PD-L1 checkpoint blockade delivered by retroviral replicating vector confers anti-tumor efficacy in murine tumor models

• Published in: Oncotarget Vol. 10; no. 23; pp. 2252 - 2269
• Main Authors: Mitchell, Leah A, Yagiz, Kader, Hofacre, Andrew, Viaud, Sophie, Munday, Anthony W, Espinoza, Fernando Lopez, Mendoza, Daniel, Rodriguez-Aguirre, Maria E, Bergqvist, Simon, Haghighi, Ali, Miner, Marin V, Accomando, William P, Burrascano, Cynthia, Gammon, Dawn, Gruber, Harry E, Jolly, Douglas J, Lin, Amy H
• Format: Journal Article
• Language: English
• Published: United States Impact Journals LLC 19.03.2019
• Subjects: Research Paper; PD-L1; single chain variable fragment; PD-1; immunotherapy; retroviral replicating vector
• ISSN: 1949-2553
• DOI: 10.18632/oncotarget.26785

Immune checkpoint inhibitors (CPIs) are associated with a number of immune-related adverse events and low response rates. We provide preclinical evidence for use of a retroviral replicating vector (RRV) selective to cancer cells, to deliver CPI agents that may circumvent such issues and increase efficacy. An RRV, RRV-scFv-PDL1, encoding a secreted single chain variable fragment targeting PD-L1 can effectively compete with PD-1 for PD-L1 occupancy. Cell binding assays showed trans-binding activity on 100% of cells in culture when infection was limited to 5% RRV-scFv-PDL1 infected tumor cells. Further, the ability of scFv PD-L1 to rescue PD-1/PD-L1 mediated immune suppression was demonstrated in a co-culture system consisting of human-derived immune cells and further demonstrated in several syngeneic mouse models including an intracranial tumor model. These tumor models showed that tumors infected with RRV-scFv-PD-L1 conferred robust and durable immune-mediated anti-tumor activity comparable or superior to systemically administered anti-PD-1 or anti PD-L1 monoclonal antibodies. Importantly, the nominal level of scFv-PD-L1 detected in serum is ∼50-150 fold less than reported for systemically administered therapeutic antibodies targeting immune checkpoints. These results support the concept that RRV-scFv-PDL1 CPI strategy may provide an improved safety and efficacy profile compared to systemic monoclonal antibodies of currently approved therapies.