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.
Author Info: (1) Division of Gene Therapy and Regulation of Gene Expression, Cima Universidad de Navarra and Instituto de Investigacion Sanitaria de Navarra (IdISNA), 31008 Pamplona, Spain. (2)
Author Info: (1) Division of Gene Therapy and Regulation of Gene Expression, Cima Universidad de Navarra and Instituto de Investigacion Sanitaria de Navarra (IdISNA), 31008 Pamplona, Spain. (2) Division of Gene Therapy and Regulation of Gene Expression, Cima Universidad de Navarra and Instituto de Investigacion Sanitaria de Navarra (IdISNA), 31008 Pamplona, Spain. (3) Division of Gene Therapy and Regulation of Gene Expression, Cima Universidad de Navarra and Instituto de Investigacion Sanitaria de Navarra (IdISNA), 31008 Pamplona, Spain. (4) Division of Gene Therapy and Regulation of Gene Expression, Cima Universidad de Navarra and Instituto de Investigacion Sanitaria de Navarra (IdISNA), 31008 Pamplona, Spain. (5) Division of Gene Therapy and Regulation of Gene Expression, Cima Universidad de Navarra and Instituto de Investigacion Sanitaria de Navarra (IdISNA), 31008 Pamplona, Spain. (6) Division of Gene Therapy and Regulation of Gene Expression, Cima Universidad de Navarra and Instituto de Investigacion Sanitaria de Navarra (IdISNA), 31008 Pamplona, Spain. (7) Division of Immunology and Immunotherapy, Cima Universidad de Navarra and Instituto de Investigacion Sanitaria de Navarra (IdISNA), 31008 Pamplona, Spain. (8) Division of Immunology and Immunotherapy, Cima Universidad de Navarra and Instituto de Investigacion Sanitaria de Navarra (IdISNA), 31008 Pamplona, Spain. (9) Division of Immunology and Immunotherapy, Cima Universidad de Navarra and Instituto de Investigacion Sanitaria de Navarra (IdISNA), 31008 Pamplona, Spain. (10) Department of Oncology, Navarrabiomed-Biomedical Research Centre, IdiSNA, 31008 Pamplona, Spain. (11) Department of Oncology, Navarrabiomed-Biomedical Research Centre, IdiSNA, 31008 Pamplona, Spain. (12) Division of Immunology and Immunotherapy, Cima Universidad de Navarra and Instituto de Investigacion Sanitaria de Navarra (IdISNA), 31008 Pamplona, Spain. (13) Division of Immunology and Immunotherapy, Cima Universidad de Navarra and Instituto de Investigacion Sanitaria de Navarra (IdISNA), 31008 Pamplona, Spain; Department of Immunology and Immunotherapy, Clinica Universidad de Navarra, 31008 Pamplona, Spain; Centro de Investigacion Biomedica en Red de Cancer (CIBERONC), 28029 Madrid, Spain. (14) Division of Gene Therapy and Regulation of Gene Expression, Cima Universidad de Navarra and Instituto de Investigacion Sanitaria de Navarra (IdISNA), 31008 Pamplona, Spain. (15) Division of Gene Therapy and Regulation of Gene Expression, Cima Universidad de Navarra and Instituto de Investigacion Sanitaria de Navarra (IdISNA), 31008 Pamplona, Spain. (16) Division of Immunology and Immunotherapy, Cima Universidad de Navarra and Instituto de Investigacion Sanitaria de Navarra (IdISNA), 31008 Pamplona, Spain. Electronic address: mshervas@unav.es. (17) Division of Gene Therapy and Regulation of Gene Expression, Cima Universidad de Navarra and Instituto de Investigacion Sanitaria de Navarra (IdISNA), 31008 Pamplona, Spain. Electronic address: csmerdou@unav.es.
