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Chimeric Antigen Receptor T Cell Therapy (CAR-T) is a new type of immunotherapy for the treatment of malignant tumors, which has shown excellent efficacy in clinical applications of hematological tumors
.
Cytokine release syndrome (CRS) is the most common adverse reaction of CAR-T cell therapy.
The clinical manifestations are diverse and involve multiple organ systems.
Severe CRS can cause multiple organ failure and even endanger the lives of patients
.
In October 2020, Tocilizumab (TCZ) was approved in China for severe or life-threatening CRS caused by CAR-T cell therapy in adult and pediatric patients 2 years and older
.
Early recognition and timely treatment of CRS has important clinical significance.
Familiar with and mastering the diagnosis, classification and treatment of CRS will bring better clinical benefits to more patients
.
Yimaitong specially invited Professor Han Weidong from the 301 Hospital of the Chinese People's Liberation Army General Hospital to be interviewed to share the clinical management experience of CAR-T CRS and the clinical application of tocilizumab in CRS
.
Yimaitong: Could you please introduce what is CAR-T treatment? Professor Han Weidong CAR-T cell therapy is an immunotherapy method.
The chimeric molecules are edited by synthetic biology methods and then introduced into T cells to achieve anti-tumor effects.
It is like installing a precise navigation system for T cells.
This system is CAR, which can specifically recognize tumor-related antigen targets, improve the recognition ability of T cells, and after recognition and binding, it will cause the activation and proliferation of T cells, thereby accurately and effectively killing tumor cells
.
The combination of a suitable costimulatory signal molecule and CAR can fully activate T cells and help improve the anti-tumor activity of CAR-T cells
.
At present, CAR-T therapy is effective in the field of B-cell malignant tumors, but its application in the field of solid tumors is still being explored
.
Yimaitong: What are the risks that CAR-T treatment will bring to patients along with the clinical benefits? Professor Han Weidong's CAR-T cells specifically recognize tumor cells and then kill tumor cells is an inflammatory process, so CAR-T treatment will bring some side effects while benefiting clinically
.
CRS: CAR-T cells specifically recognize tumor-associated antigen targets after reinfusion into the patient's body, and the recognition and binding triggers the activation of CAR-T cells, and induces a large number of inflammatory cytokines such as interleukin 1 (IL-1) and IL-2 , IL-6 and tumor necrosis factor (TNF) release
.
A large number of inflammatory cytokines released by CRS are partly derived from the above-mentioned activated CAR-T cells, and the other part is derived from cytokines represented by IL-6.
The activation of CAR-T cells further activates macrophages.
The release of large amounts of cytokines may trigger systemic CRS
.
The incidence of CRS is about 30%~60%.
The tumor burden of patients is the main factor that affects the occurrence of CRS.
The heavier the tumor burden, the higher the probability of severe CRS after CAR-T treatment.
It is necessary to carry out preventive clinical management of patients as soon as possible.
Take corresponding management measures according to the patient's CRS classification
.
Off-target effects: CAR-T cell therapy will also recognize normal body antigens and cause immune damage to them
.
For example, both tumor and normal tissue B cells express CD19 antigen.
CAR-T kills tumor cells and at the same time leads to the reduction of normal B cells.
B cells may be at a low level for a period of time after treatment, and B cells are used to maintain body fluids.
The main component of immunity, its large reduction may cause humoral immune deficiency
.
Yimaitong: Could you please talk about the recommendations of domestic and foreign guidelines on CRS management? Based on the existing clinical research data, please introduce the application of tocilizumab in the management of CRS
.
Professor Han Weidong TCZ and glucocorticoid drugs are effective methods for intervention and management of CRS.
The clinical manifestations of grade 1 CRS are simple fever, which can be relieved by supportive treatment with antipyretic and analgesics.
Grade 2 or above or grade 1 CRS appears When persistent fever is accompanied by instability of blood pressure, domestic and foreign guidelines recommend the first-line choice of TCZ
.
Domestic clinical practice believes that CRS management is "prevention more than control", and the purpose of prevention is to reduce the risk of severe CRS and shorten the duration of CRS
.
When it is clinically predicted that a patient may have severe CRS, TCZ can be used prophylactically 2-3 days before treatment to reduce the risk of severe CRS
.
TCZ has a fast onset time.
CRS patients who use ordinary antipyretics and still have a high fever should use TCZ.
If it works, the body temperature will begin to drop after about 6 hours
.
At present, the safety of TCZ has been confirmed by various studies, and no adverse events related to TCZ have been reported.
The use of TCZ will not affect the proliferation and clinical efficacy of CAR-T cells
.
Yimaitong: Based on your clinical experience, talk about the use and precautions of tocilizumab in the management of CRS
.
Professor Han Weidong CRS management is not only CRS treatment, but a process from prevention to treatment
.
Prevention of CRS: When it is clinically predicted that the patient may have severe CRS, low-dose TCZ (1-2 mg/kg) can be given prophylactically before CAR-T treatment to reduce the risk of severe CRS and reduce CAR-T cell activation After the exhaustion
.
Treatment of CRS: When CRS of grade 2 or above occurs, patients with persistent high fever and blood pressure drop are recommended to use TCZ as a first-line treatment in addition to supportive symptomatic treatment of vasoactive drugs and blood pressure drugs
.
CRS dosage: TCZ 8mg/kg intravenously for more than 1 hour (the highest dose does not exceed 800mg); if hypoxemia and hypotension cannot be improved by oxygen and fluid replacement, the administration can be repeated once every 8 hours, every 24 The dose can be repeated 3 times at most every hour, and the total dose is not more than 4 times
.
Professor Han Weidong, Doctor of Clinical Medicine, Professor, Doctoral Tutor of Clinical Oncology, Director of the Department of Biotherapy, PLA General Hospital, National tens of millions of talents, Capital Science and Technology Innovation Leading Talent, State Council Government Special Post Expert, Original Science and Technology Rising Star of the General Logistics Department, Mainly engaged in tumor treatment resistance mechanisms and tumors Clinical research on immunotherapy has successively undertaken 1 major special project of the Ministry of Science and Technology, 2 973 projects, 3 863 projects, 1 major project of the National Natural Science Foundation of China, 2 key projects, 7 general projects, and 1 Beijing Biotechnology Frontier Project Projects, 3 projects have been invested by enterprises, 4 clinical treatment technology enterprises have transferred more than 20 national invention patents and edited 3 monographs
.
As the first author or corresponding author, he has published more than 170 SCI papers in academic journals such as JCO, Cell Res, Blood, Nature Cancer, CCR, NAR, JNCI, Nat.
4 ministerial-level second-class awards or above.
In 2015, the China Research Hospital Biotherapeutics Professional Committee (Secondary Society) was established, and served as the first chairman of the "Read the original", and we will make progress together
.
Cytokine release syndrome (CRS) is the most common adverse reaction of CAR-T cell therapy.
The clinical manifestations are diverse and involve multiple organ systems.
Severe CRS can cause multiple organ failure and even endanger the lives of patients
.
In October 2020, Tocilizumab (TCZ) was approved in China for severe or life-threatening CRS caused by CAR-T cell therapy in adult and pediatric patients 2 years and older
.
Early recognition and timely treatment of CRS has important clinical significance.
Familiar with and mastering the diagnosis, classification and treatment of CRS will bring better clinical benefits to more patients
.
Yimaitong specially invited Professor Han Weidong from the 301 Hospital of the Chinese People's Liberation Army General Hospital to be interviewed to share the clinical management experience of CAR-T CRS and the clinical application of tocilizumab in CRS
.
Yimaitong: Could you please introduce what is CAR-T treatment? Professor Han Weidong CAR-T cell therapy is an immunotherapy method.
The chimeric molecules are edited by synthetic biology methods and then introduced into T cells to achieve anti-tumor effects.
It is like installing a precise navigation system for T cells.
This system is CAR, which can specifically recognize tumor-related antigen targets, improve the recognition ability of T cells, and after recognition and binding, it will cause the activation and proliferation of T cells, thereby accurately and effectively killing tumor cells
.
The combination of a suitable costimulatory signal molecule and CAR can fully activate T cells and help improve the anti-tumor activity of CAR-T cells
.
At present, CAR-T therapy is effective in the field of B-cell malignant tumors, but its application in the field of solid tumors is still being explored
.
Yimaitong: What are the risks that CAR-T treatment will bring to patients along with the clinical benefits? Professor Han Weidong's CAR-T cells specifically recognize tumor cells and then kill tumor cells is an inflammatory process, so CAR-T treatment will bring some side effects while benefiting clinically
.
CRS: CAR-T cells specifically recognize tumor-associated antigen targets after reinfusion into the patient's body, and the recognition and binding triggers the activation of CAR-T cells, and induces a large number of inflammatory cytokines such as interleukin 1 (IL-1) and IL-2 , IL-6 and tumor necrosis factor (TNF) release
.
A large number of inflammatory cytokines released by CRS are partly derived from the above-mentioned activated CAR-T cells, and the other part is derived from cytokines represented by IL-6.
The activation of CAR-T cells further activates macrophages.
The release of large amounts of cytokines may trigger systemic CRS
.
The incidence of CRS is about 30%~60%.
The tumor burden of patients is the main factor that affects the occurrence of CRS.
The heavier the tumor burden, the higher the probability of severe CRS after CAR-T treatment.
It is necessary to carry out preventive clinical management of patients as soon as possible.
Take corresponding management measures according to the patient's CRS classification
.
Off-target effects: CAR-T cell therapy will also recognize normal body antigens and cause immune damage to them
.
For example, both tumor and normal tissue B cells express CD19 antigen.
CAR-T kills tumor cells and at the same time leads to the reduction of normal B cells.
B cells may be at a low level for a period of time after treatment, and B cells are used to maintain body fluids.
The main component of immunity, its large reduction may cause humoral immune deficiency
.
Yimaitong: Could you please talk about the recommendations of domestic and foreign guidelines on CRS management? Based on the existing clinical research data, please introduce the application of tocilizumab in the management of CRS
.
Professor Han Weidong TCZ and glucocorticoid drugs are effective methods for intervention and management of CRS.
The clinical manifestations of grade 1 CRS are simple fever, which can be relieved by supportive treatment with antipyretic and analgesics.
Grade 2 or above or grade 1 CRS appears When persistent fever is accompanied by instability of blood pressure, domestic and foreign guidelines recommend the first-line choice of TCZ
.
Domestic clinical practice believes that CRS management is "prevention more than control", and the purpose of prevention is to reduce the risk of severe CRS and shorten the duration of CRS
.
When it is clinically predicted that a patient may have severe CRS, TCZ can be used prophylactically 2-3 days before treatment to reduce the risk of severe CRS
.
TCZ has a fast onset time.
CRS patients who use ordinary antipyretics and still have a high fever should use TCZ.
If it works, the body temperature will begin to drop after about 6 hours
.
At present, the safety of TCZ has been confirmed by various studies, and no adverse events related to TCZ have been reported.
The use of TCZ will not affect the proliferation and clinical efficacy of CAR-T cells
.
Yimaitong: Based on your clinical experience, talk about the use and precautions of tocilizumab in the management of CRS
.
Professor Han Weidong CRS management is not only CRS treatment, but a process from prevention to treatment
.
Prevention of CRS: When it is clinically predicted that the patient may have severe CRS, low-dose TCZ (1-2 mg/kg) can be given prophylactically before CAR-T treatment to reduce the risk of severe CRS and reduce CAR-T cell activation After the exhaustion
.
Treatment of CRS: When CRS of grade 2 or above occurs, patients with persistent high fever and blood pressure drop are recommended to use TCZ as a first-line treatment in addition to supportive symptomatic treatment of vasoactive drugs and blood pressure drugs
.
CRS dosage: TCZ 8mg/kg intravenously for more than 1 hour (the highest dose does not exceed 800mg); if hypoxemia and hypotension cannot be improved by oxygen and fluid replacement, the administration can be repeated once every 8 hours, every 24 The dose can be repeated 3 times at most every hour, and the total dose is not more than 4 times
.
Professor Han Weidong, Doctor of Clinical Medicine, Professor, Doctoral Tutor of Clinical Oncology, Director of the Department of Biotherapy, PLA General Hospital, National tens of millions of talents, Capital Science and Technology Innovation Leading Talent, State Council Government Special Post Expert, Original Science and Technology Rising Star of the General Logistics Department, Mainly engaged in tumor treatment resistance mechanisms and tumors Clinical research on immunotherapy has successively undertaken 1 major special project of the Ministry of Science and Technology, 2 973 projects, 3 863 projects, 1 major project of the National Natural Science Foundation of China, 2 key projects, 7 general projects, and 1 Beijing Biotechnology Frontier Project Projects, 3 projects have been invested by enterprises, 4 clinical treatment technology enterprises have transferred more than 20 national invention patents and edited 3 monographs
.
As the first author or corresponding author, he has published more than 170 SCI papers in academic journals such as JCO, Cell Res, Blood, Nature Cancer, CCR, NAR, JNCI, Nat.
4 ministerial-level second-class awards or above.
In 2015, the China Research Hospital Biotherapeutics Professional Committee (Secondary Society) was established, and served as the first chairman of the "Read the original", and we will make progress together
