Malignant tumors of the central nervous system (CNS) continue to be a leading cause of cancer-related mortality in both children and adults. Traditional therapies for malignant brain tumors consist of surgical resection and adjuvant chemoradiation; such approaches are often associated with extreme morbidity. Accordingly, novel, targeted therapeutics for neoplasms of the CNS, such as immunotherapy with oncolytic engineered herpes simplex virus (HSV) therapy, are urgently warranted. Herein, we discuss treatment challenges related to HSV virotherapy delivery, entry, replication, and spread, and in so doing focus on host anti-viral immune responses and the immune microenvironment. Strategies to overcome such challenges including viral re-engineering, modulation of the immunoregulatory microenvironment and combinatorial therapies with virotherapy, such as checkpoint inhibitors, radiation, and vaccination, are also examined in detail.
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This research was supported in part by grants from the Food and Drug Administration Office of Orphan Products Development (R01FD005379), the Department of Defense (W81XWH-15–1–0108) Rally Foundation for Childhood Cancer Research, Hyundai Hope on Wheels, and the Kaul Pediatric Research Institute to GKF and R01CA217179 to JMM and GYG. JDB was supported by the UAB Medical Scientist Training Program (MSTP) and an American Brain Tumor Association summer fellowship. SKT was supported by the National Cancer Institute of the National Institutes of Health under Award Number T32CA183926. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health, the U.S. FDA or the Department of Defense. The authors apologize to colleagues we couldn’t cite given limitations on the number of references.
Conflict of interest
JMM, RJW, and GYG are founders of and own stock and stock options (<8% interest) in Aettis, Inc., a biotech company that holds intellectual property surrounding oHSV. GYG currently serves as one of five unpaid members of the Board of Directors for Aettis, Inc. JMM, RJW, and GYG were also founders of and owned stock and stock options (<8%) in Catherex Inc., a biotechnology company that had licensed additional intellectual property related to oHSV. Catherex, Inc., was sold to Amgen, Inc., on 18 December 2015, and they no longer participate in any decision making or have any control of any aspect of Catherex or Amgen, although they did receive proceeds from the sale of the company. GYG has served as a paid advisor to a Program Project at the Ohio State University that seeks to find improved methods for application of distinct oHSV to treat localized and metastatic cancers. This is generally, but not specifically, related to the subject matter of this investigation. JDB has positions/equity in CITC Ltd. JDB, ASI, and GML have positions/equity Avidea Technologies. RJW is a member of the Board of Directors of Gilead Sciences. The remaining authors declare that they have no conflict of interest.
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