Genetic Modulation of Immune Cells: Overview
An introduction to how genetic modulation of immune cells works
Introduction
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- Genetic modulation of immune cells is a specific gene addition strategy that involves the introduction of modified genes to promote a stronger immune response and kill diseased cells1–6
- This module does not discuss strategies of genetic modulation that aim to avoid or suppress an immune response7
Gene Therapy Approaches to Stimulate an Immune Response
- Genetic modulation of immune cells involves the introduction of genes that promote a stronger immune response, thus killing diseased cells3
- There are three main ways in which genetic modulation has been investigated to incite immune cells to target and kill diseased cells:
1. A modified immune receptor gene could be added to immune cells that enables them to target diseased cells for destruction3,4
Examples of this include chimeric antigen receptor (CAR) T-cell therapy or T-cell receptor (TCR) therapy, where the receptor is engineered to bind to a certain protein expressed on diseased cells4,6
Immune cells are transfected with the modified gene of interest
Immune cells express the immune receptor gene of interest
Immune cells recognize diseased cells via expression of the immune receptor
An immune response is triggered, and diseased cells are destroyed
2. A cytokine gene could be introduced into diseased or non-diseased cells, particularly immune cells, to prompt an enhanced immune response3
An example of this is the use of oncolytic viral therapy2,4,8
Diseased or non-diseased cells are transfected
Diseased or non-diseased cells express the cytokine
An immune response is triggered following cytokine release, and diseased cells are destroyed
3. A gene encoding a foreign antigen could be introduced into the desired cells of the patient, triggering an immune response3,9
Examples of this type of approach are DNA and RNA vaccines1,5
Non-diseased cells are transfected with DNA or messenger RNA encoding the foreign antigen of interest
Non-diseased cells express the foreign antigen
Expressed antigens are recognized and presented by antigen-presenting cells via major histocompatibility complexes
An immune response is triggered, and diseased cells are destroyed
APC, antigen-presenting cell; DNA, deoxyribonucleic acid; MHC, major histocompatibility complex; RNA, ribonucleic acid.
These gene additions enhance the immune response toward diseased cells, which leads to their subsequent death and alleviation of the disease3–5
Clinical Applications
Genetic modulation of the immune system provides an option for the treatment of infectious diseases and complex disorders that are caused by the combined effects of multiple genetic and environmental factors4,10
- The efficacy for some of these approaches in treating hematologic malignancies has been widely recognized11,12
- Solid tumors represent an important potential target for some of these approaches, but research has shown only moderate effects and many failures in this area12
- To date, the main obstacles to treatment success include insufficient and atypical molecular targets required to attack the tumor and/or to control the tumor microenvironment
- In addition to cancer therapy, several clinical studies are being conducted in autoimmune and infectious diseases13,15–18
Examples of Approved Indications
Below are examples of approved therapies8,14,19–26
References
- Majhen D, et al. Hum Gene Ther 2014;25(4):301–317.
- Pearl TM, et al. Mol Ther Oncolytics 2019;13:14–21.
- Strachan T, Read A. Genetic approaches to treating disease. In: Human Molecular Genetics. 4th edn. Boca Raton, FL: CRC Press, 2018:696–699.
- Wang D, Gao G. Discov Med 2014;18(98):151–161.
- Zhang C, et al. Front Immunol 2019;10:594.
- Zhao L, Cao YJ. Front Immunol 2019;10:2250.
- Arruda VR, et al. Mol Ther 2009;17(9):1492–1503.
- Imlygic® [package insert]. 2015. Available at: https://www.fda.gov/media/94129/download. Accessed January 26, 2021.
- Kutzler MA, Weiner DB. Nat Rev Genet 2008;9(10):776–788.
- Murphy A, et al. Immunity 2005;22(4):403–414.
- Li D, et al. Signal Transduct Target Ther 2019;4:35.
- Zhao Z, et al. Acta Pharm Sin B 2018;8(4):539–551.
- Chang ZL, Chen YY. Trends Mol Med 2017;23(5):430–450.
- Zabdeno® [product information]. 2020. Available at: https://www.ema.europa.eu/en/documents/product-information/zabdeno-epar-product-information_en.pdf. Accessed January 26, 2021.
- Chen Y, et al. J Immunol Res 2019(7):1–9.
- Seif M, et al. Front Immunol 2019;10:2711.
- Zimmer C, et al. Coronavirus vaccine tracker. Updated November 18, 2020. Available at: https://www.nytimes.com/interactive/2020/science/coronavirus-vaccine-tracker.html. Accessed January 26, 2021.
- Bertoletti A, Tan AT. J Exp Med 2020;217(5):e20191663.
- European Medicines Agency. Mvabea (MVA-BN-Filo, recombinant). An overview of Mvabea and why it is authorised in the EU. Available at: https://www.ema.europa.eu/en/documents/overview/mvabea-epar-medicine-overview_en.pdf. Accessed January 26, 2021.
- European Medicines Agency. Zabdeno. Overview. Available at: https://www.ema.europa.eu/en/documents/product-information/zabdeno-epar-product-information_en.pdf. Accessed January 26, 2021.
- Imlygic® [product information]. 2019. Available at: https://www.ema.europa.eu/en/documents/product-information/imlygic-epar-product-information_en.pdf. Accessed January 26, 2021.
- Kymriah® [package insert]. 2018. Available at: https://www.novartis.us/sites/www.novartis.us/files/kymriah.pdf Accessed January 26, 2021.
- Kymriah® [product information]. 2020. Available at: https://www.ema.europa.eu/en/documents/product-information/kymriah-epar-product-information_en.pdf. Accessed January 26, 2021.
- Tecartus™ [package insert]. 2020. Available at: https://www.fda.gov/media/140409/download. Accessed January 26, 2021.
- Yescarta® [package insert]. 2020. Available at: https://www.fda.gov/media/108377/download. Accessed January 26, 2021.
- Yescarta® [product information]. 2020. Available at: https://www.ema.europa.eu/en/documents/product-information/kymriah-epar-product-information_en.pdf. Accessed January 26, 2021.