Childhood brain cancer is the most common solid tumor in children affecting approximately 2,500 children a year with an estimated 22,000 children living in the United States with a malignant brain tumor, which establishes this as an orphan disease. Current therapies for malignant childhood brain tumors including surgery, chemotherapy and radiation are very damaging to the developing brain of a child and can result in significant long-term brain injury and hormone dysfunction. Furthermore, approximately 25-30% of children with malignant brain cancer do not survive, and high-grade tumors that recur after current therapies are uniformly fatal. Therefore, novel therapies which target tumor cells while sparing normal cells are desperately needed. Oncolytic engineered herpes simplex virus (oHSV) therapy offers an inventive, targeted, less-toxic approach for children with incurable brain tumors and may be beneficial as an added therapy for curable tumors allowing for lower doses, and therefore, less toxicity from traditional therapies. HSV has been successfully engineered to introduce mutations (e.g. ?134.5 neurovirulence gene) in the virus that prevent infection in normal cells while maintaining the virus? ability to kill cancer cells. UAB has conducted three phase I trials of an engineered HSV G207, which has both copies of ?134.5 deleted and an insertional deletion of the ribonucleotide reductase gene for added safety, given alone and with a single small dose of radiation used to improve virus replication, in adults with recurrent high-grade brain tumors. In these trials, high doses (up to 3 x 109 plaque-forming units) were safely injected directly into the tumor or surrounding brain tissue without serious toxicities. While these trials were only designed to determine safety, many tumor responses were seen including two patients with complete (>5 years) responses. This trial data coupled with our preclinical data demonstrating that a variety of aggressive pediatric brain tumors are highly sensitive to oHSV strongly suggests that a pediatric oHSV trial would be a worthwhile endeavor. We propose to conduct a phase I clinical trial of G207 alone or combined with a single low dose of radiation in children with recurrent supratentorial brain tumors. Our primary goal is to determine safety. Our secondary aims are to obtain preliminary information on the effectiveness of and immune response to G207 and on tumor genotypic and phenotypic features which may predict a response to oHSV.

Public Health Relevance

Approximately 25-30% of children with brain cancer do not survive, and current therapies including surgery, chemotherapy and radiation are very damaging to the developing brain of a child resulting in long-term disability in survivors of childhood brain cancer. Novel, targeted therapies which improve outcomes and reduce toxicities are desperately needed. Engineered herpes simplex virus (HSV) therapy is an innovative treatment approach designed to target and kill tumor cells while sparing normal cells. The goal of the proposed study is to determine the safety of engineered HSV G207 alone and when combined with a single low dose of radiation in children with recurrent or progressive brain tumors. The information gained from this trial will be used so that additional trials with G207 can be designed to determine the overall effectiveness of the virus in different tumor types, when combined with standard therapies, and when injected in different locations in the brain.

National Institute of Health (NIH)
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Special Emphasis Panel (ZFD1)
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University of Alabama Birmingham
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Friedman, Gregory K; Bernstock, Joshua D; Chen, Dongquan et al. (2018) Enhanced Sensitivity of Patient-Derived Pediatric High-Grade Brain Tumor Xenografts to Oncolytic HSV-1 Virotherapy Correlates with Nectin-1 Expression. Sci Rep 8:13930
Waters, Alicia M; Johnston, James M; Reddy, Alyssa T et al. (2017) Rationale and Design of a Phase 1 Clinical Trial to Evaluate HSV G207 Alone or with a Single Radiation Dose in Children with Progressive or Recurrent Malignant Supratentorial Brain Tumors. Hum Gene Ther Clin Dev 28:7-16
Foreman, Paul M; Friedman, Gregory K; Cassady, Kevin A et al. (2017) Oncolytic Virotherapy for the Treatment of Malignant Glioma. Neurotherapeutics 14:333-344