What is the current safety profile of CAR-T? What are the common side effects?
CAR-T cells can have a variety of toxic side effects during treatment, the three most common of which are cytokine release syndrome (CRS), central nervous system toxicity, and B-cell depletion. These side effects are not necessarily related to the number of cells infused or the duration of infusion, but rather to the expansion and survival of CAR-T cells in vivo.
Cytokine release syndrome
CRS occurs as a result of induction of cytokine expression by cells involved in tumor immunity and initiation of a series of cytokine releases as CAR-T cells expand in vivo.
CRS causes a wide range of symptoms, from mild flu-like symptoms to multiple organ failure requiring intensive care treatment. Patients may experience a variety of symptoms including fever, tachycardia, hypotension, capillary leak syndrome, and/or respiratory distress syndrome, usually within 3 weeks of cell infusion.
The severity of CRS may correlate with the tumor load at the time of treatment, so modest pretreatment chemotherapy may be administered prior to cell infusion to reduce tumor load and improve the safety and efficacy of cell therapy.
Central nervous system toxicity
Central nervous system lesions, although also strongly associated with the development of CRS, are often grouped separately because of their incidence of up to 50%, and symptoms may include mild behavioral abnormalities, unresponsiveness, aphasia, and seizures. These symptoms are often reversible and are most often seen in patients with acute lymphoblastic leukemia (ALL).
The etiology is unclear and may be related to a number of factors including cytokine release, infiltration of CAR-T cells into the CNS, and the dose of CAR-T cell infusion.
B-cell depletion
B-cell depletion from CAR-T cell therapy is caused by normal B lymphocytes with the same tumor antigens also being attacked by CAR-T cells, and its duration is positively correlated with the duration of CAR-T cell survival in vivo, which can range from days to years. Prolonged B-cell depletion can lead to hypoimmunoglobulinemia, and regular sedation of immunoglobulin may reduce the risk of opportunistic infections.
What should I do if I have fever after CAR-T treatment? Does it affect the efficacy?
Fever after CAR-T cell therapy is often one of the clinical manifestations and signs of cytokine release syndrome and is an indirect reflection of the immune response of CAR-T cells in the body.
Patients with high fever may take nonsteroidal antipyretic analgesics, preferably acetaminophen tablets, and use ice packs, ice caps, and ice blankets to aid in cooling. The use of glucocorticosteroids may inhibit CAR-T cell function, so avoid using such drugs during fever. However, if the fever persists despite the use of various antipyretic measures, be alert to the possibility of severe cytokine release syndrome (CRS), and further strengthen the observation of changes in vital signs and monitoring of organ function. Patients who are at high risk for severe CRS should be treated with IL-6 antagonists or hormones as soon as possible.
The majority of patients currently receiving CAR-T are immunocompromised with advanced B-lymphocytic neoplasms and are also at high risk for fever due to infection after pretreatment with FC (fludarabine + cyclophosphamide) before receiving CAR-T cells. Fever due to infection can be treated with anti-infective drugs such as antibiotics.
What is cytokine release syndrome? How is it managed?
Cytokine release syndrome (CRS) occurs when CAR-T cells expand in vivo to induce cytokine expression by cells involved in tumor immunity and initiate the release of a series of cytokines.
The type of symptoms caused by CRS are broad and vary in severity, and can range from only mild flu-like symptoms to multiple organ failure requiring intensive care treatment. Patients typically experience fever, tachycardia, hypotension, capillary leak syndrome, and/or respiratory distress syndrome within 3 weeks of cell infusion, and elevated levels of cytokines such as serum IL-6, interferon, and IL-10 can be detected in the laboratory.
Patients with mild CRS are treated with symptomatic support. Patients with CRS grade 3-4 or those who meet the criteria for severe CRS should be monitored closely for vital signs and changes in mental status, as patients with severe CRS tend to have moderate to severe multi-organ dysfunction and very rapid disease progression. Therefore, clinicians need to evaluate and consider the functional status of the patient’s organs several times a day during the treatment of severe CRS, and to administer medications in a timely manner.
In addition, a multidisciplinary approach is essential in the management of CRS, so that patients can receive the most appropriate treatment.