Pharmacokinetic and pharmacodynamic characterization of CD8-targeted lentiviral vector for in vivo CD19-directed...

Given challenges with access, manufacturability, and the requirement for lymphodepletion with autologous chimeric antigen receptor (CAR)-T cell therapy, a promising alternative is in vivo-mediated gene delivery using redirected viral vectors to generate tumor-antigen-specific CAR-T cells. While data supporting in vivo CAR-T cells in patients are emerging, limited studies have described the pharmacokinetics (PK) and pharmacodynamics (PD) of this approach. Here, we evaluated the PK/PD of a novel CD8-targeted lentiviral vector called "fusosome," delivering a CD19-directed CAR transgene in xenograft mouse models. In NSG mice without target cells, the fusosome vector genomes cleared rapidly from plasma (90 minutes to 2 hours) and were detectable in tested tissues for up to 1 week. We observed prolonged persistence of viral particles in peripheral blood mononuclear cell (PBMC)-engrafted mice, with vector detection peaking within 10-40 min post-administration, depending on the tissue type. CAR transgene was detectable in various lymphoid organs after 7 days post-vector dosing. Dose-dependent tumor control and specific CAR-T cell generation were observed in tumor-bearing PBMC-engrafted mice. Overall, the PK/PD of fusosome and efficacy in the tumor model supports its potential as an in vivo gene delivery approach to treat patients with B cell lymphomas.