Short-Term Local Expression of a PD-L1 Blocking Antibody from a Self-Replicating RNA Vector Induces Potent Antitumor
Maria Cristina Ballesteros-Briones1, Eva Martisova1, Erkuden Casales1
1Division of Gene Therapy and Regulation of Gene Expression, Cima Universidad de Navarra and Instituto de Investigación Sanitaria de Navarra (IdISNA), 31008 Pamplona, Spain.
Abstract:
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.
Insights
Local expression of anti-PD-L1 antibodies using Semliki Forest virus (SFV) vectors shows potent anti-cancer effects. This novel approach, inducing interferon responses, offers a safer alternative to systemic antibody treatments.
Area of Science:
- Oncology
- Immunology
- Virology
- Gene Therapy
Background:
- Systemic immune checkpoint blockade with monoclonal antibodies (mAbs) is effective against cancer but causes adverse effects.
- Local expression of therapeutic antibodies in tumors could mitigate systemic toxicity.
Purpose of the Study:
- To develop and compare adeno-associated virus (AAV) and Semliki Forest virus (SFV) vectors for local anti-programmed death ligand 1 (aPDL1) mAb expression.
- To evaluate the anti-tumor efficacy and underlying mechanisms of SFV-mediated local aPDL1 delivery.
Main Methods:
- Development of AAV and SFV vectors encoding aPDL1 mAb.
- Intratumoral injection of vectors into MC38 and B16-OVA tumor models.
- Assessment of mAb expression, tumor regression, abscopal effects, immune cell infiltration, and gene expression.
- Combination therapy studies with SFV-LacZ and anti-CD137 mAb.
Main Results:
- Both AAV and SFV vectors achieved local aPDL1 mAb expression, with SFV-aPDL1 inducing significant tumor regressions (>40%).
- SFV-aPDL1 demonstrated superior efficacy over AAV-aPDL1 and systemic/local aPDL1 mAb, inducing abscopal effects.
- SFV-aPDL1 enhanced CD8 T cell infiltration and upregulated co-stimulatory markers, potentially due to SFV RNA replication-induced interferon responses.
Conclusions:
- Non-propagative RNA viral vectors like SFV can achieve potent, localized, and transient expression of immunomodulatory mAbs.
- SFV-mediated local aPDL1 delivery, inducing type I interferon responses, represents a promising and safer cancer treatment strategy.
- Combination therapies involving SFV vectors show enhanced anti-tumor activity.
