Oncolytic HSV-1 G207 Immunovirotherapy for Pediatric High-Grade Gliomas.
Oncolytic HSV-1 G207 Immunovirotherapy for Pediatric High-Grade Gliomas.
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DOI：
10.1056/nejmoa2024947
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发表时间：
2021-04-29
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影响因子：
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通讯作者：
Gillespie GY
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作者：
Friedman GK;Johnston JM;Bag AK;Bernstock JD;Li R;Aban I;Kachurak K;Nan L;Kang KD;Totsch S;Schlappi C;Martin AM;Pastakia D;McNall-Knapp R;Farouk Sait S;Khakoo Y;Karajannis MA;Woodling K;Palmer JD;Osorio DS;Leonard J;Abdelbaki MS;Madan-Swain A;Atkinson TP;Whitley RJ;Fiveash JB;Markert JM;Gillespie GY
复发或进展性高级别胶质瘤的儿童和青少年预后很差，历史上总生存期的中位数为5.6个月。儿童高级别胶质瘤在免疫上大多是沉默的或“冷的”，很少有肿瘤浸润性淋巴细胞。临床前，儿童脑肿瘤对基因工程1型单纯疱疹病毒(HSV-1)G207的溶瘤病毒疗法高度敏感，这种病毒缺乏在正常脑组织中复制所必需的基因。我们进行了G207的1期试验，该试验采用3+3设计，对经活检证实复发或进展性幕上脑肿瘤的儿童和青少年进行了四次剂量队列。患者接受了最多四个肿瘤内导管的立体定向放置。第二天，他们在6小时内通过控制速率输注G207(107或108个斑块形成单位)。第3组和第4组在G207注射后24小时内接受大体肿瘤体积的放射治疗(5GY)。通过培养和聚合酶链式反应检测唾液、结膜和血液中的病毒分泌量。配对的治疗前和治疗后组织样本通过免疫组织学分析检测肿瘤浸润性淋巴细胞。12例7-18岁的高级别胶质瘤患者接受了G207治疗。研究人员没有将G207归因于剂量限制的毒性作用或严重的不良事件。20例1级不良事件可能与G207有关。未检测到病毒脱落。11例患者出现放射学、神经病理或临床反应。中位总生存期为12.2个月(95%可信区间，8.0至16.4)；截至2020年6月5日，11名患者中有4名在接受G207治疗18个月后仍存活。G207能显著增加肿瘤浸润性淋巴细胞的数量。在复发或进展的儿童高级别胶质瘤患者中，G207单独和联合放射治疗有可接受的不良事件描述，并有反应的证据。G207将免疫“冷”肿瘤转化为“热”肿瘤。(由食品和药物管理局和其他机构支持；ClinicalTrials.gov编号，NCT02457845。)
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. 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. 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. 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.)