CD137 and PD-L1 targeting with immunovirotherapy induces a potent and durable antitumor immune response in glioblastoma models
Oncolytic viruses
Brain neoplasms
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The performed work was supported through the Departamento de Salud del Gobierno de Navarra (54/2018-APG); Predoctoral Fellowship from Gobierno de Navarra (VL), Instituto de Salud Carlos III y Fondos Feder (PI19/01896 MMA, PI19/01440 JGPL, PI18/00164 APG); AECC/ERA-Permed-GAL20732 (JGPL), Amigos de la Universidad de Navarra (to MP); Fundación La Caixa/Caja Navarra and Fundación ACS (APG and MA); Fundación ADEY (APG, MA), Fundación El sueño de Vicky; Asociación Pablo Ugarte-Fuerza Julen (APG and MA); Comunidad de la Guareña (JGPL, APG, MA) and Department of Defense (DOD) Team Science Award under grant CA 160525 (MA, CG-M and JF). This project also received funding from the European Research Council (ERC) under the European Union's Horizon 2020 Research and Innovation Program (817 884 ViroPedTher to MA).
Puigdelloses-Vallcorba, M. (Montserrat); García-Moure, M. (Marc); Labiano-Almiñana, S. (Sara); et al. "CD137 and PD-L1 targeting with immunovirotherapy induces a potent and durable antitumor immune response in glioblastoma models". Journal for Immunotherapy of Cancer. 9 (7), 2021, e002644
Background Glioblastoma (GBM) is a devastating primary brain tumor with a highly immunosuppressive tumor microenvironment, and treatment with oncolytic viruses (OVs) has emerged as a promising strategy for these tumors. Our group constructed a new OV named Delta-24-ACT, which was based on the Delta-24-RGD platform armed with 4-1BB ligand (4-1BBL). In this study, we evaluated the antitumor effect of Delta-24-ACT alone or in combination with an immune checkpoint inhibitor (ICI) in preclinical models of glioma. Methods The in vitro effect of Delta-24-ACT was characterized through analyses of its infectivity, replication and cytotoxicity by flow cytometry, immunofluorescence (IF) and MTS assays, respectively. The antitumor effect and therapeutic mechanism were evaluated in vivo using several immunocompetent murine glioma models. The tumor microenvironment was studied by flow cytometry, immunohistochemistry and IF. Results Delta-24-ACT was able to infect and exert a cytotoxic effect on murine and human glioma cell lines. Moreover, Delta-24-ACT expressed functional 4-1BBL that was able to costimulate T lymphocytes in vitro and in vivo. Delta-24-ACT elicited a more potent antitumor effect in GBM murine models than Delta-24-RGD, as demonstrated by significant increases in median survival and the percentage of long-term survivors. Furthermore, Delta-24-ACT modulated the tumor microenvironment, which led to lymphocyte infiltration and alteration of their immune phenotype, as ...

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