Hong Wang, Vinayak Khattar, J. Hensel
Aug 29, 2022
Molecular cancer therapeutics
Immune checkpoint inhibitors (ICIs) are promising in adjuvant settings for solid tumors and hematologic malignancies. They are currently used in the treatment as monoclonal antibodies in high concentrations, raising concerns of toxicity and adverse side effects. Among various checkpoint molecules, targeting the program cell death protein-1 (PD-1)-programmed death-ligand 1 (PD-L1) axis has garnered more clinical utility than others have. In order to develop a physiologically relevant and systemically stable level of ICIs from a one-time application by genetic antibody engineering, we endeavored using a non-pathogenic, replication-deficient recombinant adeno-associated vector (rAAV), expressing single-chain variable fragments (scFv) of PD-L1 antibody and tested in syngeneic mouse therapy models of MC38 colorectal and EMT6 breast tumors. Results of this study indicated a significant protection against PD-L1-mediated inhibition of CD8+ T cell function, against the growth of primary and secondary tumors, and durable antitumor cytotoxic T lymphocytes activity by adoptive CD8+ T cell transfer. Stable maintenance of PD-L1 scFv in vivo resulted in an increase in PD-1- CD8+ T cells, and a concomitant decrease in regulatory T cells, M2 macrophages and myeloid-derived suppressor cells in the tumor microenvironment. Overall, these data demonstrate the potential of rAAV-PD-L1-scFv as an alternative to mAb targeting of PD-L1 for tumor therapy.