Ph1 of HSV G207 and Radiation to Treat Pediatric Brain Tumors IND16294 (12/10/14)

项目摘要/摘要： 儿童脑癌是儿童最常见的实体肿瘤，影响 每年大约有2500名儿童，估计有22000名儿童生活在美国 该州患有恶性脑瘤，这使其成为一种孤儿疾病。当前 儿童恶性脑肿瘤的治疗方法包括手术、化疗和放射治疗 对儿童发育中的大脑非常有害，并可能导致显著的长期大脑 损伤和荷尔蒙失调。此外，大约25%-30%的恶性疾病儿童 脑癌不会存活，目前治疗后复发的高级别肿瘤 都是致命的。因此，针对肿瘤细胞而不针对正常细胞的新疗法 都是非常需要的。 溶瘤工程单纯疱疹病毒(OHSV)疗法提供了一种创造性的、有针对性的、 对于患有无法治愈的脑瘤的儿童来说，毒性较小的方法可能是有益的，因为 治疗可治愈的肿瘤，剂量较低，因此传统疗法的毒性较小 治疗。单纯疱疹病毒已经被成功地改造成可以引入突变(例如γ134.5 神经毒力基因)在病毒中防止正常细胞感染，同时保持 病毒杀死癌细胞的能力。UAB已经对一种工程HSV进行了三次I期试验 G207，其具有γ134.5的两个拷贝缺失和插入的核苷酸缺失 增加安全性的还原酶基因，单独给予，并与单一的小剂量辐射用于 在患有复发的高级别脑瘤的成年人中，改善病毒复制。在这些试验中，高 剂量(最多3x109个斑块形成单位)安全地直接注射到肿瘤或 周围脑组织无严重毒性。虽然这些试验的目的只是为了 确定安全性，观察到许多肿瘤反应，包括两名完全(&gt；5)的患者 几年)的回应。这项试验数据与我们的临床前数据相结合表明，各种 儿童侵袭性脑瘤对OHSV高度敏感强烈提示 OHSV试验将是一项值得的努力。 我们建议进行G207单独或联合单药的I期临床试验 小剂量放射治疗儿童复发性幕上脑肿瘤。我们的首要目标是 以确定安全性。我们的次要目标是获得有关 G207对肿瘤基因分型和表型的影响及其免疫应答 可以预测对OHSV的应答的特征。

Project Summary/Abstract: Childhood brain cancer is the most common solid tumor in children affecting approximately 2,500 children a year with an estimated 22,000 children living in the United States with a malignant brain tumor, which establishes this as an orphan disease. Current therapies for malignant childhood brain tumors including surgery, chemotherapy and radiation are very damaging to the developing brain of a child and can result in significant long-term brain injury and hormone dysfunction. Furthermore, approximately 25-30% of children with malignant brain cancer do not survive, and high-grade tumors that recur after current therapies are uniformly fatal. Therefore, novel therapies which target tumor cells while sparing normal cells are desperately needed. Oncolytic engineered herpes simplex virus (oHSV) therapy offers an inventive, targeted, less-toxic approach for children with incurable brain tumors and may be beneficial as an added therapy for curable tumors allowing for lower doses, and therefore, less toxicity from traditional therapies. HSV has been successfully engineered to introduce mutations (e.g. γ134.5 neurovirulence gene) in the virus that prevent infection in normal cells while maintaining the virus’ ability to kill cancer cells. UAB has conducted three phase I trials of an engineered HSV G207, which has both copies of γ134.5 deleted and an insertional deletion of the ribonucleotide reductase gene for added safety, given alone and with a single small dose of radiation used to improve virus replication, in adults with recurrent high-grade brain tumors. In these trials, high doses (up to 3 x 109 plaque-forming units) were safely injected directly into the tumor or surrounding brain tissue without serious toxicities. While these trials were only designed to determine safety, many tumor responses were seen including two patients with complete (>5 years) responses. This trial data coupled with our preclinical data demonstrating that a variety of aggressive pediatric brain tumors are highly sensitive to oHSV strongly suggests that a pediatric oHSV trial would be a worthwhile endeavor. We propose to conduct a phase I clinical trial of G207 alone or combined with a single low dose of radiation in children with recurrent supratentorial brain tumors. Our primary goal is to determine safety. Our secondary aims are to obtain preliminary information on the effectiveness of and immune response to G207 and on tumor genotypic and phenotypic features which may predict a response to oHSV.