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December 19, 2021/eMedClub News/--At the 63rd Annual Meeting of the American Society of Hematology (ASH) held recently, Allogene Therapeutics focused on the development of allogeneic CAR-T (AlloCAR T™) therapies Announced the positive update results of the Phase 1 study of single-dose ALLO-715 for the treatment of relapsed/refractory (r/r) multiple myeloma
.
ALLO-715 is a CAR-T therapy targeting B cell maturation antigen (BCMA) and a potential new therapy for the treatment of multiple myeloma and other BCMA-positive malignancies
.
This study used Allogene's anti-CD52 monoclonal antibody ALLO-647 as part of its differentiated lymphocyte clearance (LD) protocol
.
▲ The design of ALLO-715 (picture source: Allogene official website) As of October 14, 2021, a total of 48 patients were enrolled in the study, of which 43 patients were evaluable for safety and effectiveness, and 5 patients progressed rapidly due to disease And unable to receive treatment
.
The median time from enrollment to start of treatment was 5 days
.
The Phase 1 UNIVERSAL trial evaluated ALLO-715 at four dose levels (DL1=40M cells, DL2=160M cells, DL3=320M cells, DL4=480M cells) and two LD regimens (FCA: fludarabine, cyclophosphate) Lymphocyte clearance under amide and ALLO-647 or CA: cyclophosphamide and ALLO-647
.
This updated report mainly focuses on the optimized DL3 cell dose and FCA lymphocyte clearance
.
A higher CAR-T cell dose is associated with a higher response rate and greater AlloCAR T cell expansion
.
In the DL3 cohort, compared with the data reported on ASH 2020 last year, the overall response rate (ORR) increased from 60% to 71%, very good partial response (VGPR) or better partial response (VGPR+) rate Increased from 40% to 46%
.
VGPR+ is defined as strict complete remission (sCR), complete remission (CR) or VGPR
.
Of the patients who achieved VGPR+, 92% were negative for minimal residual disease (MRD)
.
▲ Data from the DL3 cohort (picture source: Allogene official website) At the time of data cut-off, the median follow-up time was 3.
8 months
.
The median duration of remission was 8.
3 months, and 9 patients were still in continuous remission at the time of the data cutoff
.
The longest sustained remission time after cell infusion is 12 months
.
The results showed that on the 28th day, the level of free BCMA in remission patients was reduced by 10 times, which indicates that the clearance of free BCMA is related to remission
.
Among the 43 patients whose safety can be assessed, no graft-versus-host disease (GvHD) occurred
.
Twenty-three patients (53%) reported grade 1 and 2 cytokine release syndrome (CRS), which can be controlled by standard therapies
.
In this patient population that has undergone a large number of pretreatments, 54% of patients have developed infections, including 3 cases of grade 5 infections, of which 2 cases have been reported before
.
70% of patients have grade 3 or higher neutropenia
.
Six patients (14%) had reversible low-grade neurotoxic adverse events
.
Tocilizumab and steroids are used less frequently (23% and 14%, respectively)
.
▲ Safety data of Phase 1 study (picture source: Allogene official website) ALLO-715 has been awarded the title of Regenerative Medicine Advanced Therapy (RMAT) by the FDA for the treatment of r/r multiple myeloma
.
In October of this year, during the early clinical trials of Allogene's CAR-T therapy ALLO-501A, a bone marrow biopsy was performed on a patient in the ALPHA2 study to assess pancytopenia (low blood count).
All the company's allogeneic CAR-T clinical trials were suspended by the FDA
.
Recommended reading: FDA found safety issues, Allogene universal CAR-T therapy clinical trials were suspendedYimai Meng broke the news.
According to the data released by Allogene this time on ASH, ALLO-715 is well tolerated, and GvHD has not occurred.
Safe and controllable
.
Although the Phase 1 study was temporarily shelved, no safety issues were found in itself
.
David Chang, the co-founder and CEO of Allogene, said in an interview that Allogene is still collecting data and discussing side effects with the FDA
.
But concerns about safety did not dampen the company's enthusiasm for developing spot cell therapies
.
Safety issues of allogeneic CAR-T therapy For a long time, the safety issues of allogeneic CAR-T therapy have plagued the field of cell and gene therapy, and any issues that arise in the clinical stage will be subject to strict scrutiny
.
In addition to Allogene, the well-known "spot" CAR-T giant Cellectis has also been suspended clinical trials twice by the FDA: In July 2020, the company's allogeneic CAR-T cell therapy UCARTCS1A was stopped by the FDA for the reason After receiving a level 2 dose (DL2) (reported to be 3 million cells/kg) of UCARTCS1A, a patient experienced an undisclosed level of CRS and died of cardiac arrest on day 25
.
As early as September 2017, in the clinical trial of the company's other product candidate, UCRAT123, a death also occurred.
The patient experienced a combination of grade 5 CRS and grade 4 capillary leakage on the 8th day of receiving UCRAT123.
And died on the 9th day; in November of the same year, the FDA allowed the trial to continue
.
Recommended reading: The "spot" CS1 CAR-T clinical trial was stopped by the FDA, sounding a wake-up call for the entire industry Yimai Meng revealed that allogeneic CAR-T is currently facing the main problems: Donor T cells will recognize the host body The foreign body antigen of the human body and attack it, which triggers GvHD or the host will produce a rejection response (HvG) to foreign cells; foreign T cells may be recognized by the human immune system and be quickly eliminated
.
In terms of side effects, in addition to CRS and neurotoxicity, there are side effects caused by Qinglin itself, off-target effects, non-tumor targeting effects, and tumor lysis syndrome, which are similar to autologous CAR-T therapy
.
▲ The manufacturing process of autologous CAR-T and allogeneic CAR-T therapy (picture source: Allogene official website) Although safety issues cannot be ignored, the advantages of allogeneic CAR-T therapy are also more prominent
.
Autologous CAR-T therapy is limited by expensive prices and complex individualized production and preparation processes.
Large-scale clinical promotion has always been a major challenge for pharmaceutical companies
.
Therefore, the allogeneic CAR-T therapy, which can greatly shorten the development time of the product and is more cost-effective, conforms to the development trend and successfully set off a research and development boom in the field of cell therapy
.
The allogeneic strategy aims to allow more patients to receive CAR-T treatment in a cheaper, more convenient and faster way
.
This is also one of the strategies that is currently expected to effectively reduce the cost of CAR-T treatment in addition to the production process revolution in the future
.
At present, allogeneic CAR-T has shown great potential in the treatment.
After the safety problem is properly solved, the field is expected to achieve further development
.
Reference materials: 1.
https:// -t-cell-therapy-in-relapsed-refractory-multiple-myeloma-at-the-63rd-american-society-of-hematology-annual-meeting/2.
https:// ://
.
ALLO-715 is a CAR-T therapy targeting B cell maturation antigen (BCMA) and a potential new therapy for the treatment of multiple myeloma and other BCMA-positive malignancies
.
This study used Allogene's anti-CD52 monoclonal antibody ALLO-647 as part of its differentiated lymphocyte clearance (LD) protocol
.
▲ The design of ALLO-715 (picture source: Allogene official website) As of October 14, 2021, a total of 48 patients were enrolled in the study, of which 43 patients were evaluable for safety and effectiveness, and 5 patients progressed rapidly due to disease And unable to receive treatment
.
The median time from enrollment to start of treatment was 5 days
.
The Phase 1 UNIVERSAL trial evaluated ALLO-715 at four dose levels (DL1=40M cells, DL2=160M cells, DL3=320M cells, DL4=480M cells) and two LD regimens (FCA: fludarabine, cyclophosphate) Lymphocyte clearance under amide and ALLO-647 or CA: cyclophosphamide and ALLO-647
.
This updated report mainly focuses on the optimized DL3 cell dose and FCA lymphocyte clearance
.
A higher CAR-T cell dose is associated with a higher response rate and greater AlloCAR T cell expansion
.
In the DL3 cohort, compared with the data reported on ASH 2020 last year, the overall response rate (ORR) increased from 60% to 71%, very good partial response (VGPR) or better partial response (VGPR+) rate Increased from 40% to 46%
.
VGPR+ is defined as strict complete remission (sCR), complete remission (CR) or VGPR
.
Of the patients who achieved VGPR+, 92% were negative for minimal residual disease (MRD)
.
▲ Data from the DL3 cohort (picture source: Allogene official website) At the time of data cut-off, the median follow-up time was 3.
8 months
.
The median duration of remission was 8.
3 months, and 9 patients were still in continuous remission at the time of the data cutoff
.
The longest sustained remission time after cell infusion is 12 months
.
The results showed that on the 28th day, the level of free BCMA in remission patients was reduced by 10 times, which indicates that the clearance of free BCMA is related to remission
.
Among the 43 patients whose safety can be assessed, no graft-versus-host disease (GvHD) occurred
.
Twenty-three patients (53%) reported grade 1 and 2 cytokine release syndrome (CRS), which can be controlled by standard therapies
.
In this patient population that has undergone a large number of pretreatments, 54% of patients have developed infections, including 3 cases of grade 5 infections, of which 2 cases have been reported before
.
70% of patients have grade 3 or higher neutropenia
.
Six patients (14%) had reversible low-grade neurotoxic adverse events
.
Tocilizumab and steroids are used less frequently (23% and 14%, respectively)
.
▲ Safety data of Phase 1 study (picture source: Allogene official website) ALLO-715 has been awarded the title of Regenerative Medicine Advanced Therapy (RMAT) by the FDA for the treatment of r/r multiple myeloma
.
In October of this year, during the early clinical trials of Allogene's CAR-T therapy ALLO-501A, a bone marrow biopsy was performed on a patient in the ALPHA2 study to assess pancytopenia (low blood count).
All the company's allogeneic CAR-T clinical trials were suspended by the FDA
.
Recommended reading: FDA found safety issues, Allogene universal CAR-T therapy clinical trials were suspendedYimai Meng broke the news.
According to the data released by Allogene this time on ASH, ALLO-715 is well tolerated, and GvHD has not occurred.
Safe and controllable
.
Although the Phase 1 study was temporarily shelved, no safety issues were found in itself
.
David Chang, the co-founder and CEO of Allogene, said in an interview that Allogene is still collecting data and discussing side effects with the FDA
.
But concerns about safety did not dampen the company's enthusiasm for developing spot cell therapies
.
Safety issues of allogeneic CAR-T therapy For a long time, the safety issues of allogeneic CAR-T therapy have plagued the field of cell and gene therapy, and any issues that arise in the clinical stage will be subject to strict scrutiny
.
In addition to Allogene, the well-known "spot" CAR-T giant Cellectis has also been suspended clinical trials twice by the FDA: In July 2020, the company's allogeneic CAR-T cell therapy UCARTCS1A was stopped by the FDA for the reason After receiving a level 2 dose (DL2) (reported to be 3 million cells/kg) of UCARTCS1A, a patient experienced an undisclosed level of CRS and died of cardiac arrest on day 25
.
As early as September 2017, in the clinical trial of the company's other product candidate, UCRAT123, a death also occurred.
The patient experienced a combination of grade 5 CRS and grade 4 capillary leakage on the 8th day of receiving UCRAT123.
And died on the 9th day; in November of the same year, the FDA allowed the trial to continue
.
Recommended reading: The "spot" CS1 CAR-T clinical trial was stopped by the FDA, sounding a wake-up call for the entire industry Yimai Meng revealed that allogeneic CAR-T is currently facing the main problems: Donor T cells will recognize the host body The foreign body antigen of the human body and attack it, which triggers GvHD or the host will produce a rejection response (HvG) to foreign cells; foreign T cells may be recognized by the human immune system and be quickly eliminated
.
In terms of side effects, in addition to CRS and neurotoxicity, there are side effects caused by Qinglin itself, off-target effects, non-tumor targeting effects, and tumor lysis syndrome, which are similar to autologous CAR-T therapy
.
▲ The manufacturing process of autologous CAR-T and allogeneic CAR-T therapy (picture source: Allogene official website) Although safety issues cannot be ignored, the advantages of allogeneic CAR-T therapy are also more prominent
.
Autologous CAR-T therapy is limited by expensive prices and complex individualized production and preparation processes.
Large-scale clinical promotion has always been a major challenge for pharmaceutical companies
.
Therefore, the allogeneic CAR-T therapy, which can greatly shorten the development time of the product and is more cost-effective, conforms to the development trend and successfully set off a research and development boom in the field of cell therapy
.
The allogeneic strategy aims to allow more patients to receive CAR-T treatment in a cheaper, more convenient and faster way
.
This is also one of the strategies that is currently expected to effectively reduce the cost of CAR-T treatment in addition to the production process revolution in the future
.
At present, allogeneic CAR-T has shown great potential in the treatment.
After the safety problem is properly solved, the field is expected to achieve further development
.
Reference materials: 1.
https:// -t-cell-therapy-in-relapsed-refractory-multiple-myeloma-at-the-63rd-american-society-of-hematology-annual-meeting/2.
https:// ://
