Ballesteros-Briones et al. developed viral vectors (SFV and AAV) encoding anti-PD-L1 for intratumoral delivery. In an MC38 model, SFV-aPDL1 induced only transient anti-PD-L1 expression, but showed strong antitumor efficacy, including an abscopal effect and long-term protection. SFV-aPDL1 also increased survival in a B16-OVA melanoma model. SFV-aPDL1 increased infiltration of effector CD8+ T cells and synergized with agonistic anti-CD137. AAV induced longer-term anti-PD-L1 expression, but had minimal antitumor effect, possibly because SFV RNA replication triggered local upregulation of IFN-stimulated genes, contributing to antitumor efficacy.
Immune checkpoint blockade has shown anti-cancer efficacy, but requires systemic administration of monoclonal antibodies (mAbs), often leading to adverse effects. To avoid toxicity, mAbs could be expressed locally in tumors. We developed adeno-associated virus (AAV) and Semliki Forest virus (SFV) vectors expressing anti-programmed death ligand 1 (aPDL1) mAb. When injected intratumorally in MC38 tumors, both viral vectors led to similar local mAb expression at 24 h, diminishing quickly in SFV-aPDL1-treated tumors. However, SFV-aPDL1 induced >40% complete regressions and was superior to AAV-aPDL1, as well as to aPDL1 mAb given systemically or locally. SFV-aPDL1 induced abscopal effects and was also efficacious against B16-ovalbumin (OVA). The higher SFV-aPDL1 antitumor activity could be related to local upregulation of interferon-stimulated genes because of SFV RNA replication. This was confirmed by combining local SFV-LacZ administration and systemic aPDL1 mAb, which provided higher antitumor effects than each separated agent. SFV-aPDL1 promoted tumor-specific CD8 T cells infiltration in both tumor models. In MC38, SFV-aPDL1 upregulated co-stimulatory markers (CD137/OX40) in tumor CD8 T cells, and its combination with anti-CD137 mAb showed more pronounced antitumor effects than each single agent. These results indicate that local transient expression of immunomodulatory mAbs using non-propagative RNA vectors inducing type I interferon (IFN-I) responses represents a potent and safe approach for cancer treatment.