Abstract
Purpose of the study: 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. METHODS: First, we evaluated Ad-REIC monotherapy in human and murine glioma models. In addition, we conducted combination therapy of Ad-REIC with bevacizumab. Finally, we translated into Phase1/2a clinical trial with Ad-REIC with recurrent malignant glioma. RESULTS: 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. 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. Furthermore, the combination of Ad-SGE-REIC with bevacizumab enhanced the therapeutic effect. We initiated a Phase 1/2a investigator-initiated clinical trial (jRCT2063190013) for recurrent malignant glioma in 2019 completed patient enrollment in 2024. CONCLUSION: Ad-SGE-REIC induced strong immunogenic cell death and anti-tumor immunity against glioblastoma.