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Lymphocytic disease is currently one of the most vigorously developing fields in hematology at home and abroad.
In recent years, remarkable achievements have been made in disease pathogenesis, targeting and immunotherapy.
In order to promote domestic and international peer exchanges, the First National Lymphocytic Disease Academic Conference of the Chinese Medical Association and the 2021 International Lymphoma Update Symposium will be held in Chengdu, Sichuan Province from April 16-18, 2021.
At this meeting, Professor Huang He from the First Affiliated Hospital of Zhejiang University School of Medicine introduced the new progress of CAR-T cell therapy for B-cell non-Hodgkin's lymphoma (B-NHL).
Yimaitong organized the main contents as follows.
Current status of CAR-T cell therapy for relapsed/refractory lymphoma.
At present, chimeric antigen receptor (CAR) T cell therapy is mainly used for the treatment of malignant tumors in the B cell blood system.
Statistics from major research centers, CAR-T The complete remission (CR) rate of cell therapy lymphoma is about 50%.
So far, the longest follow-up results of CAR-T cell therapy for B-NHL show that among 24 patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL), 46% of patients obtained CR and 31% of patients Progression-free survival was achieved after 5 years; among 14 patients with relapsed/refractory follicular lymphoma (FL), 71% of patients achieved CR, and 43% of patients achieved progression-free survival within 5 years.
Professor Huang He said that compared with acute lymphoblastic leukemia (ALL), CAR-T cell therapy has a relatively low remission rate for relapsed/refractory lymphoma.
The main reasons and mechanisms may include target antigen loss and tumor microenvironment immunosuppression.
And CAR-T cell function is exhausted.The progress of new CAR-T cell therapy 1.
New costimulatory molecule CD19-CAR-T cell Professor Huang He introduced that research from Professor Zhu Jun’s team from Peking University Cancer Hospital showed that the new costimulatory molecule CD19-BBz(86) CAR-T Cells have a good therapeutic effect on refractory B-cell lymphoma, and will not cause severe cytokine release syndrome (CRS) and neurotoxicity.
3 out of 6 patients in the low-dose group had a response to treatment; 4 out of 8 patients in the middle-dose group achieved partial remission (PR); 6 out of 11 patients in the high-dose group achieved CR.
Serum cytokine levels remained at a reduced level, and none of the 25 patients showed significant CRS and neurotoxicity.
It is proved that CD19-BBz(86) CAR-T cells are a safer and effective CAR-T cell therapy.
2.
CD19/CD22 sequential CAR-T cell therapy In addition, Professor Huang He introduced that the team of Professor Zhou Jianfeng from Tongji Hospital of Huazhong University of Science and Technology used CD19-CAR-T cells sequential CD22-CAR-T cells to treat relapsed/refractory B Cell tumor patients have also achieved good results: CD19/CD22 CAR-T cells have been expanded significantly, the overall response rate (ORR) is 72.
2%, the CR rate is 50%, and the safety is good.
3.
CD19/CD20 dual-target CAR-T cell therapy A study by Professor Han Weidong’s team from the Chinese People’s Liberation Army General Hospital evaluated the safety and effectiveness of CD19/CD20 dual-target CAR-T cells in 28 patients.
The results The ORR was 79%, the CR rate was 71%, and the 12-month progression-free survival (PFS) rate was 64%.
Professor Huang He said that compared with single-target CAR-T cell therapy, the efficacy of dual-target CAR-T cell therapy is significantly improved.
4.
CD19/CD22 dual-target CAR-T cell therapy Professor Huang He’s team also conducted a dual-target CAR-T cell study.
The CD19/CD22 dual-target CAR-T cell killing data in vitro and in vivo showed that the Compared with CD19 or CD22 single-target CAR-T cell therapy, CD19/CD22 dual-target CAR-T cells have higher killing efficiency. Previous studies have shown that the CR rate of CD19/CD22 CAR-T cells in the treatment of relapsed/refractory ALL is 90%, and the incidence of severe CRS is reduced by 30%.
Subsequently, the team of Professor Huang He evaluated the safety and effectiveness of CD19/CD22 dual-target CAR-T cells in the treatment of 16 B-NHL patients.
The results showed that CD19/CD22 CAR-T cells expanded significantly in vivo and had high killing activity , The other cytokines did not increase significantly.
The ORR and CR rates were 87.
5% and 62.
5%, respectively, the 2-year overall survival (OS) rate was 77.
3%, and the 2-year disease-free survival rate was 40.
2%.
5.
PD-1 targeted integration type CD19-CAR-T cell therapy Professor Huang He's team achieved targeted integration of CAR-T through CRISPR/Cas9 technology, and inserted the CAR gene directly into the PD-1 gene locus through gene editing to achieve knockout In addition to PD-1, the CAR gene is introduced at the same time (and the process does not require a lentiviral vector), that is, PD-1 site-directed integrated CD19-CAR-T cell therapy (PD-1-CD19-CAR-T).
PD-1-CD19-CAR-T has a good killing effect on CD19-B cells (PD-1 high expression) tumors.
At present, a total of 8 patients were enrolled in the relevant research of Professor Huang He's team, with an ORR of 100%, a CR rate of 87.
5% (7/8), and no CRS ≥3.
Professor Huang He said that this technology is the world's first use of CRISPR/Cas9 gene editing technology to specifically cut the PD-1 gene of T cells and introduce a CAR element targeting CD19 at the same time to prepare a targeted CD-19-CAR targeted for PD-1 integration.
-T cells.
Currently, larger-scale clinical studies are underway.
Advances in ASCT combined with CAR-T cell therapy Autologous hematopoietic stem cell transplantation (ASCT) is one of the most important methods in the treatment of lymphoma.
Professor Huang He said that the pretreatment chemotherapeutic drugs in ASCT can induce immunogenic cell apoptosis and tumor cells Apoptosis, rebuilding the ratio of CD4+/CD8+ T cells, and improving the inhibitory tumor microenvironment are conducive to improving the microenvironment in patients with lymphoma and improving the efficacy of CAR-T cell therapy.
Professor Huang He then introduced several studies on ASCT combined with CAR-T cell therapy.
Based on the collaborative exploration of ASCT and CAR-T cell therapy, Professor Zhou Jianfeng’s team conducted a single-center, single-arm study to explore the synergistic efficacy of ASCT combined with CAR-T cells in the treatment of relapsed/refractory B-lymphocyte tumors The results showed that the median follow-up was 13.
8 months, the ORR was 90.
5%, and the CR rate was 81%.
Another study from the Memorial Sloan Kettering Cancer Center (MSKCC) in the United States showed that the 2-year PFS rate of 15 patients treated with ASCT sequential CAR-T cells was 30%, but it should be noted that severe neurotoxicity The incidence was 67%.
In addition, the data of 14 patients studied by Professor Yang Jianmin's team at Shanghai Changhai Hospital showed that the 6-month PFS rate of patients with CAR-T cell therapy after ASCT was 64.
29%, and the 1-year OS rate was 65.
48%.
Professor Huang He said that more clinical studies are still needed to explore this program.
Summary At the end of the report, Professor Huang He concluded that at present, the CR rate of CAR-T cells in the treatment of lymphoma needs to be improved, and clarifying the relevant mechanisms will help improve the efficacy and develop new treatment strategies.
Among them, new CAR-T cell therapies such as dual targets and new costimulatory molecules have potential value for improving curative effects.
Finally, Professor Huang He expressed the hope that more basic and clinical researchers will work together to improve the efficacy of CAR-T cells in the treatment of lymphoma and reduce toxic and side effects.
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 Hospital Deputy Leader of the Hematopoietic Stem Cell Transplantation Group of the Hematology Branch of the Chinese Medical Association Deputy Chairman of the Chinese Marrow Bank Expert Committee Chairman of the Hematology Professional Committee of the Zhejiang Medical Association Member of the Standing Committee of the Society of Hematopoietic Stem Cell Transplantation stamped "read the original text"
In recent years, remarkable achievements have been made in disease pathogenesis, targeting and immunotherapy.
In order to promote domestic and international peer exchanges, the First National Lymphocytic Disease Academic Conference of the Chinese Medical Association and the 2021 International Lymphoma Update Symposium will be held in Chengdu, Sichuan Province from April 16-18, 2021.
At this meeting, Professor Huang He from the First Affiliated Hospital of Zhejiang University School of Medicine introduced the new progress of CAR-T cell therapy for B-cell non-Hodgkin's lymphoma (B-NHL).
Yimaitong organized the main contents as follows.
Current status of CAR-T cell therapy for relapsed/refractory lymphoma.
At present, chimeric antigen receptor (CAR) T cell therapy is mainly used for the treatment of malignant tumors in the B cell blood system.
Statistics from major research centers, CAR-T The complete remission (CR) rate of cell therapy lymphoma is about 50%.
So far, the longest follow-up results of CAR-T cell therapy for B-NHL show that among 24 patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL), 46% of patients obtained CR and 31% of patients Progression-free survival was achieved after 5 years; among 14 patients with relapsed/refractory follicular lymphoma (FL), 71% of patients achieved CR, and 43% of patients achieved progression-free survival within 5 years.
Professor Huang He said that compared with acute lymphoblastic leukemia (ALL), CAR-T cell therapy has a relatively low remission rate for relapsed/refractory lymphoma.
The main reasons and mechanisms may include target antigen loss and tumor microenvironment immunosuppression.
And CAR-T cell function is exhausted.The progress of new CAR-T cell therapy 1.
New costimulatory molecule CD19-CAR-T cell Professor Huang He introduced that research from Professor Zhu Jun’s team from Peking University Cancer Hospital showed that the new costimulatory molecule CD19-BBz(86) CAR-T Cells have a good therapeutic effect on refractory B-cell lymphoma, and will not cause severe cytokine release syndrome (CRS) and neurotoxicity.
3 out of 6 patients in the low-dose group had a response to treatment; 4 out of 8 patients in the middle-dose group achieved partial remission (PR); 6 out of 11 patients in the high-dose group achieved CR.
Serum cytokine levels remained at a reduced level, and none of the 25 patients showed significant CRS and neurotoxicity.
It is proved that CD19-BBz(86) CAR-T cells are a safer and effective CAR-T cell therapy.
2.
CD19/CD22 sequential CAR-T cell therapy In addition, Professor Huang He introduced that the team of Professor Zhou Jianfeng from Tongji Hospital of Huazhong University of Science and Technology used CD19-CAR-T cells sequential CD22-CAR-T cells to treat relapsed/refractory B Cell tumor patients have also achieved good results: CD19/CD22 CAR-T cells have been expanded significantly, the overall response rate (ORR) is 72.
2%, the CR rate is 50%, and the safety is good.
3.
CD19/CD20 dual-target CAR-T cell therapy A study by Professor Han Weidong’s team from the Chinese People’s Liberation Army General Hospital evaluated the safety and effectiveness of CD19/CD20 dual-target CAR-T cells in 28 patients.
The results The ORR was 79%, the CR rate was 71%, and the 12-month progression-free survival (PFS) rate was 64%.
Professor Huang He said that compared with single-target CAR-T cell therapy, the efficacy of dual-target CAR-T cell therapy is significantly improved.
4.
CD19/CD22 dual-target CAR-T cell therapy Professor Huang He’s team also conducted a dual-target CAR-T cell study.
The CD19/CD22 dual-target CAR-T cell killing data in vitro and in vivo showed that the Compared with CD19 or CD22 single-target CAR-T cell therapy, CD19/CD22 dual-target CAR-T cells have higher killing efficiency. Previous studies have shown that the CR rate of CD19/CD22 CAR-T cells in the treatment of relapsed/refractory ALL is 90%, and the incidence of severe CRS is reduced by 30%.
Subsequently, the team of Professor Huang He evaluated the safety and effectiveness of CD19/CD22 dual-target CAR-T cells in the treatment of 16 B-NHL patients.
The results showed that CD19/CD22 CAR-T cells expanded significantly in vivo and had high killing activity , The other cytokines did not increase significantly.
The ORR and CR rates were 87.
5% and 62.
5%, respectively, the 2-year overall survival (OS) rate was 77.
3%, and the 2-year disease-free survival rate was 40.
2%.
5.
PD-1 targeted integration type CD19-CAR-T cell therapy Professor Huang He's team achieved targeted integration of CAR-T through CRISPR/Cas9 technology, and inserted the CAR gene directly into the PD-1 gene locus through gene editing to achieve knockout In addition to PD-1, the CAR gene is introduced at the same time (and the process does not require a lentiviral vector), that is, PD-1 site-directed integrated CD19-CAR-T cell therapy (PD-1-CD19-CAR-T).
PD-1-CD19-CAR-T has a good killing effect on CD19-B cells (PD-1 high expression) tumors.
At present, a total of 8 patients were enrolled in the relevant research of Professor Huang He's team, with an ORR of 100%, a CR rate of 87.
5% (7/8), and no CRS ≥3.
Professor Huang He said that this technology is the world's first use of CRISPR/Cas9 gene editing technology to specifically cut the PD-1 gene of T cells and introduce a CAR element targeting CD19 at the same time to prepare a targeted CD-19-CAR targeted for PD-1 integration.
-T cells.
Currently, larger-scale clinical studies are underway.
Advances in ASCT combined with CAR-T cell therapy Autologous hematopoietic stem cell transplantation (ASCT) is one of the most important methods in the treatment of lymphoma.
Professor Huang He said that the pretreatment chemotherapeutic drugs in ASCT can induce immunogenic cell apoptosis and tumor cells Apoptosis, rebuilding the ratio of CD4+/CD8+ T cells, and improving the inhibitory tumor microenvironment are conducive to improving the microenvironment in patients with lymphoma and improving the efficacy of CAR-T cell therapy.
Professor Huang He then introduced several studies on ASCT combined with CAR-T cell therapy.
Based on the collaborative exploration of ASCT and CAR-T cell therapy, Professor Zhou Jianfeng’s team conducted a single-center, single-arm study to explore the synergistic efficacy of ASCT combined with CAR-T cells in the treatment of relapsed/refractory B-lymphocyte tumors The results showed that the median follow-up was 13.
8 months, the ORR was 90.
5%, and the CR rate was 81%.
Another study from the Memorial Sloan Kettering Cancer Center (MSKCC) in the United States showed that the 2-year PFS rate of 15 patients treated with ASCT sequential CAR-T cells was 30%, but it should be noted that severe neurotoxicity The incidence was 67%.
In addition, the data of 14 patients studied by Professor Yang Jianmin's team at Shanghai Changhai Hospital showed that the 6-month PFS rate of patients with CAR-T cell therapy after ASCT was 64.
29%, and the 1-year OS rate was 65.
48%.
Professor Huang He said that more clinical studies are still needed to explore this program.
Summary At the end of the report, Professor Huang He concluded that at present, the CR rate of CAR-T cells in the treatment of lymphoma needs to be improved, and clarifying the relevant mechanisms will help improve the efficacy and develop new treatment strategies.
Among them, new CAR-T cell therapies such as dual targets and new costimulatory molecules have potential value for improving curative effects.
Finally, Professor Huang He expressed the hope that more basic and clinical researchers will work together to improve the efficacy of CAR-T cells in the treatment of lymphoma and reduce toxic and side effects.
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 Hospital Deputy Leader of the Hematopoietic Stem Cell Transplantation Group of the Hematology Branch of the Chinese Medical Association Deputy Chairman of the Chinese Marrow Bank Expert Committee Chairman of the Hematology Professional Committee of the Zhejiang Medical Association Member of the Standing Committee of the Society of Hematopoietic Stem Cell Transplantation stamped "read the original text"
