Cytokine Gene Transfer: How Does It Work?

An introduction to genetic modulation of immune cells by cytokine gene transfer

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What Is Cytokine Gene Transfer?

Cytokine gene transfer is a gene immunotherapy technique in which a gene encoding a cytokine is delivered into cells, particularly immune cells, in order to treat diseases1–3

  • Cytokines are polypeptides secreted by cells that are involved in the modulation of immune and inflammatory responses. They are essential to control the magnitude of the immune response1,4

Cytokine gene transfer can be used to enhance immune responses by inducing the expression of certain cytokine(s) by diseased or nondiseased cells, with the ultimate goal of killing diseased cells3

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The rationale for cytokine gene transfer is that local expression of these molecules may result in enhanced activity against diseased cells, with lower levels of toxicity2

This approach can be used in combination with other approaches, such as gene-based vaccines and oncolytic gene therapy, to augment the immune response against diseased cells5,6

Mechanism of Cytokine Gene Transfer

Cytokine gene transfer involves cell-selective gene transfer for in situ expression of various cytokines, such as:7,8

Interleukin-1β, -2, -4, -6, -12, -24, and -27

Interferon-α, -β, and -γ

Tumor necrosis factor

Granulocyte–macrophage colony-stimulating factor (GM-CSF)

These cytokines can induce a robust immune response against diseased cells7–9

In this approach:8–10

  • The cytokine gene can be delivered into the diseased cells or into the microenvironment of diseased cells (e.g. immune cells, stromal cells, etc.) using vehicles such as viral vectors
  • Cytokine expression activates immune cells, such as macrophages, natural killer cells, or T-cell lymphocytes, which help to attack diseased cells
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IL, interleukin; IFN, interferon; TNF, tumor necrosis factor; GM-CSF, granulocyte–macrophage colony-stimulating factor.

Strategies Utilizing Cytokine Gene Transfer

Oncolytic Viral Therapy

Oncolytic viral therapy is based on the ability of replication-competent recombinant viruses to selectively infect and kill tumor cells2,6,11,12

The virus is genetically engineered to remove disease-causing genes, to replicate preferentially in tumor cells, and to deliver a cytokine-encoding gene that helps to promote an immune response against tumor cells2,7,13,14

ONCOLYTIC VIRAL VECTOR

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Figure adapted from Cancer Research Institute.13

In this approach, the infected tumor cells produce additional infectious virus particles that will spread to, infect, and kill surrounding tumor cells2,11,15

The process can be described as follows:2,11,15

  • Oncolytic viral vector is delivered via a systemic or direct injection into the tumor
  • Virus particles replicate in tumor cells, causing their lysis and subsequent release of additional virus particles, which can infect surrounding tumor cells
  • Replicated virus particles also produce cytokines that enhance the immune response
  • Following death of tumor cells, tumor-derived antigens are released, which, together with the virally derived cytokine, may promote an antitumor immune response
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Other Approaches

Another approach is the use of dendritic cells transduced ex vivo with vectors expressing a cytokine12,16,17

  • Preclinical and early stage clinical studies have investigated this approach but have shown only a modest efficacy

More recently, preclinical work indicates that direct cytokine gene transfer into the tumor microenvironment may enhance systemic immune responses and improves the therapeutic effects of dendritic cell-based therapies18

Clinical Applications of Cytokine Gene Transfer

Preclinical studies utilizing cytokine gene transfer conducted in vitro and in vivo were mostly positive, providing proof of concept for future clinical trials8

However, the clinical success of cytokine gene transfer has been limited by its modest efficacy and associated side effects due to the systemic delivery of the recombinant protein2

The use of cytokine gene transfer in combination with vector systems has led to some successes2,6

  • In 2015, talimogene laherparepvec was the first genetically modified oncolytic virus-based therapy approved in the EU and US for the treatment of melanoma15,19
    • Talimogene laherparepvec uses a genetically modified herpes simplex virus to deliver the gene encoding GM-CSF15,19
    • In addition, the herpes simplex virus-based vector is delivered with certain viral gene deletions so that it preferentially replicates in tumor cells and leads to oncolysis6

For details on the indications of talimogene laherparepvec, go to Section 1: Genetic Modulation of Immune Cells: Overview

The use of oncolytic gene therapy has also reached Phase 3 development for the treatment of hepatocellular carcinoma20,21

References

  1. O’Shea JJ, et al. 9 — Cytokines and cytokine receptors. In: Rich RR, et al (eds). Clinical Immunology. 4th edn. London, UK: Elsevier, 2013:108–135.
  2. Qian C, et al. Cell Res 2006;16(2):182–188.
  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. Zhang JM, An J. Int Anesthesiol Clin 2007;45(2):27–37.
  5. Kutzler MA, Weiner DB. Nat Rev Genet 2008;9(10):776–788.
  6. Wang D, Gao G. Discov Med 2014;18(98):151–161.
  7. Okura H, et al. Mol Cell Ther 2014;2:21.
  8. Rouanet M, et al. Int J Mol Sci 2017;18(6):1231.
  9. Kwiatkowska A, et al. Cancers (Basel) 2013;5(4):1271–1305.
  10. Lee S, Margolin K. Cancers (Basel) 2011;3(4):3856–3893.
  11. Marelli G, et al. Front Immunol 2018;9:866.
  12. Matar P, et al. J Biomed Sci 2009;16(1):30.
  13. Cancer Research Institute. Oncolytic virus therapy. Available at: https://www.cancerresearch.org/immunotherapy/treatment-types/oncolytic-virus-therapy. Accessed February 17, 2021.
  14. Howells A, et al. Front Oncol 2017;7:195.
  15. Imlygic® [package insert]. 2019. Available at: https://www.pi.amgen.com/~/media/amgen/repositorysites/pi-amgen-com/imlygic/imlygic_pi.ashx. Accessed February 17, 2021.
  16. Mazzolini G, et al. J Clin Oncol 2005;23(5):999–1010.
  17. Stripecke R. Biomedicines 2014;2(3):229–246.
  18. Wijesekera DPH, et al. FASEB Bioadv 2020;2(1):5–17.
  19. Imlygic® [product information]. 2019. Available at: https://www.ema.europa.eu/en/documents/product-information/imlygic-epar-product-information_en.pdf. Accessed February 17, 2021.
  20. ClinicalTrials.gov. NCT02562755. Available at: https://clinicaltrials.gov/ct2/show/NCT02562755. Accessed February 17, 2021.
  21. Moehler M, et al. Oncoimmunology 2019;8(8):1615817.