Glioblastoma diagnoses associate with upregulation of the immunosuppressive indoleamine-2,3-dioxygenase (IDO) enzyme, which correlates with poor prognoses. IDO inhibitors are immunometabolic adjuvants that can reverse protumor immunosuppression through increasing effector T-cell metabolism. To further stimulate antitumor T-cell activation, the OX40L-armed-oncolytic-adenovirus (Delta-24-RGDOX) can be used, which has shown to induce immune mechanisms that activate antitumor cytotoxic properties of T cells. Thus, we hypothesized that combining IDO inhibitors and Delta-24-RGDOX synergizes to produce a therapeutic effect in glioblastoma. In this study, we used a syngeneic glioblastoma orthotopic immunocompetent model to test the efficacy of combining Delta-24-RGDOX and an IDO inhibitor (1MT or indoximod). Delta-24-RGDOX treatment resulted in a significant survival benefit compared to the control groups (mean survival, 46.5 vs. 38.5 days, P=0.02). Interestingly, the combination of Delta-24-RGDOX and 1MT produced a higher percentage of long-term survivors compared to single therapy with Delta-24-RGDOX (50% vs. 20%, P=0.03). Moreover, when these long-term glioblastoma survivors were rechallenged with the same glioblastoma cells, we observed 100% survival, indicating the establishment of immune memory by the combination therapy. Furthermore, functional studies showed a significant increase in antitumor activity of splenocytes from glioblastoma-bearing combination-treated mice compared to Delta-24-RGDOX-treated mice (P=0.009). Additionally, immunophenotyping by flow cytometry revealed that glioblastoma-bearing combination-treated mice yielded the highest levels of PD-1/TIM-3/CD8+ T cells compared to all other treatment groups and decreased levels of immune-tolerant populations, including regulatory T cells and myeloid-derived suppressor cells, compared to Delta-24-RGDOX-only treated mice, and correlated with complete tumor elimination. Most importantly, these data support the use of immunometabolic adjuvants combined with virotherapy as a treatment for glioblastoma to improve its dismal outcomes.
Citation Format: Teresa T. Nguyen, Dong Ho Shin, Hong Jiang, Frederick Lang, Candelaria Gomez-Manzano, Juan Fueyo. Combined IDO inhibitor and OX40L-armed-oncolytic-adenovirus therapy improves survival in murine glioblastoma [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr A30.