Chemo-radio immunotherapy for pediatric brain tumors

脑肿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%的儿童来说， 一线治疗后复发的患者-以及每一个患有弥漫性内在脑桥胶质瘤（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。 needed.目前建议的科学前提是，常规辐射和 化疗从垂死的肿瘤细胞中释放出大量的抗原，但这通常不会引发肿瘤细胞的凋亡。 有用的免疫应答，因为免疫原性抗原呈递被肿瘤诱导的 例如吲哚胺2，3-双加氧酶（IDO）途径，这是一种深刻地 抑制对凋亡细胞的免疫反应。该提案假设，增加免疫治疗， indoximod是一种口服IDO通路抑制剂，与放疗和化疗联合使用， 延长了这些难治性患者的生存期。申请人最近完成了一个首次在- 一项在53名儿童中开展的基于吲哚西莫德的化学-放射-免疫疗法的儿科I期研究 患有复发性脑瘤这项概念验证研究显示，中位总生存期为17.2个月， 明显上级历史对照研究，毒性低。 目标1将进行吲哚西莫德免疫治疗与吲哚西莫德联合治疗的2期分层设计试验。 替莫唑胺（TMZ）化疗，添加或不添加新型低剂量部分视野（LDPF） 放疗，在91例复发性室管膜瘤，髓母细胞瘤和GBM的儿科患者。结果 指标为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），与历史对照的PFS和OS相比。 Aim 2将对30名新诊断的弥漫性内在桥脑的儿童进行2期单组试验 神经胶质瘤（DIPG），以检验一线吲哚西莫德加入标准适形放疗的假设， 随后用吲哚西莫德+ TMZ维持化学免疫疗法，将导致总体改善 与记录良好的历史对照相比的生存期（OS）。 Aim 3将使用来自新的临床前模型的机制预测来识别创新的、假设驱动的 免疫生物标志物，结合患者原始细胞的细胞内在基因组和表观基因组特征， 肿瘤，以询问这些是否允许在目标1和目标2中对患者结局进行预后风险分层。 拟议的临床试验的成功结果有可能从根本上改变这种方法 治疗复发性或难治性脑瘤的儿童。这也将对以下方面产生重大影响 将免疫治疗直接纳入高危脑肿瘤儿童的标准治疗， 在一线治疗的时候，当有真实的长期治愈的可能性时。

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.