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.
Highlights
IntroductionIn addition to its tumorselectivity, integration of retroviral replicating vector (RRV) genome into the cancer cell genome allows sustained and localized therapeutic transgene expression in the tumor microenvironment and substantial bystander effects [2, 3]
A retroviral replicating vector (RRV) platform based on an amphotropic gamma retrovirus that preferentially infects and replicates in tumor cells has been developed to address historical challenges with viral-based treatments for cancer
Among the approved checkpoint inhibitors (CPIs), programmed death-1 (PD-1) receptor occupancy has been demonstrated in circulating T cells following anti-PD-1 therapy [10, 11], it is unclear if complete saturation of PD-1 in circulating T cells serves as a surrogate biomarker for PD-1/L1 blockade in the tumor microenvironment (TME) [12, 13]
Summary
In addition to its tumorselectivity, integration of RRV genome into the cancer cell genome allows sustained and localized therapeutic transgene expression in the tumor microenvironment and substantial bystander effects [2, 3]. Unlike oncolytic viruses, RRV’s non-lytic replication process does not trigger immediate anti-viral immune responses, allowing for sustained viral replication and therapeutic transgene expression in the tumor microenvironment [4, 5]. Among the approved CPIs, PD-1 receptor occupancy has been demonstrated in circulating T cells following anti-PD-1 therapy [10, 11], it is unclear if complete saturation of PD-1 in circulating T cells serves as a surrogate biomarker for PD-1/L1 blockade in the tumor microenvironment (TME) [12, 13]
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