EXTH-42. DUAL ROLES OF PKR ORCHESTRATE ONCOLYTIC HSV SENSITIVITY AND ANTIGEN-SPECIFIC T CELL EXPANSION. (14th November 2022)

• Record Type: Journal Article
• Authors: Hong, Bangxing; Sahu, Upasana; Mullarkey, Matthew P; Hong, Evan; Guangsheng, Pei; Yan, Yuanqing; Otani, Yoshihiro; Fan, Huihui; Zhongming, Zhao; Kaur, Balveen
• Is Part Of: Neuro-oncology. Volume 24(2022)Supplement 7
• Page Start: vii218
• Page End: vii218
• Publication Date: 2022-11-14
• Subjects: Brain Neoplasms -- Periodicals; Brain -- Tumors -- Periodicals; Brain -- Cancer -- Periodicals; Nervous system -- Cancer -- Periodicals; 616.99481
• DOI: 10.1093/neuonc/noac209.840
• Languages: English
• ISSNs: 1522-8517

Abstract

Abstract: The host immune system has developed many mechanisms to defend against and clear virus infections, including PKR, cGAS-STING and TLR-MyD88 signaling pathways. Compromised anti-viral mechanisms in tumor cells allows for infection, replication and lysis by oncolytic viruses. However, compromised antiviral mechanisms, together with immune cells and the tumor microenvironment (TME), limit the sensitivity of oncolytic virus in tumor cells. We generated a novel oncolytic Herpes simplex virus, oHSV-shPKR which disables tumor-intrinsic PKR signaling. oHSV-shPKR significantly increases oHSV infection and lysis in both oncolytic virus-resistant and sensitive glioblastomas (GBMs). Infection of oHSV-shPKR in GBMs induces G2/M cell cycle arrest and inhibits tumor cell growth. oHSV-shPKR increases activation of antigen presentation cells through type I interferon signaling activation and its immune-stimulatory function to increase tumor-antigen specific CD8 T-cell expansion, including cytotoxic T lymphocytes. Preclinical studies showed that oHSV-shPKR intra-tumoral injection significantly inhibits human GBM patient derived xenograft (PDX) tumor growth in immune-deficient NSG mice and murine orthotopic GBM tumor growth in immunocompetent mice. The results demonstrate that the novel oHSV-shPKR has the potential to be used in clinical applications for both oHSV-resistant and sensitive GBM treatment.