Scientific publications
- [GENE THERAPY FOR RARE DISEASES]
- [CANCER GENE THERAPY]
- [GENE THERAPY FOR MONOGENIC ENCEPHALOPATHIES]
- [IMMUNOLOGY AND IMMUNOTHERAPY]
- [IMMUNOMODULATION AND TUMOR MICROENVIRONMENT]
- [COMBINATION STRATEGIES FOR TRANSLATIONAL IMMUNOTHERAPY]
- [ADOPTIVE CELL THERAPY ]
Short-Term Local Expression of a PD-L1 Blocking Antibody from a Self-Replicating RNA Vector Induces Potent Antitumor Responses
Maria Cristina Ballesteros-Briones, Eva Martisova, Erkuden Casales, Noelia Silva-Pilipich, Maria Buñuales, Javier Galindo, Uxua Mancheño, Marta Gorraiz, Juan J Lasarte, Grazyna Kochan, David Escors, Alfonso R Sanchez-Paulete, Ignacio Melero, Jesus Prieto, Ruben Hernandez-Alcoceba, Sandra Hervas-Stubbs, Cristian Smerdou
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.
CITATION Mol Ther. 2019 Nov 6;27(11):1892-1905. doi: 10.1016/j.ymthe.2019.09.016. Epub 2019 Sep 16.
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Our authors
![Silueta investigadores. Cima Universidad de Navarra](/.imaging/mte/cima/profesional_carrusel-80x80/dam/cima/imagenes/profesionales/silueta-cima/jcr:content/silueta-cima.png)
![María Buñueales. Programa Terapia Génica. Cima](/.imaging/mte/cima/profesional_carrusel-80x80/dam/cima/imagenes/profesionales/programas-transversales/terapia-genica/maria-bunuales-aramendia/jcr:content/maria-bunuales-aramendia.jpg)
![Uxua Mancheño. Programa Inmunología e Inmunoterapia. Cima](/.imaging/mte/cima/profesional_carrusel-80x80/dam/cima/imagenes/profesionales/programas-transversales/inmunologia-inmunoterapia/uxua-mancheno-ujue/jcr:content/uxua-mancheno-ujue.jpg)
![Marta Gorraiz. Programa de Inmunología e Inmunoterapia. Cima](/.imaging/mte/cima/profesional_carrusel-80x80/dam/cima/imagenes/profesionales/programas-transversales/inmunologia-inmunoterapia/marta-gorraiz-ayala/jcr:content/marta-gorraiz-ayala.jpg)