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Safety and efficacy of oncolytic HSV-1 G207 inoculated into the cerebellum of mice

Cancer Gene Therapy volume 27, pages 246–255 (2020)Cite this article

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Abstract

Primary malignant central nervous system (CNS) tumors are the leading cause of childhood cancer-related death and morbidity. While advances in surgery, radiation, and chemotherapy have improved the survival rates in children with malignant brain tumors, mortality persists in certain subpopulations and current therapies are associated with extreme morbidity. This is especially true for children with malignant infratentorial tumors. Accordingly, G207, a genetically engineered herpes simplex virus (HSV-1) capable of selectively targeting cancer cells has emerged as a promising therapeutic option for this patient population. Herein, we demonstrate that cerebellar inoculation of G207 was systemically non-toxic in an immunocompetent, HSV-1 sensitive mouse strain (CBA/J). Mice had neither abnormal brain/organ pathology nor evidence of G207 replication by immunohistochemistry at days 7 and 30 after cerebellar G207 inoculation. While a minute amount viral DNA was recovered in the cerebellum and brainstem of mice at day 7, no viral DNA persisted at day 30. Critically, G207 delivered to the cerebellum was able to target/treat the highly aggressive MYC-overexpressed group 3 murine medulloblastoma increasing survival vs controls. These results provide critical safety and efficacy data to support the translation of G207 for pediatric clinical trials in intractable cerebellar malignancies.

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Acknowledgements

This research was supported in part by a grant from the Rally Foundation for Childhood Cancer Research, the Truth 365, the National Institutes of Health (R01FD005379), and the Department of Defense (W81XWH-15-1-0108) to GKF, and from the National Institutes of Health (P20CA151129 to GYG and R01CA217179 to JMM and GYG). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or the Department of Defense. We thank the UAB Neuroscience Molecular Detection and Stereology Core for assistance with IHC.

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Authors and Affiliations

  1. Medical Scientist Training Program, University of Alabama at Birmingham, Birmingham, AL, 35233, USA

    Joshua D. Bernstock

  2. Department of Biomedical and Biotechnological Sciences, Physiology Section, University of Catania, 95125, Catania, Italy

    Nunzio Vicario & Rosalba Parenti

  3. Neuropathology, Children’s of Alabama, University of Alabama at Birmingham, Birmingham, AL, 35233, USA

    Rong Li

  4. Division of Pediatric Hematology and Oncology, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL, 35233, USA

    Li Nan, Stacie K. Totsch, Charles Schlappi & Gregory K. Friedman

  5. Department for Neurosurgery, Goethe University Frankfurt, Schleusenweg 2-16, 60528, Frankfurt am Main, Germany

    Florian Gessler

  6. Department of Neurology, University of Alabama at Birmingham, Birmingham, AL, 35233, USA

    Xiaosi Han

  7. Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, 35233, USA

    Elizabeth A. Beierle & Gregory K. Friedman

  8. Division of Pediatric Infectious Disease, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL, USA

    Richard J. Whitley

  9. Department of Biostatistics, University of Alabama at Birmingham, Birmingham, 35233, AL, USA

    Inmaculada Aban

  10. Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, AL, 35233, USA

    G. Yancey Gillespie, James M. Markert & Gregory K. Friedman

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  1. Joshua D. Bernstock
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Correspondence to Gregory K. Friedman.

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Conflict of interest

JMM and GYG are founders of and own stock and stock options (<8% interest) in Aettis, Inc., a biotech company that has licensed M032 HSV from The Board of Trustees of the University of Alabama for the University of Alabama at Birmingham and is developing other oHSVs that are not the subject of this current investigation. GYG currently serves as one of five unpaid members of the Board of Directors for Aettis, Inc. GYG is a founder of and owns stock and stock options (<10%) in Maji Therapeutics, which is developing other HSVs that are not the subject of the current investigation. JMM 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 the 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 equity (≤5°%) in both CITC Ltd and Avidea Technologies.

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Bernstock, J.D., Vicario, N., Li, R. et al. Safety and efficacy of oncolytic HSV-1 G207 inoculated into the cerebellum of mice. Cancer Gene Ther 27, 246–255 (2020). https://doi.org/10.1038/s41417-019-0091-0

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