Immunogenicity of Lentiviral Vectors

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Lentiviral vectors have been widely studied for use in gene therapy1

Ex vivo gene therapies that use lentiviral vectors have received regulatory approval2-6

Immune responses to both the vector and transgene are still a concern1

  • Example: Tisagenlecleucel*: a lentiviral-vector delivered CAR T-cell therapy

    • Treatment with tisagenlecleucel is associated with a risk of cytokine release syndrome2
    • The presence of pre-existing or treatment-induced antibodies is not thought to
      impact upon its safety and efficacy2

Lentiviral vectors can trigger an innate immune response1,7

Lentiviral-binding antibodies and activated complement components can opsonize (i.e. tag) lentiviral vectors1,8

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This marks the lentiviral vectors for phagocytosis by liver and spleen macrophages and APCs1

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Lentiviral vectors can trigger an adaptive immune response, which can be characterized as either humoral or cell-mediated1,7

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Humoral Immunity

Lentiviral vectors are engineered with surface proteins from an unrelated virus – this is called pseudotyping1

Vesicular stomatitis virus (VSV) surface glycoprotein is commonly used to pseudotype lentiviral vectors1

Pre-existing antibodies against lentiviral vectors are less prevalent compared with other viral vectors as humans are not a natural host for VSV infection1

However, humans may carry non-specific cross-reacting anti-VSV.G antibodies1

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Cell-Mediated Immunity

Lentiviral-derived viral antigens can induce a cell-mediated immune response and transgene-derived antigens can cause cytotoxic T cells to destroy transduced cells1

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References

  1. Annoni A, et al. Cell Immunol 2019;342:103802.
  2. Kymriah®[package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2020. Available at: https://www.novartis.us/sites/www.novartis.us/files/kymriah.pdf. Accessed May 21, 2021.
  3. Zynteglo™ [summary of product characteristics]. Utrecht, The Netherlands: bluebird bio (Netherlands) B.V.; 2021. Available at: https://www.ema.europa.eu/en/documents/product-information/zynteglo-epar-product-information_en.pdf. Accessed May 21, 2021.
  4. Libmeldy™ [summary of product characteristics]. Amsterdam, The Netherlands: Orchard Therapeutics (Netherlands) B.V.; 2021. Available at: https://www.ema.europa.eu/en/documents/product-information/libmeldy-epar-product-information_en.pdf. Accessed May 21, 2021.
  5. Breyanzi® [package insert]. Bothell, WA: Juno Therapeutics; 2021. Available at: https://packageinserts.bms.com/pi/pi_breyanzi.pdf. Accessed May 21, 2021.
  6. Abecma® [package insert]. Summit, NJ: Celgene Corporation; 2021. Available at: https://packageinserts.bms.com/pi/pi_abecma.pdf. Accessed May 25, 2021.
  7. Nayak S, Herzog RW. Gene Ther 2010;17(3):295–304.
  8. Thau L, et al. Physiology, Opsonization. In: StatPearls [Internet]. Treasure Island, FL: StatPearls Publishing; May 2021. Available at: https://www.ncbi.nlm.nih.gov/books/NBK534215/. Accessed May 21, 2021.
  1. Nayak S, Herzog RW. Gene Ther 2010;17(3):295–304.
  2. Bessis N, et al. Gene Ther 2004;11:S10–S17.