Ph1 Study of HSV G207 in Pediatric Malignant Cerebellar Tumors IND 16294 01/05/18.

项目概要/摘要： 儿童脑癌是儿童中最常见的实体瘤，影响约2，500名儿童 每年估计有22,000名儿童生活在美国患有恶性脑瘤， 这是一种罕见的疾病目前儿童恶性脑肿瘤的治疗方法包括手术， 化疗和放疗对儿童发育中的大脑有很大的损害， 长期残疾，如认知困难，神经内分泌功能障碍和神经感觉缺陷， 幸存者大约30-40%患有恶性脑癌的儿童无法存活，并且高级别肿瘤 在目前的治疗后复发的癌症都是致命的。因此，靶向肿瘤细胞同时 保留正常细胞并刺激抗肿瘤免疫反应是迫切需要的。 溶瘤工程单纯疱疹病毒（oHSV）疗法提供了一种创造性的、靶向的、毒性较小的疗法 对于患有无法治愈的脑肿瘤的儿童， 用于可治愈的肿瘤的治疗允许传统疗法的较低剂量和较低毒性。HSV已经 成功地在病毒中引入突变（例如γ134.5神经毒力基因）， 感染正常脑细胞，同时保持病毒杀死癌细胞和刺激抗肿瘤的能力。 免疫反应UAB进行了3项oHSV G207的I期试验，该试验缺失了γ134.5拷贝， 核糖核苷酸还原酶基因的插入缺失，以增加安全性，单独给药和与单个小 剂量的辐射，以增强病毒复制和抗肿瘤免疫反应，在成人复发性高， 级别的神经胶质瘤这些试验最终证明了肿瘤内或周围接种G207的安全性。 一半的患者有肿瘤反应的放射学证据，包括两名长期存活者 （5.5年）。一项关于G207治疗幕上脑肿瘤的活跃儿科试验证明了G207的安全性 在8名患者中的7名中，包括G207后> 21个月的患者， 持续缓解，无需任何额外治疗。这些试验数据加上我们的临床前数据 这表明侵袭性小儿脑肿瘤对G207高度敏感，并且缺乏可用的 对患者的治疗强烈支持对患有进行性恶性小脑肿瘤的儿童的oHSV试验。 我们建议进行G207单独和与单次低剂量的 复发性小脑脑肿瘤儿童的放射治疗。我们假设G207是安全和可耐受的 有证据表明其对儿童难治性小脑恶性肿瘤有效。我们的首要目标是确定 安全为代价的我们的第二个目标是获得初步信息的有效性和免疫反应 对G207和肿瘤基因型和表型特征，可以预测对oHSV的反应。重要的是， 该试验将支持G207用于这种毁灭性孤儿疾病的临床开发。

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 disabilities such as cognitive difficulties, neuroendocrine dysfunction, and neurosensory deficits in survivors. Approximately 30-40% 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 and stimulate an anti-tumor immune response 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 afford an improved margin of safety as an adjuvant therapy for curable tumors allowing for lower doses and less toxicity from traditional therapies. HSV has been successfully engineered to introduce mutations in the virus (e.g. γ134.5 neurovirulence gene) that prevent infection in normal brain cells while maintaining the virus’ ability to kill cancer cells and stimulate an anti-tumor immune response. UAB conducted 3 Phase I trials of oHSV 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 to enhance virus replication and an anti-tumor immune response, in adults with recurrent high- grade glioma. These trials conclusively demonstrated safety of G207 inoculated intratumorally or in surrounding brain tissue, and ≈half of patients had radiographic evidence of tumor response, including two long-term survivors (>5.5 years). An active pediatric trial of G207 in supratentorial brain tumors has demonstrated safety of G207 alone with evidence of responses to G207 in 7 of 8 patients including a patient >21months post-G207 with an ongoing response without any additional therapies. These trial data coupled with our preclinical data demonstrating that aggressive pediatric brain tumors are highly sensitive to G207 and the lack of available therapies for patients strongly support an oHSV trial for children with progressive malignant cerebellar tumors. We propose to conduct a Phase I clinical trial of G207 alone and combined with a single low dose of radiation in children with recurrent cerebellar brain tumors. We hypothesize that G207 will be safe and tolerable with evidence of efficacy in children with refractory cerebellar malignancies. 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. Importantly, this trial will support the clinical development of G207 for use in this devastating orphan disease.