Chemo-radio immunotherapy for pediatric brain tumors

脑瘤是儿童最常见的实体肿瘤。有些是可以治愈的，但对于30%-35%的儿科 在一线治疗后复发的患者--以及每个患有弥漫性固有桥脑胶质瘤(DIPG)的儿童- 用标准治疗基本上没有治愈的机会。因此，迫切需要更有效的治疗方法。 需要的。当前提议背后的科学前提是常规辐射和 化疗从死亡的肿瘤细胞中释放出大量的抗原，但这通常不会引发 有用的免疫反应，因为肿瘤诱导的免疫原性抗原提呈受到抑制 机制，如吲哚胺2，3-双加氧酶(IDO)途径，一种自然机制，深刻地 抑制对凋亡细胞的免疫反应。该提案假设增加免疫治疗使用的是 吲哚昔莫德是一种IDO途径的口服抑制剂，与放射和化疗相结合将允许 延长这些原本难以治愈的患者的生存时间。申请者最近完成了一项第一- 53例儿童基于吲哚昔莫德的放化疗方案的儿科第1期研究 患有复发的脑瘤。这项概念验证研究显示，中位总生存期为17.2个月， 明显优于历史对照研究，毒性低。 AIM 1将进行一项2期分层设计的吲哚昔莫特免疫疗法联合 替莫唑胺(TMZ)化疗，加或不加新型低剂量局部野(LDPF) 放射治疗儿童复发性室管膜瘤、髓母细胞瘤和基底膜瘤91例。结果 措施将是8个月无进展生存期(PFS)和18个月总生存期(OS)和时间 方案失败(TTRF)，与历史控制中的PFS和OS相比。 Aim 2将对30名新诊断为弥漫性固有桥脑的儿童进行第二阶段单臂试验 胶质瘤(DIPG)，为了验证一线吲哚莫特加入标准适形放射治疗的假设， 随后使用吲哚昔莫德+TMZ进行维持性化学免疫治疗，将导致总体改善 生存(OS)，与有良好记录的历史对照进行比较。 目标3将使用来自新的临床前模型的机械预测来确定创新的、假设驱动的 免疫生物标记物，结合患者原始细胞固有基因组和表观基因组特征 肿瘤，以询问这些是否允许对目标1和目标2的患者结果进行预后风险分层。 拟议的临床试验的成功结果有可能从根本上改变这一方法。 到治疗复发或难治性脑瘤的儿童。它还将对以下方面产生重大影响 将免疫治疗直接纳入高危脑瘤儿童的标准治疗， 在一线治疗的时候，当真正有可能长期治愈的时候。

Brain tumors are the most common solid tumor of childhood. Some can be cured, but for the 30-35% of pediatric patients who recur following front-line therapy – and for every child with diffuse intrinsic pontine glioma (DIPG) – there is essentially no chance of cure with standard treatment. Thus, more effective therapies are urgently needed. The scientific premise underlying the current proposal is that conventional radiation and chemotherapy release large amounts of antigen from dying tumor cells, but that this normally cannot trigger a useful immune response because immunogenic antigen-presentation is suppressed by tumor-induced mechanisms such as the indoleamine 2,3-dioxygenase (IDO) pathway, a natural mechanism that profoundly inhibits immune response to apoptotic cells. The proposal hypothesizes that adding immunologic therapy using indoximod, an oral inhibitor of the IDO pathway, in combination with radiation and chemotherapy, will allow prolonged survival in these otherwise refractory patients. The applicants have recently completed a first-in- pediatrics Phase 1 study of the proposed indoximod-based chemo-radio-immunotherapy approach in 53 children with recurrent brain tumors. This proof-of-concept study shows a median Overall Survival of 17.2 months, which is markedly superior to historical comparator studies, with low toxicity. Aim 1 will conduct a Phase 2, stratified-design trial of indoximod immunotherapy in combination with temozolomide (TMZ) chemotherapy, with or without the addition of novel Low-Dose Partial-field (LDPF) radiation, in 91 pediatric patients with recurrent ependymoma, medulloblastoma and GBM. Outcome measures will be 8-month Progression-Free Survival (PFS), and 18-month Overall Survival (OS) and Time to Regimen Failure (TTRF), as compared to PFS and OS from historical controls. Aim 2 will conduct a Phase 2 single-arm trial of 30 children with newly-diagnosed diffuse intrinsic pontine glioma (DIPG), to test the hypothesis that front-line indoximod added to standard conformal radiotherapy, followed by maintenance chemo-immunotherapy with indoximod + TMZ, will result in improved Overall Survival (OS), compared to well-documented historical controls. Aim 3 will use mechanistic predictions from novel preclinical models to identify innovative, hypothesis-driven immune biomarkers, combined with cell-intrinsic genomic and epigenomic features of the patients' original tumors, to ask whether these allow prognostic risk stratification of patient outcomes in Aim 1 and Aim 2. A successful outcome from the proposed clinical trials has the potential to fundamentally change the approach to treating children with recurrent or refractory brain tumors. It would also have major implications for incorporating immunologic therapy directly into the standard treatment for children with high-risk brain tumors, at the time of front-line treatment, when there is the real possibility of long-term cure.