Class I-restricted T-cell responses to a polymorphic peptide in a gene therapy clinical trial for α-1-antitrypsin deficiency

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 114; no. 7; pp. 1655 - 1659
• Main Authors: Calcedo, Roberto, Somanathan, Suryanarayan, Qin, Qiuyue, Betts, Michael R., Rech, Andrew J., Vonderheide, Robert H., Mueller, Christian, Flotte, Terence R., Wilson, James M.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 14.02.2017
• Subjects: Biological Sciences; gene therapy; a-1-antitrypsin; adeno-associated virus; polymorphism; immune response
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1617726114

Adeno-associated virus (AAV)-mediated gene therapy is currently being pursued as a treatment for the monogenic disorder α-1-antitrypsin (AAT) deficiency. Results from phase I and II studies have shown relatively stable and dose-dependent increases in transgene-derived wild-type AAT after local intramuscular vector administration. In this report we describe the appearance of transgene-specific T-cell responses in two subjects that were part of the phase II trial. The patient with the more robust T-cell response, which was associated with a reduction in transgene expression, was characterized more thoroughly in this study. We learned that the AAT-specific T cells in this patient were cytolytic in phenotype, mapped to a peptide in the endogenous mutant AAT protein that contained a common polymorphism not incorporated into the transgene, and were restricted by a rare HLA class I C alleles present only in this patient. These human studies illustrate the genetic influence of the endogenous gene and HLA haplotype on the outcome of gene therapy.