Strategies to Avoid the Host Immune Response

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Strategies are being considered to avoid triggering a host immune response to gene therapies. These include1,2:

Hiding the vector from the immune system

  • Use of lowest effective viral vector doses1

  • Modifications of the viral vector capsid1,3,4

    • Alteration of the capsid to remove identified epitopes
    • Use of empty capsids

  • Delivery to immune-privileged sites1

    • Injection into the liver, brain, eye

  • Prevention of transgene expression in APCs1

    • Use of tissue-specific promoters or microRNA to eliminate transgene expression in APCs

  • Isolation of the target tissue (to avoid vector dilution in the blood and exposure to NAbs) via balloon catheter delivery followed by saline flushing5

*Sites that have a unique immune status or are not subject to traditional immune surveillance1. AAV, adeno-associated virus; APC, antigen-presenting cell; NAb, neutralizing antibody; vg, vector genomes.

  • Example: Lower vector doses may not trigger T-cell responses to the capsid5

    Patients with hemophilia B receiving up to 6 × 1011 vg/kg liver-directed AAV8 did not experience an increase in liver enzymes or loss of transgene expression; at the same time, levels of factor IX transgene were just above the threshold for therapeutic efficacy6

Hiding the immune system from the vector

  • Immune suppression involves:

    • Inhibition of cell division/proliferation
    • Depletion of specific cell types via the use of antibodies
    • Transient immune suppression is the preferred strategy

  • Modulation of the immune response away from immunity and toward tolerance1

    • Inhibition of co-stimulation
    • Induction and adoptive transfer of Tregs
    • Plasmapheresis to lower antibody titers5

  • Reduction in circulating B cells prior to dosing7

  • Example: Immune suppression regimens associated with gene therapies that have received regulatory approval include:

    • Systemic corticosteroids
      pre- and post-gene therapy administration8,9
    • Tocilizumab (with or without corticosteroids)
      for the management of CRS10,11
    • Cyclosporin and mycophenolate mofetil
      pre- and post-gene therapy administration, and corticosteroids 30 minutes prior to therapy12

CRS, cytokine release syndrome; Treg, regulatory T cell.

      1. Sack BK, Herzog RW. Curr Opin Mol Ther 2009;11(5):493–503.
      2. Kay MA. Nat Rev Genet 2011;12(5):316–328;
      3. Vandamme C, et al. Hum Gene Ther 2017;28(11):1061–1074;
      4. Wang D, et al. Nat Rev Drug Discov 2019;18(5):358–378;
      5. Mingozzi F, High KA. Blood 2013;122(1):23–36;
      6. Basner-Tschakarjan E, Mingozzi F. Front Immunol 2014;5:350.
      7. Corti M, et al. Mol Ther Methods Clin Dev 2014;1. pii: 14033;
      8. Zolgensma® [package insert]. Bannockburn, IL: AveXis Inc.; 2019. Available at: https://www.avexis.com/content/pdf/prescribing_information.pdf. Accessed July 24, 2019;
      9. LuxturnaTM [package insert]. Philadelphia, PA; Spark Therapeutics, Inc.; 2017. Available at: http://sparktx.com/LUXTURNA_US_Prescribing_Information.pdf. Accessed Jul 24, 2019;
      10. Kymriah® [package insert]. East Hanover, NJ; Novartis Pharmaceuticals Corporation; 2018. Available at: https://www.pharma.us.novartis.com/sites/www.pharma.us.novartis.com/files/kymriah.pdf. Accessed July 24, 2019;
      11. Yescarta® [package insert]. Santa Monica, CA; Kite Pharma Inc.; 2017. Available at: https://www.yescarta.com/files/yescarta-pi.pdf. Accessed July 24, 2019;
      12. Glybera [summary of product characteristics]. Amsterdam, The Netherlands; uniQure biopharma B.V.; 2017. Available at: https://www.ema.europa.eu/en/documents/product-information/glybera-epar-product-information_en.pdf. Accessed July 24, 2019 [medicinal product no longer authorized].
  1. Nayak S, Herzog RW. Gene Ther 2010;17(3):295–304.
  2. Bessis N, et al. Gene Ther 2004;11:S10–S17.