Brain tumors represent the most common pediatric solid neoplasms and leading cause of childhood cancer-related morbidity and mortality. Although most adult brain tumors are supratentorial and arise in the cerebrum, the majority of pediatric brain tumors are infratentorial and arise in the posterior fossa, specifically the cerebellum. Outcomes from malignant cerebellar tumors are unacceptable despite aggressive treatments (surgery, radiation, and/or chemotherapy) that are harmful to the developing brain. Novel treatments/approaches such as oncolytic virotherapy are urgently needed. Preclinical and prior clinical studies suggest that genetically engineered oncolytic herpes simplex virus (HSV-1) G207 can safely target cerebellar malignancies and has potential to induce an antitumor immune response at local and distant sites of disease, including spinal metastases and leptomeningeal disease. Herein, we outline the rationale, design, and significance of a first-in-human immunotherapy Phase 1 clinical trial targeting recurrent cerebellar malignancies with HSV G207 combined with a single low-dose of radiation (5 Gy), designed to enhance virus replication and innate and adaptive immune responses. We discuss the unique challenges of inoculating virus through intratumoral catheters into cerebellar tumors. The trial utilizes a single arm open-label traditional 3 + 3 design with four dose cohorts. The primary objective is to assess safety and tolerability of G207 with radiation in recurrent/progressive malignant pediatric cerebellar tumors. After biopsy to prove recurrence/progression, one to four intratumoral catheters will be placed followed by a controlled-rate infusion of G207 for 6 h followed by the removal of catheters at the bedside. Radiation will be given within 24 h of virus inoculation. Patients will be monitored closely for toxicity and virus shedding. Efficacy will be assessed by measuring radiographic response, performance score, progression-free and overall survival, and quality of life. The data obtained will be invaluable in our efforts to produce more effective and less toxic therapies for children with high-grade brain tumors.

中文翻译：

---

溶瘤 HSV G207 治疗恶性小儿小脑脑肿瘤的首次人体 1 期免疫病毒疗法临床试验的设计和原理。

脑肿瘤是最常见的儿科实体肿瘤，也是儿童癌症相关发病率和死亡率的主要原因。尽管大多数成人脑肿瘤位于幕上并起源于大脑，但大多数儿童脑肿瘤位于幕下并起源于后颅窝，特别是小脑。尽管积极治疗（手术、放疗和/或化疗）对发育中的大脑有害，但恶性小脑肿瘤的结果是不可接受的。迫切需要新的治疗方法/方法，例如溶瘤病毒疗法。临床前和先前的临床研究表明，基因工程溶瘤单纯疱疹病毒 (HSV-1) G207 可以安全地靶向小脑恶性肿瘤，并有可能在局部和远处疾病部位诱导抗肿瘤免疫反应，包括脊柱转移瘤和软脑膜疾病。在此，我们概述了针对复发性小脑恶性肿瘤的首次人体免疫疗法 1 期临床试验的基本原理、设计和意义，该试验采用 HSV G207 结合单次低剂量辐射 (5 Gy)，旨在增强病毒复制和先天性和适应性免疫反应。我们讨论了通过瘤内导管将病毒接种到小脑肿瘤中的独特挑战。该试验采用单臂开放标签传统 3 + 3 设计，有四个剂量组。主要目的是评估 G207 在复发性/进展性恶性小脑小脑肿瘤中放疗的安全性和耐受性。活检证明复发/进展后，将放置 1 到 4 个瘤内导管，然后控制速度输注 G207 6 小时，然后在床边拔除导管。将在病毒接种后 24 小时内给予辐射。将密切监测患者的毒性和病毒脱落情况。疗效将通过测量放射学反应、表现评分、无进展生存和总生存以及生活质量来评估。获得的数据对于我们为患有高级别脑肿瘤的儿童提供更有效和毒性更低的疗法的努力将是非常宝贵的。无进展生存期和总生存期，以及生活质量。获得的数据对于我们为患有高级别脑肿瘤的儿童提供更有效和毒性更低的疗法的努力将是非常宝贵的。无进展生存期和总生存期，以及生活质量。获得的数据对于我们为患有高级别脑肿瘤的儿童提供更有效和毒性更低的疗法的努力将是非常宝贵的。