美国阿拉巴马大学伯明翰分校Gregory K. Friedman团队研究了溶瘤HSV-1 G207免疫病毒疗法治疗儿童高级别胶质瘤的效果。2021年4月10日，该研究发表在《新英格兰医学杂志》上。

复发或进展性高级别胶质瘤的儿童和青少年预后较差，历史中位总生存期仅为5.6个月。儿童高级别胶质瘤在免疫上基本无症状或是“冷”的，很少有肿瘤浸润淋巴细胞。临床前，儿童脑肿瘤对基因工程单纯疱疹病毒1型（HSV-1）G207溶瘤病毒疗法高度敏感，G207缺乏在正常脑组织中复制所必需的基因。

研究组进行了一项G207的临床1期试验，采用3+3设计，对四个剂量组的经活检证实复发或进展性幕上脑肿瘤的的儿童和青少年进行研究。患者接受立体定向放置多达四个肿瘤内导管。第二天，他们接受了G207控制速率输注超过6小时。第3组和第4组在G207给药后24小时内接受放疗（5Gy）。通过培养和聚合酶链反应分析对唾液、结膜和血液中的病毒脱落进行评估。通过免疫组织化学分析，检测治疗前后匹配的组织样本中肿瘤浸润的淋巴细胞。

共有12例7～18岁高级别胶质瘤患者接受G207治疗。研究人员未将剂量限制性毒性反应或严重不良事件归因于G207。20例1级不良事件可能与G207有关。未发现病毒脱落。11例患者出现影像学、神经病理学或临床缓解。中位总生存期为12.2个月，截至2020年6月5日，11名患者中有4名在G207治疗后18个月仍存活。G207能显著增加肿瘤浸润淋巴细胞的数量。

研究结果表明，单独瘤内注射G207和放疗治疗复发或进展的儿童高级别胶质瘤患者可缓解病情，且不良反应耐受。G207可将免疫上的“冷”肿瘤转化为“热”肿瘤。

附：英文原文

Title: Oncolytic HSV-1 G207 Immunovirotherapy for Pediatric High-Grade Gliomas | NEJM

Author: Gregory K. Friedman, M.D.,, James M. Johnston, M.D,, Asim K. Bag, M.B., B.S., M.D.,, Joshua D. Bernstock, M.D., Ph.D., M.P.H.,, Rong Li, M.D., Ph.D.,, Inmaculada Aban, Ph.D.,, Kara Kachurak, C.R.N.P.,, Li Nan, B.S.,, Kyung-Don Kang, Ph.D.,, Stacie Totsch, Ph.D.,, Charles Schlappi, M.D.,, Allison M. Martin, M.D.,, Devang Pastakia, M.D.,, Rene McNall-Knapp, M.D.,, Sameer Farouk Sait, M.D.,, Yasmin Khakoo, M.D.,, Matthias A. Karajannis, M.D.,, Karina Woodling, M.D., C.C.R.P.,, Joshua D. Palmer, M.D.,, Diana S. Osorio, M.D., M.P.H.,, Jeffrey Leonard, M.D.,, Mohamed S. Abdelbaki, M.D.,, Avi Madan-Swain, Ph.D.,, T. Prescott Atkinson, M.D., Ph.D.,, Richard J. Whitley, M.D.,, John B. Fiveash, M.D.,, James M. Markert, M.D., M.P.H.,, and G. Yancey Gillespie, Ph.D.

Issue&Volume: 2021-04-10

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.”

DOI: 10.1056/NEJMoa2024947

Source: https://www.nejm.org/doi/full/10.1056/NEJMoa2024947