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Sponsored by the Chinese Medical Association, Hematology Branch of Chinese Medical Association, Leukemia and Lymphoma Group of Hematology Branch of Chinese Medical Association, Hematology Hospital of Chinese Academy of Medical Sciences (Institute of Hematology, Chinese Academy of Medical Sciences), First Affiliated Hospital of University of Science and Technology of China The 16th National Leukemia and Lymphoma Academic Conference hosted by the Chinese Medical Association will be held in Hefei, Anhui Province on October 8-10, 2021
.
At this conference, Professor Huang He from the First Affiliated Hospital of Zhejiang University School of Medicine gave a theme report on "New Progress in the Research of Universal Chimeric Antigen Receptor T Cells (CAR-T Cells)".
Yimaitong organized the main contents as follows
.
Professor Huang He first briefly introduced the current status of CAR-T therapy and the advantages of universal CAR-T
.
CAR-T cell therapy technology is a major revolution in the medical field.
At present, the FDA has approved 5 CAR-T products to be marketed for the treatment of hematological tumors
.
CAR-T therapy has a complete remission (CR) rate of 70%-90% in acute leukemia, a CR rate of more than 60% in patients with multiple myeloma (MM), and a CR rate in malignant lymphoma.
50%
.
However, most CAR-T products need to be prepared individually, and there are some difficulties and challenges in the treatment process
.
A longer preparation time may result in patients being unable to reinfuse T cells due to disease progression, increasing the risk of treatment
.
The high failure rate of preparation and low T cell levels in some patients may also affect the treatment outcome of patients
.
In addition, individualized preparation has also resulted in relatively expensive CAR-T products and a heavier treatment burden
.
Professor Huang He said that in order to enable more patients to benefit from CAR-T therapy, universal CAR-T is currently an important research direction
.
The universal CAR-T does not require a long waiting time for preparation and can avoid related treatment risks
.
At the same time, the universal CAR-T is derived from healthy donors and has strong T cell activity, which can effectively avoid tumor contamination
.
In addition, the industrialized production process of universal CAR-T can effectively reduce costs and treatment costs, reduce the medical burden of patients, and increase accessibility
.
Professor Huang He then briefly introduced the clinical data of the current universal CAR-T
.
The research results reported at the 2018 ASH Conference showed that the CR/Complete Remission (CRi) rate with incomplete recovery of hematology reached 82% for the universal CAR-T treatment of B-cell acute lymphoblastic leukemia (B-ALL).
The negative rate of residual disease (MRD) reached 71%
.
The results of a study announced at the 2019 ASH Conference showed that the overall response rate (ORR) of the universal CAR-T treatment of B-cell non-Hodgkin's lymphoma (B-NHL) reached 66.
7%
.
The results of the study announced at the ASCO conference in 2020 showed that the ORR of the universal CAR-T treatment of B-NHL reached 63%, and the CR rate reached 37%
.
In this study, the general-purpose CAR-T has good safety, and the incidence of cytokine release syndrome (CRS) of grade ≥3 is only 5%
.
New progress in the research of universal CAR-T cells targeting B-cell hematological diseases The first-generation universal CAR-T cell CTA101 targets both CD19 and CD22, and knocks out the TRAC locus and CD52 gene through CRISPR/Cas9 to avoid host immune excretion Different
.
A study conducted by Professor Huang He's team explored the efficacy of CTA101 in relapsed and refractory B-ALL
.
A total of 6 patients were enrolled in the study.
All patients received pretreatment chemotherapy and infusion of CTA101 product.
The time from enrollment to infusion did not exceed 8 days
.
The results of the study show that CTA101 is safe for the treatment of relapsed and refractory B-ALL.
There is no dose-limiting toxicity (DLT), graft-versus-host disease (GVHD), and immune effector cell-related neurotoxic syndrome (ICANS).
The grade 3 CRS that occurred in the study can be recovered within 7 days after tocilizumab and glucocorticoids.
At the same time, no lentivirus with strong replication ability (RCL) was detected
.
The CR/CRi rate of CTA101 in the treatment of relapsed and refractory B-ALL reached 83.
3% (5/6).
At a median follow-up of 4.
3 months (range: 2-8), 3 patients with CR/CRi were still MRD-negative.
.
One patient received allogeneic hematopoietic stem cell transplantation in remission
.
In addition, the expansion of CAR-T cells in peripheral blood in the study is good
.
The expansion of CAR-T cells in 6 patients was monitored by qPCR, and it was found that all reached the peak value on day 10-14, and the median duration of CTA-101 in the body reached 42 days
.
By flow cytometry on the 28th day after treatment, CAR-T cell expansion could still be observed in 5 patients
.
Professor Huang He said that he looks forward to the development of follow-up multi-center studies to further verify the efficacy of CTA-101
.
New progress in the research of universal CAR-T cells for targeted T-cell hematological diseases Professor Huang He said that at present, universal CAR-T cells for targeted T-cell hematological diseases still face many challenges
.
First of all, tumorous T cells may contaminate CAR-T cells, and it is necessary to develop CAR-non-T cells (such as CAR-NK, CAR-Mac, etc.
) or prepare allogeneic CAR-T cells
.
Secondly, after CAR-T cells are reinfused into the patient's body, after suicide injury, it is necessary to select a suitable T cell target and knock out T cell related molecules through gene editing technology
.
In addition, the lack of T cells after CAR-T cell therapy is also a challenge
.
It is necessary to develop CAR-T cells with "safety switches", or to bridge allogeneic hematopoietic stem cell transplantation after CAR-T cell therapy in patients
.
Professor Pan Jing's team from Beijing Boren Hospital has carried out a study on the treatment of T-cell leukemia with CD7 CAR-T cells from donors
.
A total of 20 patients were included in the study, of which 12 patients relapsed after allogeneic hematopoietic stem cell transplantation, and 8 patients had never received a transplant before
.
Patients who relapse after transplantation use the original donor's T cells to prepare CAR-T, and non-transplant patients use haploidentical or fully-identical donor T cells to prepare CAR-T
.
The results of the study showed that 17 patients achieved CR, 1 patient had reduced extramedullary lesions, and 2 patients could not achieve CR or relapse due to loss of CD7 expression.
Among them, CD7-negative relapsed patients were detected with CD7 exon gene mutations resulting in loss of CD7 expression
.
The side effects of CD7 CAR-T are controllable.
The incidence of CRS ≥3 is only 10%, and no ICANS ≥2 occurs
.
In addition, the study found that donor-derived CD7 CAR-T was significantly amplified
.
CD7-negative T cells are expanded in large numbers to achieve cellular immune function and avoid serious infections
.
Stem cell sources and different chassis CAR immune cells have the advantages of strong clonal expansion potential, easy realization of multi-gene manipulation, and high cell consistency
.
Related studies recruit T cells from NK (iNK) cells derived from induced pluripotent stem cells (iPSC), and cooperate with T cells and anti-PD-1 antibodies to further promote the production of inflammatory cytokines and tumor killing effects
.
The iPSC-derived CD16 prepared by this method enhances the partial remission (PR) rate of NK cells in the treatment of B-cell lymphoma to 72.
7% (8/11).
The iPSC-derived CD19 CAR-NK cells prepared by this method are in vitro and in mice It also has a strong killing function
.
In addition to iPSC-derived CAR-NK cells, cord blood-derived CAR-NK cells also have good therapeutic prospects
.
Relevant studies included 11 patients with NHL or chronic lymphocytic leukemia (CLL) who were treated with CAR-NK cells derived from cord blood.
The results of the study showed that CAR-NK cells derived from cord blood are safe and free of CRS, nervous system toxicity, and GVHD
.
Eight patients achieved disease remission, of which four patients with NHL and three patients with CLL achieved CR
.
CAR-NK cells expand in the body and maintain low levels in the body for at least 12 months
.
Summary Professor Huang He finally concluded: Universal CAR-T cells have the advantage of less preparation cost and can reduce the economic burden of patients
.
Universal CAR-T cells have a good curative effect on relapsed and refractory ALL, especially for patients whose autologous CAR-T cells cannot be prepared or T cell ALL patients
.
However, the universal CAR-T cell does not last for a long time in the body and still needs to be further improved
.
For T-cell ALL patients, targeting CD7 CAR-T while removing CD+7 normal T cells may increase the risk of infection, and clinical prevention needs to be strengthened
.
The enhanced function of multi-gene editing is an important development direction for stem cell-derived cell therapy in the future
.
Professor Huang He, Chief Physician, Doctoral Supervisor, Qiushi Distinguished Professor of Zhejiang University, Dean of the First Affiliated Hospital of Zhejiang University School of Medicine, Vice Dean of Zhejiang University School of Medicine, Director of the Institute of Hematology, Zhejiang University First Affiliated to Zhejiang University School of Medicine Director of the Center for Blood and Marrow Transplantation of the HospitalDeputy Leader of the Hematopoietic Stem Cell Transplantation Group of the Chinese Medical Association Member of the Standing Committee of the Society of Hematopoietic Stem Cell Transplantation stamped "read the original text", we make progress together
.
At this conference, Professor Huang He from the First Affiliated Hospital of Zhejiang University School of Medicine gave a theme report on "New Progress in the Research of Universal Chimeric Antigen Receptor T Cells (CAR-T Cells)".
Yimaitong organized the main contents as follows
.
Professor Huang He first briefly introduced the current status of CAR-T therapy and the advantages of universal CAR-T
.
CAR-T cell therapy technology is a major revolution in the medical field.
At present, the FDA has approved 5 CAR-T products to be marketed for the treatment of hematological tumors
.
CAR-T therapy has a complete remission (CR) rate of 70%-90% in acute leukemia, a CR rate of more than 60% in patients with multiple myeloma (MM), and a CR rate in malignant lymphoma.
50%
.
However, most CAR-T products need to be prepared individually, and there are some difficulties and challenges in the treatment process
.
A longer preparation time may result in patients being unable to reinfuse T cells due to disease progression, increasing the risk of treatment
.
The high failure rate of preparation and low T cell levels in some patients may also affect the treatment outcome of patients
.
In addition, individualized preparation has also resulted in relatively expensive CAR-T products and a heavier treatment burden
.
Professor Huang He said that in order to enable more patients to benefit from CAR-T therapy, universal CAR-T is currently an important research direction
.
The universal CAR-T does not require a long waiting time for preparation and can avoid related treatment risks
.
At the same time, the universal CAR-T is derived from healthy donors and has strong T cell activity, which can effectively avoid tumor contamination
.
In addition, the industrialized production process of universal CAR-T can effectively reduce costs and treatment costs, reduce the medical burden of patients, and increase accessibility
.
Professor Huang He then briefly introduced the clinical data of the current universal CAR-T
.
The research results reported at the 2018 ASH Conference showed that the CR/Complete Remission (CRi) rate with incomplete recovery of hematology reached 82% for the universal CAR-T treatment of B-cell acute lymphoblastic leukemia (B-ALL).
The negative rate of residual disease (MRD) reached 71%
.
The results of a study announced at the 2019 ASH Conference showed that the overall response rate (ORR) of the universal CAR-T treatment of B-cell non-Hodgkin's lymphoma (B-NHL) reached 66.
7%
.
The results of the study announced at the ASCO conference in 2020 showed that the ORR of the universal CAR-T treatment of B-NHL reached 63%, and the CR rate reached 37%
.
In this study, the general-purpose CAR-T has good safety, and the incidence of cytokine release syndrome (CRS) of grade ≥3 is only 5%
.
New progress in the research of universal CAR-T cells targeting B-cell hematological diseases The first-generation universal CAR-T cell CTA101 targets both CD19 and CD22, and knocks out the TRAC locus and CD52 gene through CRISPR/Cas9 to avoid host immune excretion Different
.
A study conducted by Professor Huang He's team explored the efficacy of CTA101 in relapsed and refractory B-ALL
.
A total of 6 patients were enrolled in the study.
All patients received pretreatment chemotherapy and infusion of CTA101 product.
The time from enrollment to infusion did not exceed 8 days
.
The results of the study show that CTA101 is safe for the treatment of relapsed and refractory B-ALL.
There is no dose-limiting toxicity (DLT), graft-versus-host disease (GVHD), and immune effector cell-related neurotoxic syndrome (ICANS).
The grade 3 CRS that occurred in the study can be recovered within 7 days after tocilizumab and glucocorticoids.
At the same time, no lentivirus with strong replication ability (RCL) was detected
.
The CR/CRi rate of CTA101 in the treatment of relapsed and refractory B-ALL reached 83.
3% (5/6).
At a median follow-up of 4.
3 months (range: 2-8), 3 patients with CR/CRi were still MRD-negative.
.
One patient received allogeneic hematopoietic stem cell transplantation in remission
.
In addition, the expansion of CAR-T cells in peripheral blood in the study is good
.
The expansion of CAR-T cells in 6 patients was monitored by qPCR, and it was found that all reached the peak value on day 10-14, and the median duration of CTA-101 in the body reached 42 days
.
By flow cytometry on the 28th day after treatment, CAR-T cell expansion could still be observed in 5 patients
.
Professor Huang He said that he looks forward to the development of follow-up multi-center studies to further verify the efficacy of CTA-101
.
New progress in the research of universal CAR-T cells for targeted T-cell hematological diseases Professor Huang He said that at present, universal CAR-T cells for targeted T-cell hematological diseases still face many challenges
.
First of all, tumorous T cells may contaminate CAR-T cells, and it is necessary to develop CAR-non-T cells (such as CAR-NK, CAR-Mac, etc.
) or prepare allogeneic CAR-T cells
.
Secondly, after CAR-T cells are reinfused into the patient's body, after suicide injury, it is necessary to select a suitable T cell target and knock out T cell related molecules through gene editing technology
.
In addition, the lack of T cells after CAR-T cell therapy is also a challenge
.
It is necessary to develop CAR-T cells with "safety switches", or to bridge allogeneic hematopoietic stem cell transplantation after CAR-T cell therapy in patients
.
Professor Pan Jing's team from Beijing Boren Hospital has carried out a study on the treatment of T-cell leukemia with CD7 CAR-T cells from donors
.
A total of 20 patients were included in the study, of which 12 patients relapsed after allogeneic hematopoietic stem cell transplantation, and 8 patients had never received a transplant before
.
Patients who relapse after transplantation use the original donor's T cells to prepare CAR-T, and non-transplant patients use haploidentical or fully-identical donor T cells to prepare CAR-T
.
The results of the study showed that 17 patients achieved CR, 1 patient had reduced extramedullary lesions, and 2 patients could not achieve CR or relapse due to loss of CD7 expression.
Among them, CD7-negative relapsed patients were detected with CD7 exon gene mutations resulting in loss of CD7 expression
.
The side effects of CD7 CAR-T are controllable.
The incidence of CRS ≥3 is only 10%, and no ICANS ≥2 occurs
.
In addition, the study found that donor-derived CD7 CAR-T was significantly amplified
.
CD7-negative T cells are expanded in large numbers to achieve cellular immune function and avoid serious infections
.
Stem cell sources and different chassis CAR immune cells have the advantages of strong clonal expansion potential, easy realization of multi-gene manipulation, and high cell consistency
.
Related studies recruit T cells from NK (iNK) cells derived from induced pluripotent stem cells (iPSC), and cooperate with T cells and anti-PD-1 antibodies to further promote the production of inflammatory cytokines and tumor killing effects
.
The iPSC-derived CD16 prepared by this method enhances the partial remission (PR) rate of NK cells in the treatment of B-cell lymphoma to 72.
7% (8/11).
The iPSC-derived CD19 CAR-NK cells prepared by this method are in vitro and in mice It also has a strong killing function
.
In addition to iPSC-derived CAR-NK cells, cord blood-derived CAR-NK cells also have good therapeutic prospects
.
Relevant studies included 11 patients with NHL or chronic lymphocytic leukemia (CLL) who were treated with CAR-NK cells derived from cord blood.
The results of the study showed that CAR-NK cells derived from cord blood are safe and free of CRS, nervous system toxicity, and GVHD
.
Eight patients achieved disease remission, of which four patients with NHL and three patients with CLL achieved CR
.
CAR-NK cells expand in the body and maintain low levels in the body for at least 12 months
.
Summary Professor Huang He finally concluded: Universal CAR-T cells have the advantage of less preparation cost and can reduce the economic burden of patients
.
Universal CAR-T cells have a good curative effect on relapsed and refractory ALL, especially for patients whose autologous CAR-T cells cannot be prepared or T cell ALL patients
.
However, the universal CAR-T cell does not last for a long time in the body and still needs to be further improved
.
For T-cell ALL patients, targeting CD7 CAR-T while removing CD+7 normal T cells may increase the risk of infection, and clinical prevention needs to be strengthened
.
The enhanced function of multi-gene editing is an important development direction for stem cell-derived cell therapy in the future
.
Professor Huang He, Chief Physician, Doctoral Supervisor, Qiushi Distinguished Professor of Zhejiang University, Dean of the First Affiliated Hospital of Zhejiang University School of Medicine, Vice Dean of Zhejiang University School of Medicine, Director of the Institute of Hematology, Zhejiang University First Affiliated to Zhejiang University School of Medicine Director of the Center for Blood and Marrow Transplantation of the HospitalDeputy Leader of the Hematopoietic Stem Cell Transplantation Group of the Chinese Medical Association Member of the Standing Committee of the Society of Hematopoietic Stem Cell Transplantation stamped "read the original text", we make progress together
