Gregory K Friedman1, James M Johnston1, Asim K Bag1, Joshua D Bernstock1, Rong Li1, Inmaculada Aban1, Kara Kachurak1, Li Nan1, Kyung-Don Kang1, Stacie Totsch1, Charles Schlappi1, Allison M Martin1, Devang Pastakia1, Rene McNall-Knapp1, Sameer Farouk Sait1, Yasmin Khakoo1, Matthias A Karajannis1, Karina Woodling1, Joshua D Palmer1, Diana S Osorio1, Jeffrey Leonard1, Mohamed S Abdelbaki1, Avi Madan-Swain1, T Prescott Atkinson1, Richard J Whitley1, John B Fiveash1, James M Markert1, G Yancey Gillespie1. 1. From the Department of Pediatrics, Divisions of Pediatric Hematology-Oncology (G.K.F., K.K., L.N., K.-D.K., S.T., C.S., A.M.-S.), Pediatric Allergy and Immunology (T.P.A.), and Pediatric Infectious Disease (R.J.W.), and the Departments of Neurosurgery (G.K.F., J.M.J., J.M.M., G.Y.G.), Pathology (R.L.), Biostatistics (I.A.), and Radiation Oncology (J.B.F.), University of Alabama at Birmingham, and Children's of Alabama (G.K.F., J.M.J., R.L., K.K., A.M.-S., T.P.A., R.J.W.) - both in Birmingham; the Department of Diagnostic Imaging, St. Jude Children's Research Hospital, Memphis (A.K.B.), and the Department of Pediatrics, Vanderbilt University Medical Center, Nashville (D.P.) - both in Tennessee; the Department of Neurosurgery, Brigham and Women's Hospital and Boston Children's Hospital, Harvard Medical School, Boston (J.D.B.); the Department of Pediatrics, Albert Einstein College of Medicine (A.M.M.), and the Departments of Pediatrics (S.F.S., Y.K., M.A.K.) and Neurology (Y.K.), Memorial Sloan Kettering Cancer Center - both in New York; the Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City (R.M.-K.); the Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant (K.W., D.S.O., M.S.A.) and the Department of Pediatric Neurosurgery (J.L.), Nationwide Children's Hospital, and the Department of Radiation Oncology, Ohio State University Comprehensive Cancer Center (J.D.P.) - both in Columbus; and the Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant, Washington University School of Medicine, St. Louis (M.S.A.).
Abstract
BACKGROUND: Outcomes in children and adolescents with recurrent or progressive high-grade glioma are poor, with a historical median overall survival of 5.6 months. Pediatric high-grade gliomas are largely immunologically silent or "cold," with few tumor-infiltrating lymphocytes. Preclinically, pediatric brain tumors are highly sensitive to oncolytic virotherapy with genetically engineered herpes simplex virus type 1 (HSV-1) G207, which lacks genes essential for replication in normal brain tissue. METHODS: We conducted a phase 1 trial of G207, which used a 3+3 design with four dose cohorts of children and adolescents with biopsy-confirmed recurrent or progressive supratentorial brain tumors. Patients underwent stereotactic placement of up to four intratumoral catheters. The following day, they received G207 (107 or 108 plaque-forming units) by controlled-rate infusion over a period of 6 hours. Cohorts 3 and 4 received radiation (5 Gy) to the gross tumor volume within 24 hours after G207 administration. Viral shedding from saliva, conjunctiva, and blood was assessed by culture and polymerase-chain-reaction assay. Matched pre- and post-treatment tissue samples were examined for tumor-infiltrating lymphocytes by immunohistologic analysis. RESULTS: Twelve patients 7 to 18 years of age with high-grade glioma received G207. No dose-limiting toxic effects or serious adverse events were attributed to G207 by the investigators. Twenty grade 1 adverse events were possibly related to G207. No virus shedding was detected. Radiographic, neuropathological, or clinical responses were seen in 11 patients. The median overall survival was 12.2 months (95% confidence interval, 8.0 to 16.4); as of June 5, 2020, a total of 4 of 11 patients were still alive 18 months after G207 treatment. G207 markedly increased the number of tumor-infiltrating lymphocytes. CONCLUSIONS: Intratumoral G207 alone and with radiation had an acceptable adverse-event profile with evidence of responses in patients with recurrent or progressive pediatric high-grade glioma. G207 converted immunologically "cold" tumors to "hot." (Supported by the Food and Drug Administration and others; ClinicalTrials.gov number, NCT02457845.).
BACKGROUND: Outcomes in children and adolescents with recurrent or progressive high-grade glioma are poor, with a historical median overall survival of 5.6 months. Pediatric high-grade gliomas are largely immunologically silent or "cold," with few tumor-infiltrating lymphocytes. Preclinically, pediatric brain tumors are highly sensitive to oncolytic virotherapy with genetically engineered herpes simplex virus type 1 (HSV-1) G207, which lacks genes essential for replication in normal brain tissue. METHODS: We conducted a phase 1 trial of G207, which used a 3+3 design with four dose cohorts of children and adolescents with biopsy-confirmed recurrent or progressive supratentorial brain tumors. Patients underwent stereotactic placement of up to four intratumoral catheters. The following day, they received G207 (107 or 108 plaque-forming units) by controlled-rate infusion over a period of 6 hours. Cohorts 3 and 4 received radiation (5 Gy) to the gross tumor volume within 24 hours after G207 administration. Viral shedding from saliva, conjunctiva, and blood was assessed by culture and polymerase-chain-reaction assay. Matched pre- and post-treatment tissue samples were examined for tumor-infiltrating lymphocytes by immunohistologic analysis. RESULTS: Twelve patients 7 to 18 years of age with high-grade glioma received G207. No dose-limiting toxic effects or serious adverse events were attributed to G207 by the investigators. Twenty grade 1 adverse events were possibly related to G207. No virus shedding was detected. Radiographic, neuropathological, or clinical responses were seen in 11 patients. The median overall survival was 12.2 months (95% confidence interval, 8.0 to 16.4); as of June 5, 2020, a total of 4 of 11 patients were still alive 18 months after G207 treatment. G207 markedly increased the number of tumor-infiltrating lymphocytes. CONCLUSIONS: Intratumoral G207 alone and with radiation had an acceptable adverse-event profile with evidence of responses in patients with recurrent or progressive pediatric high-grade glioma. G207 converted immunologically "cold" tumors to "hot." (Supported by the Food and Drug Administration and others; ClinicalTrials.gov number, NCT02457845.).
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