Chemo-radio immunotherapy for pediatric brain tumors

小儿脑肿瘤的放化疗免疫治疗

• 批准号: 10477014
• 负责人: Theodore S Johnson
• 金额: $ 57.01万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10477014
• 关键词: Antigen Presentation; Antigen-Presenting Cells; Antigens; Apoptotic; Automobile Driving; Biology; Brain Neoplasms; Cells; Chemotherapy and/or radiation; Child; Childhood Brain Neoplasm; Childhood Solid Neoplasm; Clinical; Clinical Trials; Conformal Radiotherapy; Cross Presentation; DNA Mutational Analysis; Data; Dendritic Cells; Diffuse intrinsic pontine glioma; Dioxygenases; Disease; Dose; Enrollment; Ependymoma; Failure; Genomics; Glioblastoma; Histology; Immune; Immune response; Immuno-Chemotherapy; Immunologic Markers; Immunotherapy; Link; Logistic Regressions; Maintenance; Mediating; Modeling; Modification; Newly Diagnosed; Operative Surgical Procedures; Oral; Outcome; Outcome Measure; Outpatients; Pathway Analysis; Pathway interactions; Patient-Focused Outcomes; Patients; Pediatric Neoplasm; Pediatrics; Periodicity; Phase; Population; Pre-Clinical Model; Progression-Free Survivals; Radiation; Radiation therapy; Radio; Radioimmunotherapy; Recurrence; Recurrent disease; Refractory; Regimen; Regulatory T-Lymphocyte; Relapse; Resistance; Stratification; T cell receptor repertoire sequencing; T-Lymphocyte; Testing; Time; Toxic effect; Tryptophan 2,3 Dioxygenase; Tumor Markers; arm; base; biomarker-driven; chemotherapy; clinical practice; cohort; conventional therapy; disorder control; effective therapy; effector T cell; epigenomics; follow-up; genome wide methylation; high risk; immune activation; immunogenic; improved; indoleamine; inhibitor; innovation; irradiation; medulloblastoma; monocyte; neoplastic cell; novel; patient population; pediatric patients; phase 1 study; primary outcome; prognostic; radiation during childhood; risk stratification; standard care; synergism; temozolomide; transcriptome sequencing; trial design; tumor; tumor diagnosis; virtual

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.

脑瘤是儿童最常见的实体瘤。有些可以治愈，但对于30-35%的儿科