Oncolytic HSV therapy increases trametinib access to brain tumors and sensitizes them in vivo

• Published in: Neuro-oncology (Charlottesville, Va.) Va.), 2019-09, Vol.21 (9), p.1131-1140
• Main Authors: Yoo, Ji Young, Swanner, Jessica, Otani, Yoshihiro, Nair, Mitra, Park, Flora, Banasavadi-Siddegowda, Yeshavanth, Liu, Joseph, Jaime-Ramirez, Alena Cristina, Hong, Bangxing, Geng, Feng, Guo, Deliang, Bystry, Darlene, Phelphs, Mitch, Quadri, Haroon, Lee, Tae Jin, Kaur, Balveen
• Format: Article
• Language: English
• Subjects: Animals; Basic and Translational Investigations; Blood-Brain Barrier - metabolism; Brain Neoplasms - immunology; Brain Neoplasms - therapy; CD8-Positive T-Lymphocytes - drug effects; CD8-Positive T-Lymphocytes - immunology; Cell Line, Tumor; Disease Models, Animal; Glioblastoma - immunology; Glioblastoma - therapy; Glioma - immunology; Glioma - therapy; Herpesvirus 1, Human; Humans; Immunocompetence; Macrophages - drug effects; Macrophages - immunology; Mice; Microglia - drug effects; Microglia - immunology; Mitogen-Activated Protein Kinase Kinases - antagonists & inhibitors; Oncolytic Virotherapy - methods; Protein Kinase Inhibitors - pharmacology; Pyridones - pharmacology; Pyrimidinones - pharmacology; RAW 264.7 Cells; Survival Rate; Tumor Necrosis Factor-alpha - immunology; Xenograft Model Antitumor Assays
• ISSN: 1522-8517; 1523-5866
• DOI: 10.1093/neuonc/noz079

Hyperactivation of the RAS-RAF-MEK-ERK signaling pathway is exploited by glioma cells to promote their growth and evade apoptosis. MEK activation in tumor cells can increase replication of ICP34.5-deleted herpes simplex virus type 1 (HSV-1), but paradoxically its activation in tumor-associated macrophages promotes a pro-inflammatory signaling that can inhibit virus replication and propagation. Here we investigated the effect of blocking MEK signaling in conjunction with oncolytic HSV-1 (oHSV) for brain tumors. Infected glioma cells co-cultured with microglia or macrophages treated with or without trametinib were used to test trametinib effect on macrophages/microglia. Enzyme-linked immunosorbent assay, western blotting, and flow cytometry were utilized to evaluate the effect of the combination therapy. Pharmacokinetic (PK) analysis of mouse plasma and brain tissue was used to evaluate trametinib delivery to the CNS. Intracranial human and mouse glioma-bearing immune deficient and immune competent mice were used to evaluate the antitumor efficacy. Oncolytic HSV treatment rescued trametinib-mediated feedback reactivation of the mitogen-activated protein kinase signaling pathway in glioma. In vivo, PK analysis revealed enhanced blood-brain barrier penetration of trametinib after oHSV treatment. Treatment by trametinib, a MEK kinase inhibitor, led to a significant reduction in microglia- and macrophage-derived tumor necrosis factor alpha (TNFα) secretion in response to oHSV treatment and increased survival of glioma-bearing mice. Despite the reduced TNFα production observed in vivo, the combination treatment activated CD8+ T-cell mediated immunity and increased survival in a glioma-bearing immune-competent mouse model. This study provides a rationale for combining oHSV with trametinib for the treatment of brain tumors.