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


The cover for issue 23 of Oncotarget features Figure 8, "scFv PD-L1 serum levels in tumor-bearing mice," by Mitchell, et al.

Cell binding assays showed trans-binding activity on 100% of cells in culture when infection was limited to 5% RRV-sc Fv-PDL1 infected tumor cells.

Further, the ability of sc Fv 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-sc Fv-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.

Figure 1: Schematic diagram of RRV-scFv-PDL1 plasmid DNAs.

Dr. Amy H. Lin from Tocagen Inc., in San Diego, 92121, CA, USA said, "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."

In addition to its tumor-selectivity, integration of RRV genome into the cancer cell genome allows sustained and localized therapeutic transgene expression in the tumor microenvironment and substantial bystander effects.

Furthermore, unlike oncolytic viruses, RRVs 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.

PD-1 is one of the major inhibitory receptors highly expressed on tumor infiltrating lymphocytes where upon its ligation with PD-L1 reduces cytokine production and T-cell proliferation resulting in immune escape from an active anti-tumor T-cell response in the TME.

In addition to the immune suppression mediated by PD-1/PD-L1 ligation, PD-L1 can also bind to CD80/B7.1 expressed on antigen presenting cells and block activation of T-cells through CD80/B7.1 binding to CD28. As PD-L1 is a proven immuno-oncology target for many cancer types and its expression is not limited to cancer cells in the TME, use of an RRV to selectively deliver a PD-1/L1 blockade in the TME may have desirable properties.

The Lin Research Team concluded, "our study demonstrates that RRV-scFv-PDL1 checkpoint inhibition with a tumor-selective delivery and a high bystander index localized within the TME provides an attractive treatment regimen to target immune checkpoints."

Full text - https://doi.org/10.18632/oncotarget.26785

Correspondence to - Amy H. Lin - [email protected]

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

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