The mechanism of action of CAR-T
Chimeric antigen receptor T cell therapy (CAR-T therapy for short) extracts the patient’s own immune T cells from the blood and delivers them in vitro. T cells are loaded with chimeric antigen receptors (CARs) that can specifically recognize tumor cell antigens, and then the CAR-T cells are infused back into the patient. The CAR-T cells use the CAR structure to accurately identify specific cancer cells in the patient's body and interact with the cancer. After the cells are combined, the immune effect is amplified through self-growth, and ultimately all cancer cells are killed.
Toxic side effects of CAR-T
CAR-T cell immunotherapy has achieved impressive results in the treatment of certain relapsed/refractory blood cancers, and has been used in the past ten years. The mid-year period saw an explosion of growth as the immunotherapy field developed. However, severe and occasionally fatal toxicities, especially cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), remain a problem in the clinical application of CAR-T.
Cytokine release syndrome
Cytokine release syndrome (CRS), also known as Cytokine storm, is the most common after CAR-T cell infusion Toxic side effects. CRS usually occurs in the first week after CAR-T cell therapy, with a high incidence, with over 80% of patients experiencing grade 3 or above hematological toxicity and almost 100% of immunological toxicity. The incidence of CRS after CAR-T cell therapy in patients with multiple myeloma can be as high as 90%.
As early as 1993, Ferrara et al. coined the term "Cytokine storm" to describe the clinical manifestations of acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. CRS has also been reported during the influenza and COVID-19 pandemic. Simply put, CRS means that foreign pathogens or transplants activate the body's immune response. Immune cells secrete some inflammatory factors that can induce and recruit immune-enhancing factors. These factors recruit and recruit more helpers. When a pathogen is tough, it can elicit an unusually strong inflammatory response. When this factor is so strong that it is difficult for the autoimmune system to control it, a so-called "Cytokine storm" is formed. After the occurrence of CRS, it may cause multiple organ failure and even be life-threatening.
Immune effector cell-associated neurotoxicity syndrome
Immune effector cell-associated neurotoxicity syndrome (ICANS), also known as neurotoxicity, is another type of neurotoxicity after CAR-T cell therapy. Common and unique toxicities. ICANS occurs in up to 67% of leukemia patients and 62% of lymphoma patients, generally occurs within 1 to 3 weeks after CAR-T cell infusion, often accompanied by CRS, and occasionally occurs independently of CRS.
In 2017, the Neelapu team first proposed the concept of "CAR-T cell-related encephalopathy syndrome (CRES)", which refers to the headache, delirium, and tremor that occur in some patients during CAR-T cell therapy. , mental status changes, language disorders and other neurological abnormalities. In 2019, the American Society for Transplantation and Cell Therapy (ASTCT) further proposed the concept of "immune effector cell-associated neurotoxicity syndrome (ICANS)", that is, after immunotherapy including CAR-T cells, the patient's endogenous and exogenous A series of clinical manifestations of neurological abnormalities caused by the activation or involvement of T cells and other immune effector cells.
IL-6 detection and CAR-T treatment
The elevated level of circulating cytokines is one of the indicators for the diagnosis of CRS. Studies have shown that the pro-inflammatory cytokine interleukin-6 (IL-6) is significantly increased in patients with CAR-T CRS and ICANS complications, indicating that IL-6 plays an important mediating role in the development of CRS and ICANS.
Preclinical models of CRS show that transplanted human CAR-T cells activate myeloid cells through the production of IFNγ and granulocyte-macrophage colony-stimulating factor (GM-CSF), and host myeloid cells interact with tumors. And CART cells release a large amount of IL-6 and iNOS when localized. Myeloid cell hyperactivation also plays an important role in the development of ICANS.
Nonhuman primate models of ICANS show high levels of IL-6 and GM-CSF in the cerebrospinal fluid after CAR-T cell administration.
IL-6 detection is used for CRS monitoring
The knowledge of experts on CAR-T treatment of hematology in China pointed out:
1) Acute B lymphocytes During the infusion of leukemia (B-ALL) CAR-T cells, if the patient develops an adverse infusion reaction caused by allergy, the infusion should be stopped immediately, anti-allergic treatment and rescue should be carried out immediately, and the CAR-T cell preparation and the patient's peripheral blood should be detected at the same time. Blood pathogenic microorganisms, and inflammatory indicators such as peripheral blood cytokines, high-sensitivity C-reactive protein (CRP), procalcitonin (PCT), etc. are detected.
After CAR-T cell infusion, in order to prevent CRS and other related complications, vital signs, blood routine, coagulation function, liver and kidney function, and cytokines (such as IL-6, IFN- γ), CRP and other indicators.
2) When multiple myeloma (MM) patients develop CRS after CAR-T cell infusion, they should undergo daily physical examination and monitor blood routine, coagulation function, IL-6, CRP and other indicators. Assess vital signs at least every 4 hours under supervision.
IL-6 detection is used for ICANS auxiliary diagnosis
For all patients after CAR-T cell infusion, Chinese experts in the management of neurological toxicities and side effects related to CAR-T cell therapy** *It is recommended to use CARTOX-10 or ICE scoring scale to conduct neurological assessment twice a day. When a patient develops clinical manifestations of ICANS, the number of evaluations should be increased in a timely manner, and the patient's blood routine, coagulation function, cytokine levels and other indicators should be closely monitored.