Different levels of complexity in drug development
Written by: Mr. Bubu
Source: Stem cell experts
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More and more cell and gene therapy (CGT) products are available to treat various diseases and restore immune function. Impair tissue function. Cell and gene therapy products are regulated by the FDA's Center for Biologics Evaluation and Research (CBER). Before starting clinical studies, companies need to submit and receive approval of a new drug application (IND). Before marketing can begin, a biologics license application (BLA) needs to be submitted and approved.
Note: IND=investigational new drug, BLA=biologics license application.
Today, with the help of a review document[1] by Brian J Kwee and Kyung E Sung of the US FDA Center for Biologics Evaluation and Research (CBER), we Popularize science on the current status, challenges and countermeasures of cell and gene therapy products.
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Main challenges in the development of cell therapies
FDA Approved cell and gene therapy products
There are 17 cell and gene therapy products approved by the US FDA. As of 2021, they are mainly used in regenerative medicine (including treatment Hematology umbilical cord blood hematopoietic stem cells , tissue-specific cells for oral soft tissue repair, skin beauty or cartilage regeneration ), and the remaining products are used for cancer treatment (including for the treatment of B-cell malignancies) CAR-T cells and DC cells for the treatment of prostate cancer).
More details: Cell therapy in clinical practice (2): Cell products on the market
Currently, cells commonly used in clinical trials include mesenchymal stem cells (MSCs), neural stem cells (NSC), NK cells and blood mononuclear cells Cell (BMC). These cells are mainly used for disease treatment (such as cancer, nervous system, cardiovascular system diseases, respiratory system and inflammatory diseases) and regenerative medicine applications.
The main challenges of cell therapy
Cell therapy is springing up like mushrooms after a spring rain, providing an effective treatment approach for many difficult-to-treat diseases. More than 1,700 cell therapy clinical trials are active around the world, and many products have been approved by the FDA. However, there are still many challenges in the replicability and cost-effectiveness of cell and gene therapy products. The
cell preparation process usually includes: obtaining seed cells from patients (autologous cell therapy) or healthy people (allogeneic cell therapy), cell purification or gene modification (gene therapy), large-scale expansion, and finally clinical application or cryopreservation . Clinically, the amount of cells per dose in adults is about 10*6–10*9. Therefore, improving cell preparation efficiency while ensuring the critical quality attributes (CQA) of cells is the key to successful clinical cell therapy.
One challenge of cell therapy is that is expensive and is prohibitively expensive. For example, Novartis's CAR-T cell therapy Kymriah is currently priced at US$3.475 million; Gilead's CAR-T cell therapy Yescarta is currently priced at US$3.373 million. Another challenge for
cell therapies is the heterogeneity of cell therapies and variations in critical quality attributes of . Cell therapy heterogeneity includes cell heterogeneity caused by different donors, product heterogeneity caused by different processes, and treatment heterogeneity caused by different patient disease microenvironments. In the cell manufacturing process, aspects that introduce heterogeneity mainly include cell isolation, in vitro culture expansion, genetic modification, and cryopreservation.
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Common cell therapies in clinical trials
The five most common cell types in clinical trials refer only to single-cell suspension forms of pharmaceuticals, including T cells, DC, NK cells, hematopoietic stem cells and mesenchymal cells Plasma stem cells .
Immune Cell Clinical Trials
Immune cell therapies comprise more than 1,000 currently active clinical trials, including 767 T cell trials, 116 NK cell trials, and 136 DC trials.Clinical trials of immune cells (T cells, DCs, NK cells, etc.) are mainly used to treat cancer, and a few are used to treat immune diseases (including autoimmune diseases, degenerative diseases, infectious diseases, or graft-versus-host disease).
1. T cells
T cell clinical trials have increased dramatically over the past decade, thanks to the huge success of CAR-T cell therapy. Currently, T cells are the most studied cell type in all cell therapy clinical trials, accounting for 45% of total clinical trials. T cell clinical trials include genetically modified or non-genetically modified T cells. The two most important types of
are CAR-T cells and TCR-T cells . The main difference between the two is that CAR-T cells target the surface antigen and are not restricted by MHC categories; while TCR-T cells target the surface and intracellular target in an MHC-dependent manner.
2. NK cells
Like T cells, NK cells can also be used in clinical trials, but NK cells produce fewer side effects than T cells. The therapeutic effects of NK cells vary depending on the source of cells ( i.e. peripheral blood mononuclear cells, pluripotent stem cells, umbilical cord blood or NK cell lines), or the combination of combined with other therapies (i.e. chemotherapy, cytokines , immunomodulatory drugs, antibodies, CAR and cytokine genetic engineering) .
3. DC cell therapy
DC cell therapy is different because of its method of promoting cell maturation and loading antigen (i.e. mRNA transfection, tumor lysate, viral vector ), and because of its administration route (i.e. dermal Internal, subcutaneous, lymph nodes ) vary, and the efficacy also varies due to these differences.
Stem Cells Clinical Trials
Currently, there are probably more than 550 active clinical trials of hematopoietic stem cells (HSCs) and mesenchymal stem cells (MSCs) for regenerative medicine and immune modulation. Among them, 274 are HSC clinical trials and 283 are MSCs clinical trials.
1. Hematopoietic stem cells
Hematopoietic stem cells are stem cells that can produce and differentiate into all immune cells and blood cells, and can be used to rebuild the blood system. Generally speaking, before hematopoietic stem cell transplantation, patients must first receive myeloablative treatment (radiotherapy or chemotherapy) to treat related blood or immune diseases by rebuilding the patient's immune system and blood system. Therefore, HSC transplantation is commonly used to treat various blood disorders, autoimmune diseases, transplant-related diseases, and leukemias.
2. Mesenchymal stem cells
Mesenchymal stem cells are a type of adult stem cells derived from various tissues (including bone marrow, fat, placenta and umbilical cord, etc.). In 2006, the International Society for Cell Therapy (ISCT) gave the most basic definition of mesenchymal stem cells, which is the lowest identification standard for mesenchymal stem cells: MSCs grow adherently under standard culture conditions; MSCs express CD105, CD73 and CD90, do not express CD45, CD34, CD14 or CD11b, CD79α or CD19 and HLA-DR surface markers; MSCs can differentiate into osteoblasts , adipocytes and chondroblasts when induced in vitro.
Drawing from: National Regional Laboratory of Adult Stem Cells
Mesenchymal stem cells have the ability to differentiate into various mesenchymal tissues, secrete regenerative paracrine factors and regulate the immune system. Therefore, they are used to treat a variety of diseases (including blood diseases, neurological disease , cardiovascular disease and graft versus host disease).
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Summary at the end of the article
Cell therapy is currently one of the most researched treatment modalities in preclinical and clinical settings. Many cell therapy products have been approved and more are in active clinical research. How does
improve cell preparation efficiency? How to maintain cell functions and properties for a long time? This is the key to successful clinical cell therapy. biomaterials , bioreactors and microphysiological systems that simulate the human microenvironment can do it! We will talk about this part in the next issue.
References
[1] BJ Kwee, KE Sung. Engineering microenvironments for manufacturing therapeutic cells Experimental Biology and Medicine 2021; 0: 1–12
[2] What is Gene Therapy?, https://www.fda.gov/vaccines- blood-biologics/cellular-gene-therapy-products/what-gene-therapy(accessed 27 March 2021)
[3] Theregulatory process from concept to market. In Lanza R, Langer R, Joesph V,Atala A (eds) Principles of tissue engineering. 5th ed. Cambridge, MA: AcademicPress, 2020, pp.1553–72
[4] Celltherapies in the clinic. Bioeng Transl Med2021
[5] Approved Cellular and Gene Therapy Products, https://www.fda.gov /vaccines-blood-biolog
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