Phase 2 trial of a novel peptide vaccine targeting CMV antigen for newly diagnosed pediatric high grade glioma and diffuse intrinsic pontine glioma and recurrent medulloblastoma

摘要 在0-19岁的患者中，脑癌是最常见的癌症死亡原因。弥漫性固有桥 胶质瘤(DIPG)的中位总生存期(OS)约为8个月。高级别胶质瘤是 同样具有破坏性的，中位OS为16个月，复发性髓母细胞瘤(MB)的OS为 大约12个月。我们和其他人发现巨细胞病毒(CMV)抗原存在于MB中 和HGG/DIPG，但在健康脑组织中不存在。人类巨细胞病毒核酸和蛋白质表位在70年被发现 HGG/DIPG为100%，髓母细胞瘤为92%。鉴于CMV抗原在中国的普遍表达 HGG/DIPG和髓母细胞瘤，通过多肽疫苗靶向CMV抗原代表了一种新的 有选择地杀死肿瘤，而不损害正常组织的治疗。 我们小组已经开发出一种针对CMV抗原pp65的多肽疫苗(PEP-CMV)，用于儿童和 正在进行I期临床试验(NCT03299309)的年轻人。我们在17年的初步结果 患者已经证明，没有≥3级毒性，疫苗引发了免疫反应 在75%的患者中。在这个多次复发的患者队列中，11名患者中有6名接受了至少3次治疗 疫苗在核磁共振成像上显示病情稳定或部分反应。根据这些数据，我们的假设是 使用PEP-CMV疫苗治疗新诊断的HGG和DIPG或复发的MB儿童将 与历史对照相比，生成强大的免疫响应，从而改善PFS和OS。 我们的主要目标是：1)确定患者对PEP-CMV的客观应答率 复发MB，2)确定复发MB患者4个月的无进展生存期，3)至 确定新诊断的DIPG患者的1年OS，以及4)确定DIPG患者的1年PFS 新诊断的HGG。我们的次要目标是：1)进一步确定与治疗有关的毒性 方案和2)对复发的MB患者和HGG患者的2年OS患者进行1年PFS测定。我们的探索者 目标是1)描述和量化对PEP-CMV的免疫反应和2)估计血管 磁共振灌注成像对PEP-CMV治疗后肿瘤通透性的影响 从伪行进到行进。为实现总体目标，将实现以下具体目标 被追捕。目标1：进行多机构试验，评估患有PFS和OS的儿童和年轻人的PFS和OS 接受PEP-CMV治疗的新诊断的HGG、新诊断的DIPG和复发的MB。目标2：确定 接受PEP-CMV的患者的免疫原性和放射学反应。 这项研究是有影响力的，因为它有可能导致儿科恶性肿瘤治疗方式的范式转变 脑瘤的治疗是使用一种新的免疫治疗性疫苗方法来代替有毒的辐射和 化疗。

Abstract Brain cancer is the most common cause of cancer death in patients age 0-19. Diffuse intrinsic pontine glioma (DIPG) has a median overall survival (OS) of approximately 8 months. High grade glioma (HGG) is similarly devastating, with a median OS of 16 months, and recurrent medulloblastoma (MB) has an OS of approximately 12 months. We and others have found that cytomegalovirus (CMV) antigens are present in MB and HGG/DIPG but not in healthy brain tissue. Human CMV nucleic acids and protein epitopes in found in 70- 100% of HGG/DIPG and 92% of medulloblastoma. Given the prevalence of CMV antigen expression in HGG/DIPG and medulloblastoma, targeting CMV antigens through peptide vaccination represents a novel treatment to selectively kill tumor while leaving normal tissue unharmed. Our group has developed a peptide vaccine (PEP-CMV) directed to the CMV antigen, pp65, in children and young adults that is being evaluated in a Phase I clinical trial (NCT03299309). Our preliminary results in 17 patients have shown that there have been no ≥ 3 Grade toxicities and that vaccines elicited immune responses in 75% of patients. In this multiply recurrent cohort of patients, six of 11patients who received at least three vaccines demonstrated stable disease or partial responses on MRI. Given this data, our hypothesis is that treatment of children with a newly diagnosed HGG and DIPG or recurrent MB using the PEP-CMV vaccine will generate a robust immune response resulting in improved PFS and OS compared to historical controls. Our Primary Objectives are: 1) to determine the objective response rate to PEP-CMV in patients with recurrent MB, 2) to determine the progression-free survival at 4 months in patients with recurrent MB, 3) to determine 1 year OS in patients with newly-diagnosed DIPG, and 4) to determine 1 year PFS in patients with newly diagnosed HGG. Our Secondary Objectives are: 1) to further define treatment related toxicities of this regimen and 2) to determine 1 year PFS in patients with recurrent MB and 2 year OS in HGG. Our Exploratory objectives are 1) to describe and quantify the immune response to PEP-CMV and 2) to estimate the vascularity and permeability of tumors in response to PEP-CMV using perfusion MRI to better differentiate tumor progression from pseudoprogression. To attain the overall objectives, the following specific aims will be pursued. Aim 1: Conduct a multi-institutional trial to assess the PFS and OS of children and young adults with newly diagnosed HGG, newly diagnosed DIPG, and recurrent MB who receive PEP-CMV. Aim 2: Determine the immunogenicity and radiographic responses of patients who receive PEP-CMV. This study is impactful because it has the potential to cause a paradigm shift in the way malignant pediatric brain tumors are treated, using a novel immunotherapeutic vaccine approach in lieu of toxic radiation and chemotherapy.