Aside from the cloud, what are the key points of non-clinical research on genetically modified cell therapy products?

"On June 22, 2021, the first domestic CAR-T cell therapy product produced by Fosun Kate, Akilunsai injection, was approved for marketing, declaring that China has entered the era of cell therapy and will usher in CAR-T.
The era of cell therapy blowout! Cell therapy products are currently very cutting-edge products, and have shown increasing application value in the treatment of cancer, blood diseases, cardiovascular diseases, diabetes, and Alzheimer's disease.
Cell therapy products have been developed as drugs.
Become a hot spot
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" On December 3, 2021, the official website of the Center for Drug Evaluation of the National Medical Products Administration officially released the "Technical Guidelines for Non-clinical Research of Gene Modified Cell Therapy Products (Trial)" (written on November 30, 2021), The implementation since the date of release reflects the importance and concern of China’s regulatory authorities on genetically modified cell therapy products.
This is to better guide and promote the development of genetically modified cell therapy products.
The Drug Evaluation Center has conducted industry research, document collection and Expert consultation seminars and other work, based on the existing "Technical Guidelines for Research and Evaluation of Cell Therapy Products" (for trial implementation), and based on the current scientific understanding of genetically modified cell therapy products, A brief introduction to the relevant laws and regulations and policy framework of the "Guiding Principles of Clinical Research Technology (Trial)"
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1 The regulation of genetically modified cell therapy products is becoming more and more professional.
1 Policy formulation background The improvement of China's drug review system has accelerated the launch of cell therapy products, which will help shorten the time to market for innovative drugs and drugs that are urgently needed in clinical use
.
On June 22, 2021, the first domestic CAR-T cell therapy product produced by Fosun Kate, Akilunsai injection, was approved for marketing, declaring that my country has entered the era of cell therapy and will usher in CAR-T cells.
The era of therapy blowout
.
Regulatory authorities are working hard to formulate guidelines that meet the development needs of the cell therapy product industry.
In 2021, CDE will successively issue technical guidance and regulatory documents covering multiple stages from preclinical, clinical, and application and marketing requirements, so as to provide more cell therapy drugs to the market in the future.
Provide guidelines and management practices, but the registration and clinical research of cell therapy products have special requirements, which may have long-term and unpredictable risks.
Therefore, traditional guidelines may not be fully applicable to cell therapy products.
Features Formulate relevant policies and regulations
.
China has issued a series of guidelines for the supervision of genetically modified cell therapy products, such as "CAR-T cell therapy product quality control testing research and non-clinical research considerations" (released in June 2018), "Cell therapy product research and evaluation technical guidelines "(trial Implementation) (December 22, 2017 release) and so on
.
The European Union EMA updated the "Guideline on quality, non-clinical and clinical aspects of medical products containing genetically modified cells" (effective June 1, 2021) on November 3, 2020.
medicinal products containing genetically modified cells)
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The guidelines provide guidance for the development and evaluation of drug products containing genetically modified cells, covering quality, non-clinical and clinical, and pharmacovigilance and environmental risk assessment recommendations related to genetically modified cell therapy drugs
.
2 The concept of genetically modified cell therapy products is based on the newly issued guidelines in China-"Guiding Principles for Non-clinical Research Technologies for Gene Modified Cell Therapy Products (Trial)", which defines genetically modified cell therapy products as those that have undergone genetic modification , Replacement, addition or deletion, etc.
) to change its biological characteristics and intended to be used to treat human diseases.
Living cell products, such as genetically modified immune cells (such as natural killer (NK) cells, dendritic cells, T cells) Cells and macrophages, etc.
), genetically modified stem cells (such as pluripotent induced stem cells, hematopoietic stem cells, etc.
) and cell products derived from them, etc.

.
3 Introduction to the types of genetically modified cell therapy products Currently, genetically modified cell therapy products include: 1.
CAR-T cell technology products: namely chimeric antigen receptor T cell (CAR-T), such as CAR- T and CAR-NK cells; 2.
TCR-T cell technology products: T cell receptor (T cell receptor, TCR) genetically engineered T cells (TCR-T), etc.
; 3.
Genetically modified stem cells: including pluripotent Somatic cells (such as hematopoietic stem cells), and pluripotent stem cells (human embryonic stem cells)
.
2 What are the main concerns of non-clinical research on genetically modified cell therapy products? 1 What is the purpose of non-clinical research? Genetic modification of cells will change their biological characteristics, and at the same time will bring new safety risks, such as the risk of gene editing off-target risk, vector insertion mutation risk, vector recombination risk, and the risk of expressed transgenic products
.
Therefore, non-clinical research should be fully carried out to collect information for risk and benefit assessment.
The main purposes are: (1) To clarify the purpose, function and mechanism of the product of genetic modification, and to clarify the biology used in the proposed patient population Reasonable; (2) Provide supporting basis for the choice of the route of administration, administration procedure, and dose of clinical trials; (3) According to potential risk factors, clarify the characteristics of toxicity reactions, predict the possible adverse reactions in the human body, and determine The clinical monitoring indicators of adverse reactions provide a reference for formulating clinical risk control measures
.
2 What are the considerations for the selection of test substances for non-clinical research? (1) Test substance for non-clinical research: It should be able to represent the quality and safety of the sample for clinical use.
For critical non-clinical research, the product of genetically modified cell therapy for clinical use should be used as the test substance as much as possible
.
The samples used in in vitro and in vivo non-clinical research should meet the quality standard requirements of the corresponding development stage
.
If the subsequent preparation process is changed, the similarities and differences between the non-clinical use samples and the clinical samples to be used and their possible impact on the effectiveness and safety of the human body should be clarified
.
(2) In special circumstances, alternative products can be considered: (human-derived cell products expressing animal homologous genes or animal-derived alternative cell products).
The alternative products should adopt similar production processes as the products intended for clinical use, and may affect their effectiveness.
Conduct comparative studies with key quality parameters of safety to evaluate the quality similarity of alternative products and products to be used clinically and their impact on the predictability of non-clinical data
.
3 What are the considerations for non-clinical research animal species/model selection? When conducting non-clinical in vivo studies, relevant animal species/models should be selected as much as possible
.
The genetically modified cell should be able to exhibit the desired functional activity in the selected animal in its intended mode of action
.
Therefore, when selecting relevant animals, it is necessary to consider the characteristics of the product and the intended clinical use, including but not limited to the following factors: (1) The similarity of the animal's biological response to genetically modified cells and transgene expression products with the expected human response; ( 2) Animal immune tolerance to genetically modified cells of heterogeneous origin; (3) Similarity of animal pathophysiological characteristics with the intended patient population; (4) Feasibility of clinical intended delivery/administration methods
.
4 Non-clinical validity and proof-of-concept considerations.
In vivo proof-of-concept tests should be considered as much as possible
.
When designing in vivo proof-of-concept experiments, it is recommended to use disease model animals
.
For genetically modified cells that are expected to survive or function for a long time in the human body, if relevant animal models are not available, alternative methods are recommended to evaluate the potential long-term effects of genetically modified cells, such as the use of alternative products for in vivo proof-of-concept tests.
, Evaluate the long-term effects of genetically modified cells within a feasible time window
.
5 Special considerations for pharmaceutical research on three specific types of genetically modified cell products (1) CAR or TCR-modified immune cells: As far as possible, various methods should be used to assess the risk of target-related toxicity and off-target toxicity
.
(2) Cell products derived from induced pluripotent stem cells: They have tumorigenic risks and can form teratomas in the body.
Under normal circumstances, tumorigenicity tests should be completed before the first clinical trial; if the design is scientific and reasonable, the evaluation can be satisfied On request, the risk of tumorigenicity can also be assessed in a toxicity study of sufficient duration
.
(3) Cell products prepared by gene editing technology: Perform in vitro on-target and off-target activity evaluation to confirm the specificity of the modified enzyme or guide RNA to the target gene sequence
.
When evaluating off-target activity, the impact of species-specific differences, differences in cell pathophysiological status, or differences in cell types on the predictability of non-clinical data should also be evaluated
.
When necessary, the potential impact of gene editing on cell phenotype and physiological function should also be analyzed
.
3 Conclusion The purpose of non-clinical research is to determine the effectiveness and safety of drugs.
Due to the characteristics of genetically modified cell therapy products, the key challenge is how to carry out non-clinical research? In non-clinical evaluation, there are big differences and special risk considerations from traditional small molecule drugs and monoclonal antibodies
.
At present, the approval of genetically modified cell therapy products is more cautious.
The implementation of the regulatory policy of the "Technical Guidelines for Non-clinical Research of Genetically Modified Cell Therapy Products (Trial)" provides an opportunity for the development of genetically modified cell therapy products and guides the genetically modified cell therapy industry Healthy development
.
References [1] and columnist in the field of cell and gene therapy, Dr.
Sinan Biomedical senior engineer and licensed pharmacist, a porter of pharmaceutical policies and regulations in the self-media era, and insists on the goal of lifelong learning.
Combine, and strive to achieve the unity of knowledge and action
.