Immunogenicity Profiles of Selected Gene Therapies
Strategies are being considered to avoid triggering a host immune response to gene therapies. These include1,2:
Voretigene neparvovec-rzyl3
Viral vector: AAV
Transgene: RPE65
Delivery method: In vivo – subretinal injection to the eye
Target site: Retina
Immunogenicity in clinical trials
- Immune reactions were mild
- No patients experienced a clinically significant cytotoxic T-cell response to the AAV vector or transgene
- Patients received systemic corticosteroids pre- and post-treatment, which may have reduced the potential of an immune response
*Brand name: Luxturna™. AAV, adeno-associated virus; RPE65, retinal pigment epithelium-specific 65 kDa protein.
Tisagenlecleucel4
Viral vector: Lentiviral
Transgene: Chimeric antigen receptor (CAR)
Delivery method: Ex vivo
Target site: T cells
Immunogenicity in clinical trials
- Cytokine release syndrome* occurred in 79% of the 68 pediatric and young adults with r/r ALL and 74%of the 106 adult patients with r/r DLBCL
- Median time to onset was 3 days
- Median time to resolution was 8 days
- Five patients died within 30 days of treatment
- Severe or life-threatening CRS should be treated using tocilizumab with/without corticosteroids
- Pre-existing and treatment-induced anti-murine CAR19 antibodies did not affect the clinical response, initial expansion, and persistence
- Cytokine release syndrome* occurred in 79% of the 68 pediatric and young adults with r/r ALL and 74%of the 106 adult patients with r/r DLBCL
*CRS is a disorder characterized by fever, tachypnea, headache, tachycardia, hypotension, rash, and/or hypoxia caused by the release of cytokines5. ALL, acute lymphoblastic leukemia; CRS, cytokine release syndrome; DLBCL, diffuse large B-cell lymphoma; r/r, relapsed or refractory.
References
- Kay MA. Nat Rev Genet 2011;12(5):316–328.
- Sack BK, Herzog RW. Curr Opin Mol Ther 2009;11(5):493–503.
- LuxturnaTM [package insert]. Philadelphia, PA; Spark Therapeutics, Inc.; 2017. Available at: http://sparktx.com/LUXTURNA_US_Prescribing_Information.pdf. Accessed July 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.
- U.S. Department of Health and Human Services. Common Terminology Criteria for Adverse Events (CTCAE) version 5.0, 2017. Available at: https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_Reference_5x7.pdf. Accessed April 4, 2019.