Department of Neurosurgery, Brigham and Women's Hospital, Harvard University, Boston, Massachusetts, USA.
Diagnostic Imaging, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Hum Gene Ther. 2020 Oct;31(19-20):1132-1139. doi: 10.1089/hum.2020.101. Epub 2020 Aug 17.
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.
脑肿瘤是最常见的小儿实体瘤，也是导致儿童癌症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，起源于大脑，但大多数小儿脑肿瘤位于幕下，起源于后颅窝，特别是小脑。尽管采用了对发育中的大脑有害的积极治疗（手术、放疗和/或化疗），恶性小脑肿瘤的治疗效果仍不理想。因此，迫切需要新的治疗方法/策略，如溶瘤病毒治疗。临床前和先前的临床研究表明，经过基因工程改造的溶瘤单纯疱疹病毒（HSV-1）G207 可以安全地靶向小脑恶性肿瘤，并有可能在疾病的局部和远处部位（包括脊柱转移和软脑膜疾病）引发抗肿瘤免疫反应。在此，我们概述了一项首次人体免疫治疗 I 期临床试验的原理、设计和意义，该试验用 HSV G207 联合单次低剂量放疗（5Gy）治疗复发性小脑恶性肿瘤，旨在增强病毒复制和固有及适应性免疫反应。我们讨论了通过肿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性传统 3+3 设计，共设四个剂量组。主要目的是评估 G207 联合放疗在复发性/进行性小儿恶性小脑肿瘤中的安全性和耐受性。在活检证实复发/进展后，将放置 1 至 4 个肿瘤内导管，然后进行 6 小时的 G207 控速输注，随后在床边取出导管。放疗将在病毒接种后 24 小时内进行。将密切监测患者的毒性和病毒脱落情况。通过评估影像学反应、功能评分、无进展生存期和总生存期以及生活质量来评估疗效。这些数据对于我们努力为患有高级别脑肿瘤的儿童开发更有效和毒性更低的治疗方法将具有重要价值。
