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·Altaltaltalt December 17, 2021/MedClub News/--Recently, at the 63rd American Society of Hematology (ASH) Annual Meeting in 2021, Precigen announced cells based on its non-viral vector UltraCAR-T™ platform Therapy PRGN-3006 has positive clinical data from the Phase 1/1b clinical trial for the treatment of relapsed or refractory (r/r) acute myeloid leukemia (AML)
.
Acute myeloid leukemia (AML) is a blood and bone marrow cancer that progresses rapidly and is one of the most common types of leukemia in adults
.
It is estimated that there are about 20,000 new cases in the United States each year, and about 43,000 new cases in Europe each year
.
Most AML patients will eventually relapse, and the prognosis of patients with relapsed or refractory AML is poor.
The 5-year survival rate is about 25%, and the 5-year survival rate for patients over 65 years old is less than 5%
.
PRGN-3006 is a multi-gene autologous CAR-T cell therapy that expresses three gene products at the same time: 1) CAR that specifically targets CD33.
CD33 is over-expressed on cancer cells in patients with AML and less expressed on normal hematopoietic stem cells 2) Membrane-bound IL-15 (mbIL15) enhances the durability of UltraCAR-T in vivo and better maintains the preferred stem cell-like memory phenotype; 3) A kill switch that can eliminate CAR-T cells when necessary to improve Treatment control
.
In January last year, the US FDA granted PRGN-3006 the title of "orphan drug" for the treatment of AML
.
This phase 1/1b clinical trial is mainly in the phase of dose escalation to evaluate the safety of PRGN-3006 and to identify patients who have not undergone lymphocyte depletion (cohort 1) and patients who have undergone lymphocyte depletion (cohort 2) by intravenous injection The maximum tolerated dose (MTD) of PRGN-3006, and to evaluate the durability and anti-tumor activity of PRGN-3006 in patients
.
Cohort 1 (N=9) and Cohort 2 (N=6) both received pretreatment with a median of 4 (range: 1-6) and 3 (range: 1-7) before the trial
.
The test data shows that 15 patients with r/rAML: ➤ Seven months after a single injection of PRGN-3006 in cohort 1, UltraCAR-T cells can still be detected in the blood of the patients
.
In the three dose level trials in cohort 1, according to the European LeukemiaNet (ELN) standard, 3 of 9 patients (33%) had stable disease (SD) for more than 3 months, and 1 patient SD lasted more than 7 months
.
➤ Cohort 2 In the two lowest-dose level treatment cohorts, the objective response rate (ORR) was 50% (3/6), including the ORR of dose level 1 was 33% (1/3), and the ORR of dose level 2 was 67%(2/3)
.
▲Summary of objective response data (picture source: Precigen's official website) In terms of safety, PRGN-3006 is well tolerated, has no dose-limiting toxicity (DLT), no neurotoxicity at any dose level, and has a relatively high incidence of adverse events (AE) Low
.
Dr.
Helen Sabzevari, President and CEO of Precigen, said: “We are excited about the interim data of the trial.
These data demonstrate the extraordinary potential and flexibility of the UltraCAR-T platform.
Based on the positive trial data of PRGN-3006, we believe that UltraCAR- T cells have the potential to improve the prognosis of cancer patients
.
In addition to PRGN-3006, Precigen’s similar products include PRGN-3005, both of which are multi-gene CARs developed by the company using the UltraCAR-T platform based on the Sleeping Beauty (SB) transposition system.
-T therapy
.
Precigen's UltraCAR-T platform has the following significant advantages: the use of multi-gene vectors for non-viral gene transfer to express multiple effector genes to have better tumor targeting specificity and control; mbIL15 co-existence Expression can enhance the specificity and durability of UltraCAR-T cell immune activation and help solve the problem of T cell exhaustion; ▲Green: tumor cells
.
Traditional CAR-T cells are difficult to inhibit aggressive entities in in vitro culture for a long time The growth of tumor cells (expressed by green fluorescent protein), but UltraCAR-T cells can continuously kill tumor cells and inhibit tumor growth
.
(Video source: Precigen company official website) The control switch realizes the control of T cells and improves potential safety ;Using proprietary non-viral gene transfer technology can quickly produce UltraCAR-T cells without ex vivo proliferation, thus greatly reducing the waiting time of patients
.
▲UltraCAR-T platform (picture source: Precigen company official website) At present, CAR-T The mainstream way of treatment is to use genetic technology to modify T cells and multiply them outside the patient's body
.
However, whether it is cell therapy that requires gene modification or gene therapy that uses gene delivery and modification as a treatment method, most of them are currently based on Viral vectors
.
However, the manufacturing process of viral vectors is complicated, expensive, and strictly controlled
.
In addition, viral vectors have challenges in evaluating the effectiveness and safety of the vectors and transportation
.
Therefore, the production and supply of vectors may be one of the biggest limiting factors in the field of cell and gene therapy
.
The purpose of the non-viral vector system based on transposon technology is to change the way of gene delivery and eliminate the need for culturing T cells in vitro in cell therapy, speed up treatment and reduce costs
.
The transposon system in CAR-T cell therapy.
The non-viral vector system based on transposon technology, in addition to the "Sleeping Beauty" (SB) transposon, and piggyBac (PB) transposon, can be overcome The problem of transient expression, and the inherent ability of stable expression and integration into nuclear genes, has made great progress in the application of CAR-T cell therapy in recent years
.
➤ SB transposon system The SB transposon system is a member of the Tc1/mariner transposon superfamily.
After Ivics et al.
revealed its transposable activity in 1997, it was gradually developed as a non-viral vector
.
When the system is transposed, the transposable sequence and transposase are carried out in a “cut-and-paste” manner.
The transposon vector system can carry a foreign DNA sequence during transposition.
This feature can be used for transgene, Gene screening and gene therapy fields
.
It can be transposed in most vertebrate cells cultured in vitro, mediating the stable integration and long-term expression of foreign genes
.
▲SB transposon (picture source: Internet) is operated in a non-viral way, which improves safety and can produce CAR-T cells very quickly (two days or less)
.
The two biggest highlights of this technology .
Representative company: Ziopharm OncologyPrecigen Recommended reading: The first patient of TriArm and Ziopharm based on the "Sleeping Beauty" system of CD19 CAR-T cells was administered in Taiwan Yimai Meng broke the news that "Sleeping Beauty" CAR-T therapy completed the first solid tumor patient Drug delivery, cell therapy based on transposon technology has obvious advantages Yimai Meng broke the news ➤PB transposon system PB transposon was first discovered in moths in 1983, and was successfully used for gene manipulation of mammalian cells in 2005
.
Like other transposons, it has two components: a transposon and a transposase
.
The most important thing for the PB transposon technology is that the transposase can excise the transposon in a completely seamless manner, leaving no sequence or mutation
.
The PB transposon system can effectively deliver a large number of CAR genes to T cells.
It has the advantages of a high percentage of Tscm produced, a large load (over 200kb has been proven), reduced risk, stability and efficiency, low production cost, and short time
.
▲PB transposon (picture source: cyagen.
com) Representative company: Poseida Therapeutics Shanghai Cell Therapy Group Recommended reading: Poseida announced that its first autologous CAR-T drug candidate P-PSMA-101 has completed its first patient administrationYimai Meng broke the news! Shanghai Cell Therapy Group's first domestic non-viral vector CAR-T cell therapy product was accepted by the IND! Reference materials: 1.
https:// -acute-myeloid-leukemia/recommended articles
.
Acute myeloid leukemia (AML) is a blood and bone marrow cancer that progresses rapidly and is one of the most common types of leukemia in adults
.
It is estimated that there are about 20,000 new cases in the United States each year, and about 43,000 new cases in Europe each year
.
Most AML patients will eventually relapse, and the prognosis of patients with relapsed or refractory AML is poor.
The 5-year survival rate is about 25%, and the 5-year survival rate for patients over 65 years old is less than 5%
.
PRGN-3006 is a multi-gene autologous CAR-T cell therapy that expresses three gene products at the same time: 1) CAR that specifically targets CD33.
CD33 is over-expressed on cancer cells in patients with AML and less expressed on normal hematopoietic stem cells 2) Membrane-bound IL-15 (mbIL15) enhances the durability of UltraCAR-T in vivo and better maintains the preferred stem cell-like memory phenotype; 3) A kill switch that can eliminate CAR-T cells when necessary to improve Treatment control
.
In January last year, the US FDA granted PRGN-3006 the title of "orphan drug" for the treatment of AML
.
This phase 1/1b clinical trial is mainly in the phase of dose escalation to evaluate the safety of PRGN-3006 and to identify patients who have not undergone lymphocyte depletion (cohort 1) and patients who have undergone lymphocyte depletion (cohort 2) by intravenous injection The maximum tolerated dose (MTD) of PRGN-3006, and to evaluate the durability and anti-tumor activity of PRGN-3006 in patients
.
Cohort 1 (N=9) and Cohort 2 (N=6) both received pretreatment with a median of 4 (range: 1-6) and 3 (range: 1-7) before the trial
.
The test data shows that 15 patients with r/rAML: ➤ Seven months after a single injection of PRGN-3006 in cohort 1, UltraCAR-T cells can still be detected in the blood of the patients
.
In the three dose level trials in cohort 1, according to the European LeukemiaNet (ELN) standard, 3 of 9 patients (33%) had stable disease (SD) for more than 3 months, and 1 patient SD lasted more than 7 months
.
➤ Cohort 2 In the two lowest-dose level treatment cohorts, the objective response rate (ORR) was 50% (3/6), including the ORR of dose level 1 was 33% (1/3), and the ORR of dose level 2 was 67%(2/3)
.
▲Summary of objective response data (picture source: Precigen's official website) In terms of safety, PRGN-3006 is well tolerated, has no dose-limiting toxicity (DLT), no neurotoxicity at any dose level, and has a relatively high incidence of adverse events (AE) Low
.
Dr.
Helen Sabzevari, President and CEO of Precigen, said: “We are excited about the interim data of the trial.
These data demonstrate the extraordinary potential and flexibility of the UltraCAR-T platform.
Based on the positive trial data of PRGN-3006, we believe that UltraCAR- T cells have the potential to improve the prognosis of cancer patients
.
In addition to PRGN-3006, Precigen’s similar products include PRGN-3005, both of which are multi-gene CARs developed by the company using the UltraCAR-T platform based on the Sleeping Beauty (SB) transposition system.
-T therapy
.
Precigen's UltraCAR-T platform has the following significant advantages: the use of multi-gene vectors for non-viral gene transfer to express multiple effector genes to have better tumor targeting specificity and control; mbIL15 co-existence Expression can enhance the specificity and durability of UltraCAR-T cell immune activation and help solve the problem of T cell exhaustion; ▲Green: tumor cells
.
Traditional CAR-T cells are difficult to inhibit aggressive entities in in vitro culture for a long time The growth of tumor cells (expressed by green fluorescent protein), but UltraCAR-T cells can continuously kill tumor cells and inhibit tumor growth
.
(Video source: Precigen company official website) The control switch realizes the control of T cells and improves potential safety ;Using proprietary non-viral gene transfer technology can quickly produce UltraCAR-T cells without ex vivo proliferation, thus greatly reducing the waiting time of patients
.
▲UltraCAR-T platform (picture source: Precigen company official website) At present, CAR-T The mainstream way of treatment is to use genetic technology to modify T cells and multiply them outside the patient's body
.
However, whether it is cell therapy that requires gene modification or gene therapy that uses gene delivery and modification as a treatment method, most of them are currently based on Viral vectors
.
However, the manufacturing process of viral vectors is complicated, expensive, and strictly controlled
.
In addition, viral vectors have challenges in evaluating the effectiveness and safety of the vectors and transportation
.
Therefore, the production and supply of vectors may be one of the biggest limiting factors in the field of cell and gene therapy
.
The purpose of the non-viral vector system based on transposon technology is to change the way of gene delivery and eliminate the need for culturing T cells in vitro in cell therapy, speed up treatment and reduce costs
.
The transposon system in CAR-T cell therapy.
The non-viral vector system based on transposon technology, in addition to the "Sleeping Beauty" (SB) transposon, and piggyBac (PB) transposon, can be overcome The problem of transient expression, and the inherent ability of stable expression and integration into nuclear genes, has made great progress in the application of CAR-T cell therapy in recent years
.
➤ SB transposon system The SB transposon system is a member of the Tc1/mariner transposon superfamily.
After Ivics et al.
revealed its transposable activity in 1997, it was gradually developed as a non-viral vector
.
When the system is transposed, the transposable sequence and transposase are carried out in a “cut-and-paste” manner.
The transposon vector system can carry a foreign DNA sequence during transposition.
This feature can be used for transgene, Gene screening and gene therapy fields
.
It can be transposed in most vertebrate cells cultured in vitro, mediating the stable integration and long-term expression of foreign genes
.
▲SB transposon (picture source: Internet) is operated in a non-viral way, which improves safety and can produce CAR-T cells very quickly (two days or less)
.
The two biggest highlights of this technology .
Representative company: Ziopharm OncologyPrecigen Recommended reading: The first patient of TriArm and Ziopharm based on the "Sleeping Beauty" system of CD19 CAR-T cells was administered in Taiwan Yimai Meng broke the news that "Sleeping Beauty" CAR-T therapy completed the first solid tumor patient Drug delivery, cell therapy based on transposon technology has obvious advantages Yimai Meng broke the news ➤PB transposon system PB transposon was first discovered in moths in 1983, and was successfully used for gene manipulation of mammalian cells in 2005
.
Like other transposons, it has two components: a transposon and a transposase
.
The most important thing for the PB transposon technology is that the transposase can excise the transposon in a completely seamless manner, leaving no sequence or mutation
.
The PB transposon system can effectively deliver a large number of CAR genes to T cells.
It has the advantages of a high percentage of Tscm produced, a large load (over 200kb has been proven), reduced risk, stability and efficiency, low production cost, and short time
.
▲PB transposon (picture source: cyagen.
com) Representative company: Poseida Therapeutics Shanghai Cell Therapy Group Recommended reading: Poseida announced that its first autologous CAR-T drug candidate P-PSMA-101 has completed its first patient administrationYimai Meng broke the news! Shanghai Cell Therapy Group's first domestic non-viral vector CAR-T cell therapy product was accepted by the IND! Reference materials: 1.
https:// -acute-myeloid-leukemia/recommended articles
