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Short-Term Local Expression of a PD-L1 Blocking Antibody from a Self-Replicating RNA Vector Induces Potent Antitumor Responses.
Ballesteros-Briones, Maria Cristina; Martisova, Eva; Casales, Erkuden; Silva-Pilipich, Noelia; Buñuales, Maria; Galindo, Javier; Mancheño, Uxua; Gorraiz, Marta; Lasarte, Juan J; Kochan, Grazyna; Escors, David; Sanchez-Paulete, Alfonso R; Melero, Ignacio; Prieto, Jesus; Hernandez-Alcoceba, Ruben; Hervas-Stubbs, Sandra; Smerdou, Cristian.
Afiliación
  • Ballesteros-Briones MC; Division of Gene Therapy and Regulation of Gene Expression, Cima Universidad de Navarra and Instituto de Investigación Sanitaria de Navarra (IdISNA), 31008 Pamplona, Spain.
  • Martisova E; Division of Gene Therapy and Regulation of Gene Expression, Cima Universidad de Navarra and Instituto de Investigación Sanitaria de Navarra (IdISNA), 31008 Pamplona, Spain.
  • Casales E; Division of Gene Therapy and Regulation of Gene Expression, Cima Universidad de Navarra and Instituto de Investigación Sanitaria de Navarra (IdISNA), 31008 Pamplona, Spain.
  • Silva-Pilipich N; Division of Gene Therapy and Regulation of Gene Expression, Cima Universidad de Navarra and Instituto de Investigación Sanitaria de Navarra (IdISNA), 31008 Pamplona, Spain.
  • Buñuales M; Division of Gene Therapy and Regulation of Gene Expression, Cima Universidad de Navarra and Instituto de Investigación Sanitaria de Navarra (IdISNA), 31008 Pamplona, Spain.
  • Galindo J; Division of Gene Therapy and Regulation of Gene Expression, Cima Universidad de Navarra and Instituto de Investigación Sanitaria de Navarra (IdISNA), 31008 Pamplona, Spain.
  • Mancheño U; Division of Immunology and Immunotherapy, Cima Universidad de Navarra and Instituto de Investigación Sanitaria de Navarra (IdISNA), 31008 Pamplona, Spain.
  • Gorraiz M; Division of Immunology and Immunotherapy, Cima Universidad de Navarra and Instituto de Investigación Sanitaria de Navarra (IdISNA), 31008 Pamplona, Spain.
  • Lasarte JJ; Division of Immunology and Immunotherapy, Cima Universidad de Navarra and Instituto de Investigación Sanitaria de Navarra (IdISNA), 31008 Pamplona, Spain.
  • Kochan G; Department of Oncology, Navarrabiomed-Biomedical Research Centre, IdiSNA, 31008 Pamplona, Spain.
  • Escors D; Department of Oncology, Navarrabiomed-Biomedical Research Centre, IdiSNA, 31008 Pamplona, Spain.
  • Sanchez-Paulete AR; Division of Immunology and Immunotherapy, Cima Universidad de Navarra and Instituto de Investigación Sanitaria de Navarra (IdISNA), 31008 Pamplona, Spain.
  • Melero I; Division of Immunology and Immunotherapy, Cima Universidad de Navarra and Instituto de Investigación Sanitaria de Navarra (IdISNA), 31008 Pamplona, Spain; Department of Immunology and Immunotherapy, Clinica Universidad de Navarra, 31008 Pamplona, Spain; Centro de Investigación Biomédica en Red de Cá
  • Prieto J; Division of Gene Therapy and Regulation of Gene Expression, Cima Universidad de Navarra and Instituto de Investigación Sanitaria de Navarra (IdISNA), 31008 Pamplona, Spain.
  • Hernandez-Alcoceba R; Division of Gene Therapy and Regulation of Gene Expression, Cima Universidad de Navarra and Instituto de Investigación Sanitaria de Navarra (IdISNA), 31008 Pamplona, Spain.
  • Hervas-Stubbs S; Division of Immunology and Immunotherapy, Cima Universidad de Navarra and Instituto de Investigación Sanitaria de Navarra (IdISNA), 31008 Pamplona, Spain. Electronic address: mshervas@unav.es.
  • Smerdou C; Division of Gene Therapy and Regulation of Gene Expression, Cima Universidad de Navarra and Instituto de Investigación Sanitaria de Navarra (IdISNA), 31008 Pamplona, Spain. Electronic address: csmerdou@unav.es.
Mol Ther ; 27(11): 1892-1905, 2019 11 06.
Article en En | MEDLINE | ID: mdl-31563534
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Virus ARN / Expresión Génica / Antígeno B7-H1 / Vectores Genéticos / Anticuerpos Monoclonales / Neoplasias Límite: Animals / Female / Humans Idioma: En Revista: Mol Ther Asunto de la revista: BIOLOGIA MOLECULAR / TERAPEUTICA Año: 2019 Tipo del documento: Article País de afiliación: España Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Virus ARN / Expresión Génica / Antígeno B7-H1 / Vectores Genéticos / Anticuerpos Monoclonales / Neoplasias Límite: Animals / Female / Humans Idioma: En Revista: Mol Ther Asunto de la revista: BIOLOGIA MOLECULAR / TERAPEUTICA Año: 2019 Tipo del documento: Article País de afiliación: España Pais de publicación: Estados Unidos