PD-L1 checkpoint blockade delivered by retroviral replicating vector confers anti-tumor efficacy in murine tumor models
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Leah A. Mitchell1, Kader Yagiz1, Andrew Hofacre1, Sophie Viaud1, Anthony W. Munday1, Fernando Lopez Espinoza1, Daniel Mendoza1, Maria E. Rodriguez-Aguirre1, Simon Bergqvist2, Ali Haghighi1, Marin V. Miner1, William P. Accomando1, Cynthia Burrascano1, Dawn Gammon1, Harry E. Gruber1, Douglas J. Jolly1 and Amy H. Lin1
1 Tocagen Inc., San Diego, 92121, CA, USA
2 Biofizik, Inc., San Diego, 92121, CA, USA
|Amy H. Lin,||email:||[email protected]|
Keywords: immunotherapy; single chain variable fragment; retroviral replicating vector; PD-L1; PD-1
Received: January 08, 2019 Accepted: March 04, 2019 Published: March 19, 2019
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.
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