Leveraging gene therapy to achieve long-term continuous or controllable expression of biotherapeutics

Sci Adv. 2022 Jul 15;8(28):eabm1890. doi: 10.1126/sciadv.abm1890. Epub 2022 Jul 13.

Abstract

T cells redirected to cancer cells either via a chimeric antigen receptor (CAR-T) or a bispecific molecule have been breakthrough technologies; however, CAR-T cells require individualized manufacturing and bispecifics generally require continuous infusions. We created an off-the-shelf, single-dose solution for achieving prolonged systemic serum levels of protein immunotherapeutics via adeno-associated virus (AAV) gene transfer. We demonstrate proof of principle in a CD19+ lymphoma xenograft model using a single intravenous dose of AAV expressing a secreted version of blinatumomab, which could serve as a universal alternative for CD19 CAR-T cell therapy. In addition, we created an inducible version using an exon skipping strategy and achieved repeated, on-demand expression up to at least 36 weeks after AAV injection. Our system could be considered for short-term and/or repeated expression of other transgenes of interest for noncancer applications.

MeSH terms

  • Antigens, CD19 / genetics
  • Genetic Therapy
  • Humans
  • Immunotherapy, Adoptive
  • Receptors, Antigen, T-Cell / metabolism
  • Receptors, Chimeric Antigen* / genetics

Substances

  • Antigens, CD19
  • Receptors, Antigen, T-Cell
  • Receptors, Chimeric Antigen