Impact of the Immune Response on Gene Therapy


Immune Response Against the Transgene Product

The transgene product may be recognized as a foreign antigen, thus triggering an immune response1

  • Antibodies that neutralize the transgene product may be produced1
  • T-cell responses against the transgene-expressing cells may be triggered1
  • Transgene products that share homology with other self-antigens are more likely to be tolerated2

Preclinical studies using AAV vectors suggest that the target tissue plays a role in determining the immune response to a transgene1

  • Intramuscular administration is associated with a higher risk of an immune response compared with administration to other tissues, e.g. the liver1

The immune response to gene therapies can have safety consequences3,4

An important safety concern related to gene therapy is the risk of cytokine release syndrome5,6

What is cytokine release syndrome (CRS)?

  • CRS is a disorder characterized by fever, tachypnea, headache, tachycardia, hypotension, rash, and/or hypoxia caused by the release of cytokines7
  • Laboratory findings: high CRP; high IL-6, IL‑10, IFN-γ, TNF-α, sgp130, sIL6R, and ferritin; deranged coagulation parameters; elevated creatinine and liver enzymes; cytopenias8,9

Ornithine transcarbamylase deficiency trial fatality10,11

  • In 1999, a patient died after being administered a high concentration of an adenoviral vector-based gene therapy, which activated an innate immune response consisting of the acute release of inflammatory cytokines10,11

What causes CRS?

  • It can be induced by cell lysis or therapeutic T-cell activation8
  • This causes cytokine release and activates the innate immune response, which is followed by further cytokine release8
  • It can be triggered by infections and certain drugs, including gene therapy8,10

Cytokine release syndrome warnings associated with approved products5,6

  • Tisagenlecleucel (lentiviral vector) and axicabtagene ciloleucel* (retroviral vector) are CAR T-cell therapies that carry warnings for the risk of CRS5,6
  • They should not be administered to patients with active infections or inflammatory disorders5,6

The immune response to gene therapies can reduce efficacy3,4

  • Although AAV vectors have also been shown to induce an innate immune response in preclinical studies, the clinical implications of this are largely unknown12,13

A loss or lack of efficacy can arise as a result of the immunogenicity of the capsid or transgene product14

A humoral immune response to a viral vector can lead to the production of neutralizing antibodies (NAbs), which can reduce transduction efficiency13,15,16

  • Example: In a clinical trial of AAV2 factor IX* in patients with severe hemophilia B, a patient with a NAb titer of 1:2 expressed peak levels of factor IX that were ~11% of normal. However, another patient with a higher NAb titer of 1:17 had a lower circulating factor IX level that was 3% of normal16

Increasing capsid doses above those currently in use may aid in reducing the effects of NAbs, although this risks exposing cells to higher capsid loads13

Lower Doses

  • At lower doses, antibody neutralization can lead to a lack of efficacy
  • As the dose increases, the issue of neutralizing antibodies may be overcome
  • At higher doses, a capsid-specific T-cell response can develop, resulting in the loss of efficacy

Higher Doses

  • Higher vector doses have also been shown to elicit a stronger innate immune response*17


  1. Basner-Tschakarjan E, Mingozzi F. Front Immunol 2014;5:350.
  2. Annoni A, et al. Cell Immunol 2018. pii: S0008-8749(18)30187-4. doi: 10.1016/j.cellimm.2018.04.012.
  3. Nayak S, Herzog RW. Gene Ther 2010;17(3):295–304.
  4. Bessis N, et al. Gene Ther 2004;11:S10–S17.
  5. Yescarta® [package insert]. Santa Monica, CA; Kite Pharma, Inc.; 2017. Available at: Accessed July 24, 2019.
  6. Kymriah® [package insert]. East Hanover, NJ; Novartis Pharmaceuticals Corporation; 2018. Available at: Accessed July 24, 2019.
  7. U.S. Department of Health and Human Services. Common Terminology Criteria for Adverse Events (CTCAE) version 5.0, 2017. Available at: Accessed April 4, 2019.
  8. Shimabukuro-Vornhagen A, et al. J Immuno Ther Cancer 2018;6(1):56.
  9. Teachey DT, et al. Cancer Discov 2016;6(6):664–679.
  10. Verma IM. Mol Ther 2000;2(5):415–416.
  11. Wilson JM. Mol Genet Metab 2009;96(4):151–157.
  12. Vandamme C, et al. Human Gene Ther 2017;28(11):1061–1074.
  13. Mingozzi F, High KA. Blood 2013;122(1):23–36.
  14. Mingozzi F, Büning H. Front Immunol 2015;6:120.
  15. Sack BK, Herzog RW. Curr Opin Mol Ther 2009;11(5):493–503.
  16. Manno CS, et al. Nat Med 2006;12(3):342–347.
  17. Shao W, et al. JCI Insight 2018;3(12):e120474.
  1. Nayak S, Herzog RW. Gene Ther 2010;17(3):295–304.
  2. Bessis N, et al. Gene Ther 2004;11:S10–S17.