Strategies to Avoid the Host Immune Response
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
- Systemic corticosteroids
CRS, cytokine release syndrome; Treg, regulatory T cell.
- Sack BK, Herzog RW. Curr Opin Mol Ther 2009;11(5):493–503.
- Kay MA. Nat Rev Genet 2011;12(5):316–328;
- Vandamme C, et al. Hum Gene Ther 2017;28(11):1061–1074;
- Wang D, et al. Nat Rev Drug Discov 2019;18(5):358–378;
- Mingozzi F, High KA. Blood 2013;122(1):23–36;
- Basner-Tschakarjan E, Mingozzi F. Front Immunol 2014;5:350.
- Corti M, et al. Mol Ther Methods Clin Dev 2014;1. pii: 14033;
- Zolgensma® [package insert]. Bannockburn, IL: AveXis Inc.; 2019. Available at: https://www.avexis.com/content/pdf/prescribing_information.pdf. Accessed July 24, 2019;
- LuxturnaTM [package insert]. Philadelphia, PA; Spark Therapeutics, Inc.; 2017. Available at: http://sparktx.com/LUXTURNA_US_Prescribing_Information.pdf. Accessed Jul 24, 2019;
- 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;
- Yescarta® [package insert]. Santa Monica, CA; Kite Pharma Inc.; 2017. Available at: https://www.yescarta.com/files/yescarta-pi.pdf. Accessed July 24, 2019;
- 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].
- Nayak S, Herzog RW. Gene Ther 2010;17(3):295–304.
- Bessis N, et al. Gene Ther 2004;11:S10–S17.