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Immune cell therapy is to use the body's own or donor-derived immune cells, cultured in vitro, amplified or activated, and then returned to the patient's body to stimulate or enhance the body's immune function, thereby eliminating tumor cells, pathogens or virus infections and other abnormal cells A new type of treatment.
Since 1986, the leader of immune cell therapy and Steven Rosenberg of the National Cancer Institute (NCI) first proposed genetic engineering to modify T cell technology, immune cell therapy products have experienced more than 30 years of development, and now the field of immune cell therapy has ushered in Craze.
More and more companies have devoted themselves to this field.
Various types of cell therapies such as CAR-T, TCR-T, TIL, CAR-NK, etc.
are in full bloom, and have been applied to a wide range of tumor and immune fields.
Recently (March 27, 2021), the BCMA CAR-T cell therapy product Abecma (idecabtagene vicleucel; ide-cel) jointly developed by Bristol-Myers Squibb (BMS) and bluebird bio (bluebird) was approved by the FDA for marketing.
This is already the fifth CAR-T product approved by the FDA.
There are also two Chinese companies that have submitted applications for the marketing of CAR-T cell therapy products to the National Medical Products Administration (NMPA), namely Fosun Kate’s Akilunza injection (FKC876) and WuXi Junuo’s Ruiji Orense injection (Relma-cel, R & D code: JWCAR029).
However, behind the upsurge of immune cell therapy, we must see that immune cell therapy is still an emerging field.
On the one hand, people still have many unknown problems in the scientific understanding of immune cell therapy.
On the other hand, many new technologies are continuously entering the field, and people do not yet have enough data to support the evaluation of new technologies.Compared with traditional medicine, immune cell therapy has completely different characteristics.
There is great heterogeneity in its cell sources, types, and in vitro operations.
In addition, as a kind of "living cell" drugs, immune cell drugs will continue to change in the human body, and the treatment principles and in vivo effects are also more complicated.
▲ Data source: Xingyao Research Institute In view of this, there are difficulties in immune cell therapy from scientific research to commercial production, non-clinical research, production technology, and quality control testing.
For example, in non-clinical research, the pharmacological characterization of immune cell therapy is special; in terms of production process, the preparation process is immature, the cost is high, and the yield is small; in terms of quality control, the starting material varies greatly, and the evaluation of efficacy and safety is complicated Difficulties that need to be overcome.
Therefore, the development and supervision of immune cell therapy are facing numerous challenges.
For companies interested in immune cell therapy, these are all problems that must be solved.
Thermo Fisher is well versed in the industrialization of cellular immunotherapy and provides a practical path for turning "good research" into "good medicine.
"
Provide immune cell therapy application solutions in the second quarter of 2021, covering the pre-marketing pharmacology of immune cell therapy, production process and quality control analysis, CAR-T full-process solutions, and the exploration of innovative fields (NK TIL macrophages) and other technical content.
Identify the QR code to obtain the overall solution Preclinical pharmacokinetics (PK) of immune cell therapy Traditional pharmacokinetic ADME research is not suitable for immune cell therapy products.
Taking "living cell" CAR-T as an example, the "CAR-T cell therapy product quality control test research and non-clinical research considerations" pointed out that the PK test of CAR-T cells mainly focuses on the proliferation level and distribution of target cells in the body Circumstances and duration.
CAR-T cells have the ability to actively migrate and replicate in the body, and their biodistribution and PK curve after administration are unique.
According to analysis, Novartis Kymriah and Gilead Yescarta have similar PK characteristics in the body.
After clonal expansion in 7-14 days, the number reaches a peak, and then there is a shrinking period until about 3 months.
The last part of the memory subgroup may remain in the body for several years.
▲ CAR-T in vivo pharmacokinetics (picture source: ANNUAL REVIEWS) The detection methods of pre-clinical PK research include: direct imaging technology, flow cytometry, immunohistochemistry technology, quantitative PCR technology, etc.
Pharmacodynamics (PD) The PD study of CAR-T can be divided into in vitro efficacy testing and in vivo efficacy studies.
The efficacy of CAR-T in vitro can be reflected by the tumor killing rate or proliferation inhibition rate, and can also be detected by the expression of IFN-γ and the phenotypic changes of CAR-T cells.
In in vivo studies, the efficacy of CAR-T requires observation of tumor load, tumor cell number, and cytokine changes in animals; and comprehensive tumor volume, weight, animal survival and other indicators.
In addition, it is also necessary to observe relevant indicators reflecting the targeting activity of CAR-T and organ involvement.
Commonly used detection methods for PD include: bioluminescence imaging, flow cytometry, ELISA, MSD, and conventional pharmacological or pathological methods.
Thermo Fisher's Invitrogen Attune NxT is a highly intelligent flow cytometer, designed for efficient detection, saving experimental time, and providing a full range of solutions for cell and functional analysis.
▲ The production process and quality control analysis of Invitrogen Attune NxT flow cytometry analyzer immune cell therapy.
As mentioned at the beginning of this article, the process and quality control of immune cell therapy are facing difficulties such as high cost, low yield, complex efficacy and safety evaluation, etc.
.
In fact, manufacturing companies can actually overcome these pain points through two strategies, one is to improve process efficiency and stability, and the other is to reduce the failure rate in the production process.
For the former, the use of a modular production system can improve production efficiency.
In addition, the use of innovative products and solutions can increase the yield of plasmids and viral vectors. For the latter, companies can use more closed production systems and new and rapid detection methods to improve product process quality control and reduce production failure rates.
Modular and closed production system In the past, the production of immune cells was dominated by traditional manual labor.
However, manual operation was not only inefficient, but also difficult to ensure stability; and open production brought about a large area, pollution risk, and product consistency.
Differences, time-consuming, and large cell loss also greatly limit the success rate and final use of the product.
With the development of technology, modular and closed manufacturing systems have now become the development trend of the industry, which has the advantage of improving productivity and safety.
In the "Technical Guidelines for Cell Therapy Product Research and Evaluation (Trial)" document formulated by the State Food and Drug Administration, it is also recommended to adopt a closed or semi-closed preparation process as much as possible to reduce the risk of contamination and cross-contamination.
The first two companies that have commercialized CAR-T products, Novartis and Gilead/Kite, have both experienced the transformation from manual to automated and closed processes.
They have deployed advanced cell therapy manufacturing facilities networks to improve competitiveness while reducing The turnaround time of product manufacturing is conducive to the timely treatment of patients.
▲ Novartis Kymriah's preparation process (picture source: Molecular Therapy) closed manufacturing system can also reduce the need for ISO standard clean room and reduce the space cost of the clean room; combined with digital connections, these systems can achieve repeatability and reproducibility.
Track and comply with GMP production process.
If a modular design is adopted and the most suitable program is selected or designed for each process step to optimize the entire manufacturing process, the efficiency and practicability of the instrument can also be greatly improved.
For example, time-consuming processes such as cell expansion can be separated from fast processes such as buffer exchange and cell concentration, which may reduce the investment in facilities and fixed equipment by as much as 70%.
Thermo Fisher's GibcoTM CTSTM RoteaTM countercurrent centrifugal system is a flexible, expandable and closed cell processing system suitable for cell therapy production.
This versatile system can provide extraordinary flexibility in cell therapy development and production systems.
It applies the mature countercurrent centrifugation method to a wide range of cell processing applications, such as CAR-T therapy, stem cell therapy and PBMC separation.
▲ Considerations for the quality control of the GibcoTM CTSTM RoteaTM countercurrent centrifugal system In order to improve process efficiency and stability, and reduce the failure rate in the production process, in addition to using a closed automated process system as much as possible to enhance the stability of the process, it can also be used Raw materials of high quality and high batch stability are used for production, and the production process and quality standards are strictly controlled.
➤ The selection of raw materials for immune cell therapy refers to all the biological and chemical raw materials used in the production process.
Take CAR-T cell products as an example.
The raw materials for such products include culture media, PBMC separation reagents, T cell sorting reagents, activators, cytokines, serum or serum substitutes, etc.
The quality of raw materials has a very large impact and risk on the stability, safety, efficiency and purity of downstream cell therapy products.
Therefore, the quality of the final product must be considered at the beginning, and a high-quality GMP with sufficient documentation support should be selected.
Only with high-grade cell therapy raw materials can there be safe and efficient product output; if the raw materials are changed in the later clinical stage, the price to be paid will be very high.
➤ Identification of cell therapy products The identification of biological products such as cell therapy products is a key quality standard for proving products.
Manufacturers need to submit the identification of biological products to regulatory agencies for review as an additional condition for drug approval.
The characterization of biological products includes: determination of physical and chemical properties, biological activity, immunochemical properties, purity and impurities, etc.
It should be noted that characterization requires appropriate techniques and methods to establish corresponding specifications.
▲ Image source: Characterization of shimadzu.
dk is also one of the most important challenges for the manufacture of cell therapy products.
For example, a large number of cells are usually used.
Therefore, manufacturers need to focus on reducing the amount of samples used and choosing better and better choices.
Analysis methods that can predict results, etc. In addition, these inspections need to achieve continuous monitoring of the product in order to better process control and real-time release.
Therefore, when selecting a characteristic identification method, the ease of use of the method should be considered, and whether the selected method has relevant technical support during implementation and verification.
➤ Production process control and quality testing Take the production process of CAR-T cell therapy as an example.
Intermediate control testing can mainly focus on cell proliferation and quality, such as cell number, viability, phenotype, sterility, etc.
The final batch release test may be relatively more stringent, including indicators and tests for safety, product nature, purity, dosage, and efficacy.
▲ The key quality attributes of Novartis Kymriah (picture source: Molecular Therapy) are based on the "CAR-T Cell Therapeutic Product Quality Control Testing Research and Non-clinical Research Considerations" issued by China Food and Drug Control Institute, the quality of CAR-T cell therapeutic products Control research and testing items should generally include: cell number and cell viability, cell phenotype, CAR positive rate test, biological efficacy test, sterility test, detection of mycoplasma, pyrogen/endotoxin, CAR-T cell genome Detection of viral vector copy number and integration, RCr/rCL detection, process residue detection and tumor cell residue detection, etc.
For allogeneic CAR-T cells, histocompatibility antigen detection and nucleic acid method should be used to detect specific human viruses.
Endotoxin detection is an essential part of the production process.
Whether it is light absorption or fluorescence endotoxin detection, the Thermo Scientific™ microplate reader can provide a suitable detection solution.
Thermo Scientific™ microplate microplate reader includes Varioskan LUX, Multiskan SkyHigh/Multiskan FC, Fluoroskan/Fluoroskan FL/Luminoskan, which is flexible in application, excellent in performance, and easy to use.
It is widely used in various microplate-based experiments. ▲ The Thermo Scientific™ Microplate Microplate Reader Immune Cell Therapy Solution empowers cell therapy projects at all stages of the market launch process, which is developing rapidly from R&D to clinical trials to commercial approval.
However, it is an arduous task to push R&D results to the market, and it faces many challenges such as regulatory supervision, process amplification, stability and consistency, and risk control.
In order to meet the needs of clinical and final commercial scale production of cells, on the one hand, high-quality GMP-grade cell therapy raw materials and adequate documentation support are essential to minimize risks, reduce the burden on the quality control system, and meet regulatory requirements ; On the other hand, establishing a robust, repeatable and sustainable process as early as possible can help accelerate development and avoid delays associated with production changes.
Thermo Fisher Scientific has long been cooperating with cell and gene therapy developers to help companies transform cell therapy from discovery to clinical research and commercial production by providing innovative technologies and products, as well as expertise, services and customized solutions.
Thermo Fisher provides a highly specialized CTS (Cell Therapy Systems) product line endorsed by more than 100 leading clinical application cases.
It is produced in accordance with cGMP standards, has strict testing and supporting documents, and contains a more effective regulatory approach than research-grade products.
In addition, the CTS series of products support the large-scale production of cell therapy and optimize costs; the flexible and closed production system is suitable for a wide range of cell treatments, and can improve productivity and safety.
It is believed that relying on the milestones supported by solid data, the connection will draw the road to the success of the large-scale and commercialization of cell therapy.
Click "Read the full text" below to get technical support for immune cell therapy and even more chances to win gifts!
Since 1986, the leader of immune cell therapy and Steven Rosenberg of the National Cancer Institute (NCI) first proposed genetic engineering to modify T cell technology, immune cell therapy products have experienced more than 30 years of development, and now the field of immune cell therapy has ushered in Craze.
More and more companies have devoted themselves to this field.
Various types of cell therapies such as CAR-T, TCR-T, TIL, CAR-NK, etc.
are in full bloom, and have been applied to a wide range of tumor and immune fields.
Recently (March 27, 2021), the BCMA CAR-T cell therapy product Abecma (idecabtagene vicleucel; ide-cel) jointly developed by Bristol-Myers Squibb (BMS) and bluebird bio (bluebird) was approved by the FDA for marketing.
This is already the fifth CAR-T product approved by the FDA.
There are also two Chinese companies that have submitted applications for the marketing of CAR-T cell therapy products to the National Medical Products Administration (NMPA), namely Fosun Kate’s Akilunza injection (FKC876) and WuXi Junuo’s Ruiji Orense injection (Relma-cel, R & D code: JWCAR029).
However, behind the upsurge of immune cell therapy, we must see that immune cell therapy is still an emerging field.
On the one hand, people still have many unknown problems in the scientific understanding of immune cell therapy.
On the other hand, many new technologies are continuously entering the field, and people do not yet have enough data to support the evaluation of new technologies.Compared with traditional medicine, immune cell therapy has completely different characteristics.
There is great heterogeneity in its cell sources, types, and in vitro operations.
In addition, as a kind of "living cell" drugs, immune cell drugs will continue to change in the human body, and the treatment principles and in vivo effects are also more complicated.
▲ Data source: Xingyao Research Institute In view of this, there are difficulties in immune cell therapy from scientific research to commercial production, non-clinical research, production technology, and quality control testing.
For example, in non-clinical research, the pharmacological characterization of immune cell therapy is special; in terms of production process, the preparation process is immature, the cost is high, and the yield is small; in terms of quality control, the starting material varies greatly, and the evaluation of efficacy and safety is complicated Difficulties that need to be overcome.
Therefore, the development and supervision of immune cell therapy are facing numerous challenges.
For companies interested in immune cell therapy, these are all problems that must be solved.
Thermo Fisher is well versed in the industrialization of cellular immunotherapy and provides a practical path for turning "good research" into "good medicine.
"
Provide immune cell therapy application solutions in the second quarter of 2021, covering the pre-marketing pharmacology of immune cell therapy, production process and quality control analysis, CAR-T full-process solutions, and the exploration of innovative fields (NK TIL macrophages) and other technical content.
Identify the QR code to obtain the overall solution Preclinical pharmacokinetics (PK) of immune cell therapy Traditional pharmacokinetic ADME research is not suitable for immune cell therapy products.
Taking "living cell" CAR-T as an example, the "CAR-T cell therapy product quality control test research and non-clinical research considerations" pointed out that the PK test of CAR-T cells mainly focuses on the proliferation level and distribution of target cells in the body Circumstances and duration.
CAR-T cells have the ability to actively migrate and replicate in the body, and their biodistribution and PK curve after administration are unique.
According to analysis, Novartis Kymriah and Gilead Yescarta have similar PK characteristics in the body.
After clonal expansion in 7-14 days, the number reaches a peak, and then there is a shrinking period until about 3 months.
The last part of the memory subgroup may remain in the body for several years.
▲ CAR-T in vivo pharmacokinetics (picture source: ANNUAL REVIEWS) The detection methods of pre-clinical PK research include: direct imaging technology, flow cytometry, immunohistochemistry technology, quantitative PCR technology, etc.
Pharmacodynamics (PD) The PD study of CAR-T can be divided into in vitro efficacy testing and in vivo efficacy studies.
The efficacy of CAR-T in vitro can be reflected by the tumor killing rate or proliferation inhibition rate, and can also be detected by the expression of IFN-γ and the phenotypic changes of CAR-T cells.
In in vivo studies, the efficacy of CAR-T requires observation of tumor load, tumor cell number, and cytokine changes in animals; and comprehensive tumor volume, weight, animal survival and other indicators.
In addition, it is also necessary to observe relevant indicators reflecting the targeting activity of CAR-T and organ involvement.
Commonly used detection methods for PD include: bioluminescence imaging, flow cytometry, ELISA, MSD, and conventional pharmacological or pathological methods.
Thermo Fisher's Invitrogen Attune NxT is a highly intelligent flow cytometer, designed for efficient detection, saving experimental time, and providing a full range of solutions for cell and functional analysis.
▲ The production process and quality control analysis of Invitrogen Attune NxT flow cytometry analyzer immune cell therapy.
As mentioned at the beginning of this article, the process and quality control of immune cell therapy are facing difficulties such as high cost, low yield, complex efficacy and safety evaluation, etc.
.
In fact, manufacturing companies can actually overcome these pain points through two strategies, one is to improve process efficiency and stability, and the other is to reduce the failure rate in the production process.
For the former, the use of a modular production system can improve production efficiency.
In addition, the use of innovative products and solutions can increase the yield of plasmids and viral vectors. For the latter, companies can use more closed production systems and new and rapid detection methods to improve product process quality control and reduce production failure rates.
Modular and closed production system In the past, the production of immune cells was dominated by traditional manual labor.
However, manual operation was not only inefficient, but also difficult to ensure stability; and open production brought about a large area, pollution risk, and product consistency.
Differences, time-consuming, and large cell loss also greatly limit the success rate and final use of the product.
With the development of technology, modular and closed manufacturing systems have now become the development trend of the industry, which has the advantage of improving productivity and safety.
In the "Technical Guidelines for Cell Therapy Product Research and Evaluation (Trial)" document formulated by the State Food and Drug Administration, it is also recommended to adopt a closed or semi-closed preparation process as much as possible to reduce the risk of contamination and cross-contamination.
The first two companies that have commercialized CAR-T products, Novartis and Gilead/Kite, have both experienced the transformation from manual to automated and closed processes.
They have deployed advanced cell therapy manufacturing facilities networks to improve competitiveness while reducing The turnaround time of product manufacturing is conducive to the timely treatment of patients.
▲ Novartis Kymriah's preparation process (picture source: Molecular Therapy) closed manufacturing system can also reduce the need for ISO standard clean room and reduce the space cost of the clean room; combined with digital connections, these systems can achieve repeatability and reproducibility.
Track and comply with GMP production process.
If a modular design is adopted and the most suitable program is selected or designed for each process step to optimize the entire manufacturing process, the efficiency and practicability of the instrument can also be greatly improved.
For example, time-consuming processes such as cell expansion can be separated from fast processes such as buffer exchange and cell concentration, which may reduce the investment in facilities and fixed equipment by as much as 70%.
Thermo Fisher's GibcoTM CTSTM RoteaTM countercurrent centrifugal system is a flexible, expandable and closed cell processing system suitable for cell therapy production.
This versatile system can provide extraordinary flexibility in cell therapy development and production systems.
It applies the mature countercurrent centrifugation method to a wide range of cell processing applications, such as CAR-T therapy, stem cell therapy and PBMC separation.
▲ Considerations for the quality control of the GibcoTM CTSTM RoteaTM countercurrent centrifugal system In order to improve process efficiency and stability, and reduce the failure rate in the production process, in addition to using a closed automated process system as much as possible to enhance the stability of the process, it can also be used Raw materials of high quality and high batch stability are used for production, and the production process and quality standards are strictly controlled.
➤ The selection of raw materials for immune cell therapy refers to all the biological and chemical raw materials used in the production process.
Take CAR-T cell products as an example.
The raw materials for such products include culture media, PBMC separation reagents, T cell sorting reagents, activators, cytokines, serum or serum substitutes, etc.
The quality of raw materials has a very large impact and risk on the stability, safety, efficiency and purity of downstream cell therapy products.
Therefore, the quality of the final product must be considered at the beginning, and a high-quality GMP with sufficient documentation support should be selected.
Only with high-grade cell therapy raw materials can there be safe and efficient product output; if the raw materials are changed in the later clinical stage, the price to be paid will be very high.
➤ Identification of cell therapy products The identification of biological products such as cell therapy products is a key quality standard for proving products.
Manufacturers need to submit the identification of biological products to regulatory agencies for review as an additional condition for drug approval.
The characterization of biological products includes: determination of physical and chemical properties, biological activity, immunochemical properties, purity and impurities, etc.
It should be noted that characterization requires appropriate techniques and methods to establish corresponding specifications.
▲ Image source: Characterization of shimadzu.
dk is also one of the most important challenges for the manufacture of cell therapy products.
For example, a large number of cells are usually used.
Therefore, manufacturers need to focus on reducing the amount of samples used and choosing better and better choices.
Analysis methods that can predict results, etc. In addition, these inspections need to achieve continuous monitoring of the product in order to better process control and real-time release.
Therefore, when selecting a characteristic identification method, the ease of use of the method should be considered, and whether the selected method has relevant technical support during implementation and verification.
➤ Production process control and quality testing Take the production process of CAR-T cell therapy as an example.
Intermediate control testing can mainly focus on cell proliferation and quality, such as cell number, viability, phenotype, sterility, etc.
The final batch release test may be relatively more stringent, including indicators and tests for safety, product nature, purity, dosage, and efficacy.
▲ The key quality attributes of Novartis Kymriah (picture source: Molecular Therapy) are based on the "CAR-T Cell Therapeutic Product Quality Control Testing Research and Non-clinical Research Considerations" issued by China Food and Drug Control Institute, the quality of CAR-T cell therapeutic products Control research and testing items should generally include: cell number and cell viability, cell phenotype, CAR positive rate test, biological efficacy test, sterility test, detection of mycoplasma, pyrogen/endotoxin, CAR-T cell genome Detection of viral vector copy number and integration, RCr/rCL detection, process residue detection and tumor cell residue detection, etc.
For allogeneic CAR-T cells, histocompatibility antigen detection and nucleic acid method should be used to detect specific human viruses.
Endotoxin detection is an essential part of the production process.
Whether it is light absorption or fluorescence endotoxin detection, the Thermo Scientific™ microplate reader can provide a suitable detection solution.
Thermo Scientific™ microplate microplate reader includes Varioskan LUX, Multiskan SkyHigh/Multiskan FC, Fluoroskan/Fluoroskan FL/Luminoskan, which is flexible in application, excellent in performance, and easy to use.
It is widely used in various microplate-based experiments. ▲ The Thermo Scientific™ Microplate Microplate Reader Immune Cell Therapy Solution empowers cell therapy projects at all stages of the market launch process, which is developing rapidly from R&D to clinical trials to commercial approval.
However, it is an arduous task to push R&D results to the market, and it faces many challenges such as regulatory supervision, process amplification, stability and consistency, and risk control.
In order to meet the needs of clinical and final commercial scale production of cells, on the one hand, high-quality GMP-grade cell therapy raw materials and adequate documentation support are essential to minimize risks, reduce the burden on the quality control system, and meet regulatory requirements ; On the other hand, establishing a robust, repeatable and sustainable process as early as possible can help accelerate development and avoid delays associated with production changes.
Thermo Fisher Scientific has long been cooperating with cell and gene therapy developers to help companies transform cell therapy from discovery to clinical research and commercial production by providing innovative technologies and products, as well as expertise, services and customized solutions.
Thermo Fisher provides a highly specialized CTS (Cell Therapy Systems) product line endorsed by more than 100 leading clinical application cases.
It is produced in accordance with cGMP standards, has strict testing and supporting documents, and contains a more effective regulatory approach than research-grade products.
In addition, the CTS series of products support the large-scale production of cell therapy and optimize costs; the flexible and closed production system is suitable for a wide range of cell treatments, and can improve productivity and safety.
It is believed that relying on the milestones supported by solid data, the connection will draw the road to the success of the large-scale and commercialization of cell therapy.
Click "Read the full text" below to get technical support for immune cell therapy and even more chances to win gifts!
