Symptoms include fever, hypotension, hypoxemia, neuropsychiatric abnormalities, fatigue, muscle soreness, loss of appetite, diarrhea, gastrointestinal bleeding, liver and kidney function damage, pulmonary hemorrhage, arrhythmia, cardiac arrest, coagulation abnormalities, etc. Among these, fever, hypotension, hypoxemia, and neuropsychiatric abnormalities are the most common and require close attention. In addition, during our clinical practice of CAR-T cell therapy, we have also encountered rare situations such as massive gastrointestinal bleeding, diffuse alveolar hemorrhage, arrhythmia, cardiac arrest, and severe coagulation abnormalities. If any of these conditions are not handled properly, they will seriously threaten the patient's life and require early close attention and timely intervention.
The occurrence and severity of CRS are closely related to the following factors:
Tumor Burden: Generally speaking, the heavier the tumor burden, the higher the probability of severe CRS after CAR-T cell therapy.
CAR-T Cell Structure: The structure of CAR-T cells during preparation also has an important impact on CRS. Using CD28 as a co-stimulatory molecule will cause CAR-T cells to rapidly expand in a short period of time. While killing tumor cells, CRS may also be aggravated. Using 4-1BB as a co-stimulatory molecule results in relatively moderate early T cell expansion in vivo and longer persistence in vivo. In addition, third-generation CAR-T cells have enhanced killing effects compared to second-generation cells, not only strengthening the ability of CAR-T cells to specifically recognize tumor antigens and bind to them, but also significantly amplifying cell signals transmitted from the extracellular region, causing cascade amplification of downstream cell killing effects. Correspondingly, the CRS brought about may be more severe than that of second-generation CAR-T cells.
CAR-T Cell Infusion Dose: Currently, there is no unified standard dose for acute lymphoblastic leukemia or lymphoma, but it is generally believed that under the same conditions, the larger the dose of CAR-T cells infused, the higher the risk of causing severe CRS.
Type of Disease Treated with CAR-T: Our clinical practice has found that for different targets or different primary diseases, the severity of CRS occurrence also varies. Usually, the most severe is acute B-lymphoblastic leukemia, followed by B-cell lymphoma. Relatively stable are BCMA-CAR-T cell therapy for multiple myeloma and CD30-CAR-T cell therapy for Hodgkin's lymphoma. CD33-CAR-T cell therapy for acute myeloid leukemia can cause severe CRS and other complications and is not a highly safe target. Our team is seeking to explore other safer and more efficient targets.
CAR-T cell therapy, similar to allogeneic hematopoietic stem cell transplantation, is a systematic project, not simply infusing CAR-T cells. Therefore, pre-infusion, during-infusion, and post-infusion management are all very important and related to the success of CAR-T cell therapy. Based on the high-risk factors for CRS mentioned above.
Currently, there is no unified conclusion on the understanding of neurotoxicity during CAR-T cell therapy. Some scholars believe it is a manifestation of systemic CRS in the nervous system, while others believe it is a special pathophysiological process caused by CAR-T cells independent of CRS. The incidence of neurotoxicity is not as high as reported in the literature. The occurrence of central nervous system toxicity is not significantly correlated with whether the patient has tumor central nervous system infiltration. Multiple studies and our clinical practice have confirmed that CAR-T cells can cross the blood-brain barrier and clear central nervous system leukemia. Some studies believe it is the direct effect of CAR-T cell toxicity on the central nervous system, but this has not been confirmed. The pathophysiological mechanism of its occurrence is also unclear. Similar events have occurred in patients treated with bispecific T-cell engagers, but there is no participation of CAR-T cells in the treatment process with bispecific antibodies. Therefore, in other patients with central CRS, we selected some patients to test cerebrospinal fluid and found that in addition to significantly increased protein, cytokine levels were also significantly increased. Combined with literature, we speculate that the occurrence of nervous system toxicity may be related to damage to the blood-brain barrier, endothelial cell damage, and massive entry of cytokines.
Neurotoxicity can manifest as decreased calculation ability, time and place disorientation, visual field defects, delirium, agitation, mental abnormalities, and even coma, especially in pediatric patients whose blood-brain barrier is weaker and may be more prone to neurotoxicity than adults. Once neurotoxicity occurs, it needs to be treated immediately. In the case of controlled systemic CRS, tocilizumab should be used with caution as it may further increase intracranial cytokine concentrations, leading to aggravated central toxicity. Once central toxicity is considered, dexamethasone should be used immediately, which has good central penetration. The dosage should be rapidly reduced after symptom control. If necessary, intrathecal injection of glucocorticoids can be considered, and dehydration and antiepileptic drugs should be used according to the situation.
Since patients receiving CAR-T cell therapy are basically refractory or relapsed cases who have previously received intensive or multi-line treatment at other medical centers, or even one or two hematopoietic stem cell transplants, such patients' immune function is severely compromised. During CAR-T cell therapy, they need to receive fludarabine and cyclophosphamide pretreatment, further lowering immune function. Coupled with factors such as CAR-T cells and CRS, the recovery of white blood cells and other cells in patients is slower than in those receiving chemotherapy alone. This series of factors determines that patients receiving CAR-T cell therapy are high-risk groups for infection.
From the beginning of patient admission, especially for patients who have previously received intensive treatment, throat and anal swabs should be screened for drug-resistant bacteria colonization. If present, they should be treated according to routine protocols for drug-resistant bacteria colonization to avoid deep infections during treatment that could endanger life. During CAR-T cell therapy, routine prophylaxis can be used following the routine for hematopoietic stem cell transplantation, using co-trimoxazole and acyclovir, etc., and monitoring cytomegalovirus nucleic acid during the course of the disease. Once the patient develops fever, it should be treated immediately according to the principles of neutropenia with fever. During the treatment process, special attention should be paid to the emergence of multi-drug resistant bacteria. Once multi-drug resistant bacteria appear, the condition progresses rapidly, and respiratory failure, shock, and other symptoms may occur in a short period of time leading to death.
