35). This suggests that CRS may contribute to neurological adverse events. Furthermore, M. Shao et al. (36) retrospectively analyzed the adverse events of 37 R/R MM patients treated with BCMA-targeted CAR-T cells. All of the 37 patients had CRS, and 34 (91%) had at least one coagulation parameter abnormality. The values of coagulation parameters were positively correlated with the severity of CRS, as well as with the levels of cytokines such as IL-6, IL-10 and IFN-γ. The findings suggest that these factors may play an important role in CRS-related coagulopathy as well as a connection between coagulopathy and CRS. In addition, J. Zhou et al. (37) retrospectively analyzed 133 patients with R/R lymphoma who received CAR-T cells therapy. Studies have found that severe neutropenia, anemia, and thrombocytopenia frequently occur after CAR-T cells infusion. Further studies found that both neutropenia and severe thrombocytopenia in severe patients were associated with the incidence of CRS and the levels of associated inflammatory factors. The above studies all reflect that CRS is an adverse events and a initiating factor causing various SAEs.

In this study, 244 patients (20.20%) developed nervous system SAEs. The incidence of clinical symptoms from high to low was encephalopathy (94 cases), speech impairment (33 cases), seizure (24 cases), somnolence (20 cases), confusion (11 cases), syncope (8 cases), and brain oedema (8 cases), headache (8 cases), etc ( Table 2 ). The most common life-threatening neurological adverse event is encephalopathy, probably due to the significant effects of CAR-T cells on cerebral vessels. Secondly, the high incidence of severe speech complications found in this study suggests that the language center may also be an easy target for CAR-T cells. Seizures are also very common, indicating that CAR-T cells disrupt brain neuronal electrical activity.

Neurotoxicity caused by CAR-T cells, also known as ICANS, is the primary cause of these complications (38). Similarly, studies have demonstrated that the most common ICANS with CAR-T cells include encephalopathy, headache, tremor, dizziness, aphasia, delirium, insomnia, and anxiety (39, 40). L. Lv et al. (41)explored the safety of CAR-T cells for central nervous system lymphoma (CNSL). A total of 63 patients were included in 8 studies in the meta-analysis, and the incidence of grade 3 or above neurotoxicity was found to be 12%. Besides, A. Gajra et al. (42) investigated adverse neurologic events associated with CAR-T cells therapy in patients with R/R large B-cell lymphoma. There are a lot of neurologic adverse events associated with CAR-T cells therapy in the real world, which is a testament to the truthfulness of clinical trial reports. Although real data on CAR-T cells-associated neurotoxicity are limited, one study found an inverse association between grade 3-4 neurotoxicity and OS (43). According to these studies, neurological dysfunction is universal and important in the clinical application of CAR-T cells therapy.

In this study, 103 patients (8.53%) developed respiratory, thoracic and mediastinal SAEs. The incidence of clinical symptoms from high to low were hypoxia (45 cases), respiratory failure (18 cases), dyspnea (12 cases), pleural effusion (10 cases), pulmonary edema (6 cases), ARDS (6 cases), pneumonitis (2 cases), etc ( Table 2 ). The most common SAEs of the respiratory system is hypoxemia, and the disease can progress to respiratory failure. Common co-symptoms are dyspnea, pleural effusion, pulmonary edema, ARDS, and pneumonia.

Researchers have found that respiratory SAEs are a leading cause of death associated with CAR-T cells therapy. J. Pan et al. (44) evaluated the safety of anti-CD7 CAR-T cells in 20 patients with R/R T cells acute lymphoblastic leukemia (NCT04689659). The results of the study found that all adverse events were reversible, except for one patient who died from a related fungal pneumonia. Similarly, in the study of R. Benjamin et al. (45), two treatment-related deaths occurred. One was caused by neutropenic sepsis complicated by CRS, and the other by pulmonary hemorrhage with persistent cytopenia. K. Rejeski et al. (46) described the clinical course of a 59-year-old patient with R/R large B-cell lymphoma who received Axicabtagene-Ciloleucel. Severe pneumonia eventually leads to respiratory failure and death. Furthermore, respiratory adverse events may be affected by CRS. A. Goldman et al. (47) retrospectively analyzed adverse events in 2657 patients who received CD19-targeted CAR-T cells therapy. Cardiopulmonary adverse events occurred in 546 patients (20.5%). Ultimately, the mortality rate for cardiopulmonary adverse events was 30.9%. Studies have shown associations between CAR-T cells and various cardiopulmonary adverse events, including rapid respiratory failure, hypoxemia, arrhythmias, cardiomyopathy, pericardial and pleural diseases. In addition, the overlapping reports of cardiopulmonary adverse events and CRS were found in 68.3% of the cases. CRS may also be involved in the pathogenesis of severe cardiopulmonary adverse events, which should be considered in the multidisciplinary evaluation and monitoring of CAR-T cells recipients.

In this study, 116 patients (9.60%) had vascular SAEs, and the main clinical SAEs were hypotension (109 cases), thrombosis (3 cases), hypertension (3 cases), etc ( Table 2 ). 68 patients (5.63%) had cardiac SAEs. The incidence of SAEs from high to low are sinus tachycardia (28 cases), atrial fibrillation (10 cases), cardiac arrest (8 cases), and supraventricular fibrillation tachycardia (5 cases), left ventricular systolic dysfunction (5 cases), heart failure (5 cases), myocardial dysfunction (2 cases), etc ( Table 2 ). Studies have found that the main SAEs of vascular complications is hypotension, the pathogenesis may be due to the occurrence of inflammation in the body produces a large number of inflammatory cytokines released into the blood, resulting in peripheral vascular dilatation (48, 49). Arrhythmias occur in the cardiovascular system to compensate for hypotension, so the most common arrhythmias are sinus tachycardia and atrial fibrillation. Severe arrhythmias can progress to cardiac arrest and eventually lead to heart failure (50). In addition, symptoms of left ventricular dysfunction have been seen in clinical studies (48, 51). Therefore, the occurrence of adverse cardiovascular events may be due to the massive cytokine release during CAR-T cells therapy.

Cardiovascular toxicity is not uncommon in patients receiving CAR-T cells therapy (52). Adam Goldman et al. (47) found that the occurrence of tachyarrhythmia was a major adverse effect of the heart. Atrial fibrillation is the main tachyarrhythmia, followed by ventricular arrhythmia. Studies have also shown an association between CAR-T cells and symptoms such as tachyarrhythmia, cardiomyopathy, pericardial and pleural disease. Additionally, 10-30% of patients also exhibit decreased left ventricular ejection function (48). R. M. Alvi et al. (53) also reported a new reduction in ejection fraction in 8 of 137 patients, 5 patients also experienced arrhythmias, and 6 patients experienced cardiovascular death. To examine cardiovascular adverse events associated with CAR-T cells, A. Guha et al. (54) used the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) to observe 996 cases in which the most commonly reported cardiovascular adverse event was arrhythmia (77.6%). This was followed by heart failure (14.3%) and myocardial infarction (0.5%). Cardiovascular adverse events associated with CAR-T cells therapy were also associated with higher mortality. Therefore, the use of CAR-T cells in tumor therapy should be vigilant for cardiovascular events.

In this study, 48 patients (3.97%) had gastrointestinal SAEs. The incidence of SAEs from high to low were abdominal pain (13 cases), diarrhea (9 cases), nausea (5 cases), colitis (4 cases), dysphagia (4 cases), pancreatitis (3 cases), etc ( Table 2 ). The adverse events of CAR-T cells on the digestive system are relatively less, and SAEs are mainly caused by gastroenteritis leading to abdominal pain, diarrhea and other clinical manifestations. A small number of adverse events of pancreatitis were also observed. These results suggest that CAR-T cells may be mainly through its cytokines acting on gastrointestinal mucosa, leading to impaired barrier function and the progression of mucositis (55). The incidence of SAEs in the digestive system is significantly less than that in the nervous, immune, cardiovascular and respiratory systems. Moreover, the severity of adverse effects is relatively mild, and no serious life-threatening adverse events have been reported.

Infection-related SAEs occurred in 116 patients (9.60%). The incidence of SAEs from high to low were lung infection (33 cases), upper respiratory infection(7 cases), sepsis (22 cases), bacteraemia(15 cases), Covid-19(4 cases), and Covid-19 pneumonia(3 cases), etc ( Table 2 ). The most common infection is a respiratory tract infection, which can involve the lungs in severe cases. Telli Dizman et al. (56) conducted a systematic review and meta-analysis of the incidence of severe infections in hematological malignancies treated with CAR-T cells. The severe infection rate was 16.2%, with the respiratory tract being the most common site of infection. This also confirms the above views. The common pathogen is bacteria, but it can also be seen in clinical studies of COVID-19 infection. Besides, severe bacteremia and septicemia are often seen. The immune barrier function may be impaired during CAR-T cells therapy, allowing opportunistic pathogens to flourish (57).

Most infections after CAR-T cells therapy occur after neutropenia and/or severe CRS, indicating a greater degree of immune impairment (58, 59). Furthermore, most CAR-T cells recipients had previously received other antitumor therapies, including autologous and allogeneic hematopoietic cell transplants. Preexisting cytopenia and hypogammaglobulinemia increase the likelihood of infection (60, 61). The occurrence of CRS co-infection may lead to a greater impact on the body, which may not respond well to antimicrobial therapy. In the study conducted by J. A. Hill et al. (58), 80% of patients had their first infection within the first 10 days after CAR-T cells infusion, mainly with gram-negative bacterial infections. Besides, 42% of patients had predominantly viral infections within 30 days of infusion, including respiratory viral infections and cytomegaloviremia and pneumonia. Later infection may reflect a state of immunoglobulin deficiency and lymphocytopenia (58). These studies suggest that serious infection-related adverse events associated with CAR-T cells therapy are not only related to CRS, but also to the patient’s immunocompromised physical condition, posing a serious threat to patient health.

Blood and lymphatic system SAEs were found in 228 patients (18.87%). The incidence of SAEs from high to low is febrile neutropenia (187 cases), neutropenia (12 cases), anaemia (9 cases), pancytopenia (8 cases), thrombocytopenia (5 cases), and disseminated intravascular coagulation (DIC) (5 cases), etc ( Table 2 ). The most common SAEs of hemolymph system is neutropenia. As an important immune cell, neutrophils play an important role in preventing the invasion of pathogenic microorganisms. However, neutrophil depletion during CAR-T cells treatment may account for the susceptibility of the body to infection-related diseases. Besides, the study found that patients also had a decrease in various blood cells and platelets (62), which indicates that the blood system may be seriously damaged during the treatment.

When injected into the bloodstream to kill tumors, CAR-T cells have been shown to be hemotoxic (62). L. Wang et al. (63) retrospectively studied the characteristics and risk factors of new-onset severe cytopenia after CAR-T cells infusion in 76 patients with R/R acute lymphoblastic leukemia. A high incidence of new severe cytopenia was found, including severe neutropenia (56,70%), severe anemia (66,53%), and severe thrombocytopenia (64,48%). The study also found that people with higher levels of CRS had higher incidence and longer duration of severe cytopenia. Multivariate analysis showed that the occurrence of CRS and higher grade of CRS were risk factors for prolonged hematotoxicity. These observations lead to the conclusion that the occurrence of CRS is associated with the incidence of severe cytopenia, suggesting that CRS may be a direct or indirect cause of hemotoxicity.

General SAEs occurred in 133 patients (11.01%). The incidence of SAEs from high to low was pyrexia (116 cases), multi-organ failure (7 cases), fatigue (3 cases), etc ( Table 2 ). The most common adverse effect of the body is pyrexia, which is mainly caused by the massive release of inflammatory factors into the blood during CRS, but the possibility of subsequent infection after the immune system is compromised cannot be ruled out (57). Therefore, it is difficult to distinguish CRS or infection from fever alone during CAR-T cell therapy.