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Oncotarget. 2019 Mar 19;10(23):2252-2269. doi: 10.18632/oncotarget.26785. eCollection 2019 Mar 19.

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

Author information

1
Tocagen Inc., San Diego, 92121, CA, USA.
2
Biofizik, Inc., San Diego, 92121, CA, USA.

Abstract

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.

KEYWORDS:

PD-1; PD-L1; immunotherapy; retroviral replicating vector; single chain variable fragment

Conflict of interest statement

CONFLICTS OF INTEREST LAM, KY, AH, SV, AWM, FLE, DM, MERA, AH, WPA, CB, DG, HEG, DJJ and AHL are or were full time employees of Tocagen and hold stock or stock options in Tocagen.

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