Research Papers:

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

Leah A. Mitchell, Kader Yagiz, Andrew Hofacre, Sophie Viaud, Anthony W. Munday, Fernando Lopez Espinoza, Daniel Mendoza, Maria E. Rodriguez-Aguirre, Simon Bergqvist, Ali Haghighi, Marin V. Miner, William P. Accomando, Cynthia Burrascano, Dawn Gammon, Harry E. Gruber, Douglas J. Jolly and Amy H. Lin _

PDF  |  Full Text  |  Supplementary Files  |  How to cite  |  Order a Reprint

Oncotarget. 2019; 10:2252-2269. https://doi.org/10.18632/oncotarget.26785

Metrics: PDF 908 views  |   Full Text 1491 views  |   ?  


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

Correspondence to:

Amy H. Lin,email: alin@tocagen.com

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.

Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.
PII: 26785