10166- ACT-9 TRANSLATING BASIC RESEARCH ON AD-REIC FOR RECURRENT GLIOBLASTOMA INTO AN INVESTIGATOR-INITIATED CLINICAL TRIAL

Abstract Glioblastoma is the most aggressive type of brain tumor, and the development of new treatments is urgently needed. A viral gene therapy incorporating the tumor suppressor gene REIC/Dkk-3 discovered at Okayama University was conducted from basic research to investigator-initiated clinical trials. Here, we present the results from basic research to clinical application.In 2014, we confirmed the antitumor effects of the first-generation Ad-REIC product, Ad-CAG-REIC, in both in vitro and in vivo experiments using human glioblastoma cells (Gene Ther, 2014). Subsequently, we developed the second-generation formulation, Ad-SGE-REIC, which enhances the expression of the REIC/Dkk-3 gene. Ad-SGE-REIC induced stronger endoplasmic reticulum stress and higher levels of cell death. In addition, Ad-SGE-REIC demonstrated a more potent antitumor effect than Ad-CAG-REIC in both immunodeficient models using human glioblastoma cells and immunocompetent models using mouse glioblastoma cells. Significant infiltration of CD8-positive and CD11c-positive cells were observed, suggesting immunogenic cell death (Sci Rep, 2016). Furthermore, the combination of Ad-SGE-REIC with Bevacizumab enhanced the therapeutic effect (PLoS One, 2022).Based on these results, we initiated a Phase 1/2a investigator-initiated clinical trial (jRCT2063190013, Future Oncol, 2020) for recurrent malignant glioma in 2019, supported by the AMED Translational Research Program Seeds C, and completed patient enrollment in 2022. We are currently evaluating the safety and efficacy of this trial. Additionally, since 2023, under the AMED P-PROMOTE, we have been exploring biomarkers for Ad-REIC. Ad-SGE-REIC has the potential to be a novel treatment for recurrent glioblastoma.