title: Virotherapy with a Semliki Forest Virus-Based Vector Encoding IL12 Synergizes with PD-1/PD-L1 Blockade.
abstract: Virotherapy and checkpoint inhibitors can be combined for the treatment of cancer with complementarity and potential for synergistic effects. We have developed a cytolytic but nonreplicative viral vector system based on Semliki Forest virus that encodes IL12 (SFV-IL12). Following direct intratumoral injection, infected cells release transgenic IL12, die, and elicit an inflammatory response triggered by both abundantly copied viral RNA and IL12. In difficult-to-treat mouse cancer models, such as those derived from MC38 and bilateral B16-OVA, SFV-IL12 synergized with an anti-PD-1 monoclonal antibody (mAb) to induce tumor regression and prolong survival. Similar synergistic effects were attained upon PD-L1 blockade. Combined SFV-IL12 + anti-PD-1 mAb treatment only marginally increased the elicited cytotoxic T-lymphocyte response over SFV-IL12 as a single agent, at least when measured by in vivo killing assays. In contrast, we observed that SFV-IL12 treatment induced expression of PD-L1 on tumor cells in an IFNγ-dependent fashion. PD-L1-mediated adaptive resistance thereby provides a mechanistic explanation of the observed synergistic effects achieved by the SFV-IL12 + anti-PD-1 mAb combination.
authors.affiliation: Division of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), and University Clinic, University of Navarra, Pamplona, Navarra, Spain. imelero@unav.es jquetglas@unav.es.
authors.forename: José I
authors.initials: JI
authors.lastname: Quetglas
authors.affiliation: Division of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), and University Clinic, University of Navarra, Pamplona, Navarra, Spain.
authors.forename: Sara
authors.initials: S
authors.lastname: Labiano
authors.affiliation: Division of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), and University Clinic, University of Navarra, Pamplona, Navarra, Spain.
authors.forename: M Ángela
authors.initials: MÁ
authors.lastname: Aznar
authors.affiliation: Division of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), and University Clinic, University of Navarra, Pamplona, Navarra, Spain.
authors.forename: Elixabet
authors.initials: E
authors.lastname: Bolaños
authors.affiliation: Division of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), and University Clinic, University of Navarra, Pamplona, Navarra, Spain.
authors.forename: Arantza
authors.initials: A
authors.lastname: Azpilikueta
authors.affiliation: Division of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), and University Clinic, University of Navarra, Pamplona, Navarra, Spain.
authors.forename: Inmaculada
authors.initials: I
authors.lastname: Rodriguez
authors.affiliation: Division of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), and University Clinic, University of Navarra, Pamplona, Navarra, Spain.
authors.forename: Erkuden
authors.initials: E
authors.lastname: Casales
authors.affiliation: Division of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), and University Clinic, University of Navarra, Pamplona, Navarra, Spain.
authors.forename: Alfonso R
authors.initials: AR
authors.lastname: Sánchez-Paulete
authors.affiliation: Division of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), and University Clinic, University of Navarra, Pamplona, Navarra, Spain.
authors.forename: Víctor
authors.initials: V
authors.lastname: Segura
authors.affiliation: Division of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), and University Clinic, University of Navarra, Pamplona, Navarra, Spain.
authors.forename: Cristian
authors.initials: C
authors.lastname: Smerdou
authors.affiliation: Division of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), and University Clinic, University of Navarra, Pamplona, Navarra, Spain. imelero@unav.es jquetglas@unav.es.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Melero
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D005260:Female; D005822:Genetic Vectors; D018664:Interleukin-12 / Q000235:genetics* / Q000276:immunology; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000276:immunology / Q000628:therapy*; D050130:Oncolytic Virotherapy; D061026:Programmed Cell Death 1 Receptor / Q000276:immunology*; D012672:Semliki forest virus / Q000235:genetics*; D013154:Spleen / Q000166:cytology
chemical_list: D000911:Antibodies, Monoclonal; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D018664:Interleukin-12