Genetic Modulation of Immune Cells: Overview

An introduction to how genetic modulation of immune cells works

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Introduction

    • 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

Hematologic Malignancies11,12

Examples

  • Acute lymphoblastic leukemia
  • Chronic lymphocytic leukemia
  • Lymphoma
  • Multiple myeloma

Solid Tumors12

Examples

  • Breast cancer
  • Melanoma
  • Sarcoma

Autoimmune 
Diseases13

Examples

  • Autoimmune encephalomyelitis
  • Hemophilia
  • Pemphigus vulgaris

Infectious 
Diseases13–17

Examples

  • Hepatitis B virus
  • Hepatitis C virus
  • Human immunodeficiency virus
  • Human cytomegalovirus
  • Opportunistic fungal infections
  • Ebola virus infection
  • Coronavirus disease 2019 (COVID-19)
  • 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

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Tisagenlecleucel

Indications

  • In the US: Indicated for patients up to 25 years of age with B-cell precursor acute lymphoblastic leukemia that is refractory or in second or later relapse, and for adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma22
  • In the EU: Indicated for pediatric and young adult patients up to and including 25 years of age with B-cell acute lymphoblastic leukemia that is refractory, in relapse post transplant, or in second or later relapse, and for adult patients with relapsed or refractory DLBCL after two or more lines of systemic therapy23

Axicabtagene ciloleucel

Indications

  • In the US: Indicated for the treatment of adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, including DLBCL not otherwise specified, primary mediastinal large B-cell lymphoma, high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma25
  • In the EU: Indicated for the treatment of adult patients with relapsed or refractory DLBCL and primary mediastinal large B-cell lymphoma, after two or more lines of systemic therapy26

Brexucabtagene autoleucel

Indication

  • In the US: Indicated for the treatment of adult patients with relapsed or refractory mantle cell lymphoma24
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Talimogene laherparepvec (T-VEC)

Indications

  • In the US: Indicated for the local treatment of unresectable cutaneous, subcutaneous, and nodal lesions in patients with recurrent melanoma after initial surgery8
  • In the EU: Indicated for the treatment of adults with unresectable melanoma that is regionally or distantly metastatic (Stage IIIB, IIIC, and IVM1a) with no bone, brain, lung, or other visceral disease21
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Ab26.ZEBOV-GP (recombinant)

Indication

  • In the EU: Indicated (as part of the MVA-BN-Filo vaccine regimen) for the prevention of the disease caused by Ebola virus (Zaire ebolavirus species) in individuals ≥1 year of age14,19,20

References

  1. Majhen D, et al. Hum Gene Ther 2014;25(4):301–317.
  2. Pearl TM, et al. Mol Ther Oncolytics 2019;13:14–21.
  3. Strachan T, Read A. Genetic approaches to treating disease. In: Human Molecular Genetics. 4th edn. Boca Raton, FL: CRC Press, 2018:696–699.
  4. Wang D, Gao G. Discov Med 2014;18(98):151–161.
  5. Zhang C, et al. Front Immunol 2019;10:594.
  6. Zhao L, Cao YJ. Front Immunol 2019;10:2250.
  7. Arruda VR, et al. Mol Ther 2009;17(9):1492–1503.
  8. Imlygic® [package insert]. 2015. Available at: https://www.fda.gov/media/94129/download. Accessed January 26, 2021.
  9. Kutzler MA, Weiner DB. Nat Rev Genet 2008;9(10):776–788.
  10. Murphy A, et al. Immunity 2005;22(4):403–414.
  11. Li D, et al. Signal Transduct Target Ther 2019;4:35.
  12. Zhao Z, et al. Acta Pharm Sin B 2018;8(4):539–551.
  13. Chang ZL, Chen YY. Trends Mol Med 2017;23(5):430–450.
  14. 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.
  15. Chen Y, et al. J Immunol Res 2019(7):1–9.
  16. Seif M, et al. Front Immunol 2019;10:2711.
  17. 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.
  18. Bertoletti A, Tan AT. J Exp Med 2020;217(5):e20191663.
  19. 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.
  20. 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.
  21. 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.
  22. Kymriah® [package insert]. 2018. Available at: https://www.novartis.us/sites/www.novartis.us/files/kymriah.pdf Accessed January 26, 2021.
  23. 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.
  24. Tecartus™ [package insert]. 2020. Available at: https://www.fda.gov/media/140409/download. Accessed January 26, 2021.
  25. Yescarta® [package insert]. 2020. Available at: https://www.fda.gov/media/108377/download. Accessed January 26, 2021.
  26. 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.