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Multiple myeloma (MM) is a malignant tumor that originates from plasma cells.
The application of proteasome inhibitors (PI), immunomodulators (IMiD) and monoclonal antibody drugs has significantly improved the long-term MM patients compared with traditional chemotherapy.
Survival, but as an incurable malignant hematological tumor, MM will relapse in almost all patients
.
In recent years, the research of CAR-T, antibody-drug conjugates (ADC) and bispecific antibodies (BsAb) targeting B cell maturation antigen (BCMA) targets for cellular immunotherapy has progressed rapidly, and relevant excellent research reports have been repeated at home and abroad.
A prominence in the meeting
.
Professor Chen Wenming from the Department of Hematology, Beijing Chaoyang Hospital, Capital Medical University, and his team conducted a study (LUMMICAR-1 study) to explore the treatment of relapsed and refractory multiple myeloma (RRMM) with fully human anti-BCMA autologous CAR-T cell CT053 ), and was selected for the 2021 ASH poster presentation.
Yimaitong invited Professor Chen Wenming to interview and share the progress of RRMM treatment
.
Yimaitong: First of all, would you please introduce the current status of MM treatment in my country? What are the treatment difficulties? In recent years, Professor Chen Wenming, more and more MM therapeutic drugs have been approved for the market, such as IMiD lenalidomide, pomalidomide, thalidomide, PI bortezomib, ixazomib, CD38 monoclonal antibody up to Ray properly, especially monoclonal antibodies, nuclear export inhibitors Medinaceli nisoldipine the like
.
In addition, MM therapeutics that have been marketed abroad are also conducting multiple clinical trials in China.
In addition, China's CAR-T cell technology research is at the world's leading level
.
Therefore, there is almost no gap between the availability of domestic drugs for the treatment of MM and foreign countries
.
Although many new drugs are currently on the market in China, the prices of the drugs are relatively high and the medical insurance coverage ratio is relatively low
.
Therefore, the application of new drugs for many patients is subject to certain restrictions
.
Yimaitong: In recent years, the research of CAR-T therapy, ADC and BsAb targeted at BCMA has made rapid progress, and relevant excellent research reports have repeatedly emerged in domestic and foreign conferences
.
So can you please introduce the reasons why BCMA has become a popular target? Professor CHEN Wenming express multiple myeloma cell surface antigens, such as the more commonly used CD38, CD138, BCMA and the like
.
Although CD38 and CD138 are highly expressed, their expression levels are not stable after stimulation by other antibodies.
BCMA is not only highly expressed on the surface of myeloma cells, but also stably expressed under exogenous stimulation.
These characteristics make it a MM treatment Is a very popular target
.
For the BCMA target, three types of drugs have been developed, ADC, bispecific antibody and CAR-T
.
ADC is a cytotoxic drug that kills myeloma cells mainly through two ways.
On the one hand, the drug binds to myeloma cells through the BCMA antibody, thereby introducing the coupled cytotoxic drug, causing DNA damage and apoptosis in myeloma cells.
On the other hand, ADC drugs can also kill myeloma cells through antibody-dependent cell-mediated cytotoxicity (ADCC)
.
Bispecific antibodies and CAR-T both use T cells to kill tumor activity.
Bispecific antibodies are equivalent to a bridge.
They bind to the BCMA target on myeloma cells and CD3 on T cells to activate T cell immunity and induce Myeloma cells are lysed, and CAR-T directly expresses anti-BCMA antibodies on the surface of T cells.
After the antibodies bind to tumor cells, T cells are activated.
The activated T cells have anti-tumor activity.
Therefore, the two have similarities in mechanism
.
Yimaitong: You and your team explore the efficacy and safety of fully humanized anti-BCMA autologous CAR-T cell CT053 in the treatment of RRMM (LUMMICAR-1 study), which was selected for this year’s ASH poster presentation.
Could you please introduce this study? The result and significance? Professor Chen Wenming CT053 is a CAR-T cell therapy for RRMM patients.
We explored its safety and efficacy in RRMM patients (≥3 lines of previous treatment)
.
The preliminary observation results were reported at the 2020 ASH conference, and the long-term follow-up results of the phase I clinical trial were announced at the 2021 ASH conference
.
A total of 14 patients were enrolled and divided into two dose groups, 3 cases in the 1×108 CAR-T cell group and 11 cases in the 1.
5×108 CAR-T cell group
.
As of July 8, 2021, with a median follow-up of 13.
6 months, CT053 was well tolerated, and the most common adverse event (AE) ≥ grade 3 was hematological toxicity (occurring within 3 months after infusion), and no occurrence Dose-limiting toxicity (DLT) or dose-related death, no cytokine release syndrome (CRS) or neurotoxicity ≥ grade 3
.
The overall response rate (ORR) was 100% (14/14), the minimal residual disease (MRD) negative sCR rate was 78.
6% (11/14), and the ≥VGPR rate was 92.
9% (13/14)
.
The CR/sCR rate of patients without extramedullary disease (EMD) was 91.
7% (11/12)
.
The 12-month PFS rate was 85.
7%, and the 12-month PFS rate of EMD patients was as high as 100%
.
Phase II clinical trials are underway.
I think this is a very promising CAR-T cell drug for the treatment of MM
.
Yimaitong: In the treatment of MM, can the therapies targeting BCMA (CAR-T therapy, ADC and BsAb) move forward? Professor Chen Wenming currently, the clinical trials of ADC, bispecific antibodies and CAR-T for the treatment of MM are for patients with relapsed and refractory end-line therapy.
If these drugs are used in the front line, the effect may be better
.
At present, the exploration of the front-line application of ADC drugs targeting BCMA in combination with other cytotoxic drugs (such as PI) is also being carried out, and it is expected to further improve the efficacy and remission rate of patients
.
Bispecific antibodies need to use the T cells in the patient to kill the tumor.
If the application is late, the number and function of T cells in the body will be affected after the patient undergoes multiple chemotherapy.
Therefore, you can try the front-line application of bispecific antibodies, and the efficacy may be better.
Well, the current use of bispecific antibodies for first to third-line treatment is also being explored
.
CAR-T is also exploring first-line treatment, maintenance therapy, MRD removal or treatment for patients with first to third-line relapses.
It is expected that patients in the future can benefit from CAR-T treatment at different stages of treatment
.
Yimaitong: A study published by American researchers at this year’s ASH annual meeting showed that targeted BCMA therapy seems to be related to bacterial and viral infections.
Compared with CAR-T recipients, repeated BsAb medications may be caused by severe bacterial infections.
Why, what is your opinion on this? Professor Chen Wenming BCMA is not only expressed on the surface of myeloma cells, but also on the surface of mature B cells
.
Therefore, bispecific antibodies and CAR-T cells targeting BCMA not only eliminate tumor cells, but also mature B cells.
Therefore, patients will develop humoral immune deficiency.
After humoral immune deficiency, patients have a significant risk of bacterial and viral infections.
Increase
.
In order to prevent bacterial or viral infections and improve the immunity of patients, patients can be infused with gamma globulin regularly to reduce the risk of infection
.
Yimaitong: What do you think is the key exploration direction of RRMM in the future? Professor Chen Wenming has seen more and more new drugs for the treatment of MM in recent years, including PI, IMiD, monoclonal antibodies and small molecule targeted drugs, as well as bispecific antibodies and CAR-T cell therapy
.
With so many treatment options, especially in second-line, third-line and back-line treatment, how to arrange and combine to maximize the benefits of patients should be the most important issue that needs to be explored in the future
.
Professor Chen Wenming Chief Physician, Professor, Doctor of Medicine, Doctoral Supervisor, Director of the Department of Hematology, Beijing Chaoyang Hospital, Capital Medical University, Director of Beijing Multiple Myeloma Medical Research Center, Director of the Department of Hematology, Capital Medical University, Consultant of the International Myeloma Working Group and China Multiple Myeloma Working Group Expert Committee Member of the Hematology Professional Committee of the Chinese Medical Education Association Member of the Standing Committee of the Hematology Branch of the Chinese Society of Integrative Medicine Member of the Transplantation Group, Member of the Hematology and Tumor Branch of the Chinese Anti-Cancer Association, stamp "read the original text", and we will make progress together
The application of proteasome inhibitors (PI), immunomodulators (IMiD) and monoclonal antibody drugs has significantly improved the long-term MM patients compared with traditional chemotherapy.
Survival, but as an incurable malignant hematological tumor, MM will relapse in almost all patients
.
In recent years, the research of CAR-T, antibody-drug conjugates (ADC) and bispecific antibodies (BsAb) targeting B cell maturation antigen (BCMA) targets for cellular immunotherapy has progressed rapidly, and relevant excellent research reports have been repeated at home and abroad.
A prominence in the meeting
.
Professor Chen Wenming from the Department of Hematology, Beijing Chaoyang Hospital, Capital Medical University, and his team conducted a study (LUMMICAR-1 study) to explore the treatment of relapsed and refractory multiple myeloma (RRMM) with fully human anti-BCMA autologous CAR-T cell CT053 ), and was selected for the 2021 ASH poster presentation.
Yimaitong invited Professor Chen Wenming to interview and share the progress of RRMM treatment
.
Yimaitong: First of all, would you please introduce the current status of MM treatment in my country? What are the treatment difficulties? In recent years, Professor Chen Wenming, more and more MM therapeutic drugs have been approved for the market, such as IMiD lenalidomide, pomalidomide, thalidomide, PI bortezomib, ixazomib, CD38 monoclonal antibody up to Ray properly, especially monoclonal antibodies, nuclear export inhibitors Medinaceli nisoldipine the like
.
In addition, MM therapeutics that have been marketed abroad are also conducting multiple clinical trials in China.
In addition, China's CAR-T cell technology research is at the world's leading level
.
Therefore, there is almost no gap between the availability of domestic drugs for the treatment of MM and foreign countries
.
Although many new drugs are currently on the market in China, the prices of the drugs are relatively high and the medical insurance coverage ratio is relatively low
.
Therefore, the application of new drugs for many patients is subject to certain restrictions
.
Yimaitong: In recent years, the research of CAR-T therapy, ADC and BsAb targeted at BCMA has made rapid progress, and relevant excellent research reports have repeatedly emerged in domestic and foreign conferences
.
So can you please introduce the reasons why BCMA has become a popular target? Professor CHEN Wenming express multiple myeloma cell surface antigens, such as the more commonly used CD38, CD138, BCMA and the like
.
Although CD38 and CD138 are highly expressed, their expression levels are not stable after stimulation by other antibodies.
BCMA is not only highly expressed on the surface of myeloma cells, but also stably expressed under exogenous stimulation.
These characteristics make it a MM treatment Is a very popular target
.
For the BCMA target, three types of drugs have been developed, ADC, bispecific antibody and CAR-T
.
ADC is a cytotoxic drug that kills myeloma cells mainly through two ways.
On the one hand, the drug binds to myeloma cells through the BCMA antibody, thereby introducing the coupled cytotoxic drug, causing DNA damage and apoptosis in myeloma cells.
On the other hand, ADC drugs can also kill myeloma cells through antibody-dependent cell-mediated cytotoxicity (ADCC)
.
Bispecific antibodies and CAR-T both use T cells to kill tumor activity.
Bispecific antibodies are equivalent to a bridge.
They bind to the BCMA target on myeloma cells and CD3 on T cells to activate T cell immunity and induce Myeloma cells are lysed, and CAR-T directly expresses anti-BCMA antibodies on the surface of T cells.
After the antibodies bind to tumor cells, T cells are activated.
The activated T cells have anti-tumor activity.
Therefore, the two have similarities in mechanism
.
Yimaitong: You and your team explore the efficacy and safety of fully humanized anti-BCMA autologous CAR-T cell CT053 in the treatment of RRMM (LUMMICAR-1 study), which was selected for this year’s ASH poster presentation.
Could you please introduce this study? The result and significance? Professor Chen Wenming CT053 is a CAR-T cell therapy for RRMM patients.
We explored its safety and efficacy in RRMM patients (≥3 lines of previous treatment)
.
The preliminary observation results were reported at the 2020 ASH conference, and the long-term follow-up results of the phase I clinical trial were announced at the 2021 ASH conference
.
A total of 14 patients were enrolled and divided into two dose groups, 3 cases in the 1×108 CAR-T cell group and 11 cases in the 1.
5×108 CAR-T cell group
.
As of July 8, 2021, with a median follow-up of 13.
6 months, CT053 was well tolerated, and the most common adverse event (AE) ≥ grade 3 was hematological toxicity (occurring within 3 months after infusion), and no occurrence Dose-limiting toxicity (DLT) or dose-related death, no cytokine release syndrome (CRS) or neurotoxicity ≥ grade 3
.
The overall response rate (ORR) was 100% (14/14), the minimal residual disease (MRD) negative sCR rate was 78.
6% (11/14), and the ≥VGPR rate was 92.
9% (13/14)
.
The CR/sCR rate of patients without extramedullary disease (EMD) was 91.
7% (11/12)
.
The 12-month PFS rate was 85.
7%, and the 12-month PFS rate of EMD patients was as high as 100%
.
Phase II clinical trials are underway.
I think this is a very promising CAR-T cell drug for the treatment of MM
.
Yimaitong: In the treatment of MM, can the therapies targeting BCMA (CAR-T therapy, ADC and BsAb) move forward? Professor Chen Wenming currently, the clinical trials of ADC, bispecific antibodies and CAR-T for the treatment of MM are for patients with relapsed and refractory end-line therapy.
If these drugs are used in the front line, the effect may be better
.
At present, the exploration of the front-line application of ADC drugs targeting BCMA in combination with other cytotoxic drugs (such as PI) is also being carried out, and it is expected to further improve the efficacy and remission rate of patients
.
Bispecific antibodies need to use the T cells in the patient to kill the tumor.
If the application is late, the number and function of T cells in the body will be affected after the patient undergoes multiple chemotherapy.
Therefore, you can try the front-line application of bispecific antibodies, and the efficacy may be better.
Well, the current use of bispecific antibodies for first to third-line treatment is also being explored
.
CAR-T is also exploring first-line treatment, maintenance therapy, MRD removal or treatment for patients with first to third-line relapses.
It is expected that patients in the future can benefit from CAR-T treatment at different stages of treatment
.
Yimaitong: A study published by American researchers at this year’s ASH annual meeting showed that targeted BCMA therapy seems to be related to bacterial and viral infections.
Compared with CAR-T recipients, repeated BsAb medications may be caused by severe bacterial infections.
Why, what is your opinion on this? Professor Chen Wenming BCMA is not only expressed on the surface of myeloma cells, but also on the surface of mature B cells
.
Therefore, bispecific antibodies and CAR-T cells targeting BCMA not only eliminate tumor cells, but also mature B cells.
Therefore, patients will develop humoral immune deficiency.
After humoral immune deficiency, patients have a significant risk of bacterial and viral infections.
Increase
.
In order to prevent bacterial or viral infections and improve the immunity of patients, patients can be infused with gamma globulin regularly to reduce the risk of infection
.
Yimaitong: What do you think is the key exploration direction of RRMM in the future? Professor Chen Wenming has seen more and more new drugs for the treatment of MM in recent years, including PI, IMiD, monoclonal antibodies and small molecule targeted drugs, as well as bispecific antibodies and CAR-T cell therapy
.
With so many treatment options, especially in second-line, third-line and back-line treatment, how to arrange and combine to maximize the benefits of patients should be the most important issue that needs to be explored in the future
.
Professor Chen Wenming Chief Physician, Professor, Doctor of Medicine, Doctoral Supervisor, Director of the Department of Hematology, Beijing Chaoyang Hospital, Capital Medical University, Director of Beijing Multiple Myeloma Medical Research Center, Director of the Department of Hematology, Capital Medical University, Consultant of the International Myeloma Working Group and China Multiple Myeloma Working Group Expert Committee Member of the Hematology Professional Committee of the Chinese Medical Education Association Member of the Standing Committee of the Hematology Branch of the Chinese Society of Integrative Medicine Member of the Transplantation Group, Member of the Hematology and Tumor Branch of the Chinese Anti-Cancer Association, stamp "read the original text", and we will make progress together