Short-Term Local Expression of a PD-L1 Blocking Antibody from a Self-Replicating RNA Vector Induces Potent Antitumor Responses.

Autor:	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 Cáncer (CIBERONC), 28029 Madrid, Spain., 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.
Jazyk:	angličtina
Zdroj:	Molecular therapy : the journal of the American Society of Gene Therapy [Mol Ther] 2019 Nov 06; Vol. 27 (11), pp. 1892-1905. Date of Electronic Publication: 2019 Sep 16.
DOI:	10.1016/j.ymthe.2019.09.016
Abstrakt:	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. (Copyright © 2019 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu