Chemo-immunotherapy strategy for pediatric high grade glioma

儿童高级别胶质瘤的化学免疫治疗策略

基本信息

批准号：
10296214
负责人：
Maria G Castro
金额：
$ 42.9万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-15 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10296214
关键词：
ATRX gene Affect Agonist Apolipoprotein A-I Biological Assay Blood Blood - brain barrier anatomy Bone Marrow Brain Brain Neoplasms CD8-Positive T-Lymphocytes Cause of Death Caveolae Cell Death Cell surface Cells Cerebral hemisphere Chemotherapy and/or radiation Childhood Childhood Brain Neoplasm Childhood Glioma Cholesterol DNA Damage DNA Repair DNA Repair Pathway Data Development Disease Progression Drug Delivery Systems Endocytosis Excision Exhibits Gene Expression Genetic Genetic Engineering Genetically Engineered Mouse Glioma High Density Lipoproteins Histones Human Immune Immunity Immuno-Chemotherapy Immunologic Memory Immunotherapeutic agent Impairment Implant In Vitro Ionizing radiation Lesion Leucocytic infiltrate Malignant Childhood Neoplasm Malignant neoplasm of brain Mediating Membrane Microdomains Modality Modeling Molecular Mus Mutation Nonhomologous DNA End Joining Patients Pattern Pharmaceutical Preparations Phenotype Phospholipids Pre-Clinical Model Predisposition Radiation Recurrence Reporting Research Resistance Rodent Rodent Model SR-B proteins Safety Site Sleeping Beauty Subgroup System T cell response TLR9 gene TP53 Gene Inactivation TP53 gene Testing Therapeutic Time Transposase Treatment Effectiveness Treatment Efficacy Variant base blood-brain barrier permeabilization brain cell brain parenchyma caveolin 1 chemotherapeutic agent chemotherapy clinical translation cytotoxicity draining lymph node effective therapy experimental study homologous recombination human model immunogenic cell death in vitro Model in vivo inhibitor/antagonist local drug delivery mouse model nanodisk neoplastic cell novel therapeutics peptidomimetics response standard of care stem cells therapy outcome treatment response tumor tumor microenvironment tumor progression uptake young adult

项目摘要

Abstract Pediatric brain tumors are the leading cause of death in children with cancer in the U.S. Among them, pediatric high-grade gliomas (pHGGs) are one of the most common and aggressive forms of brain cancer, with a median survival of 9-15 months.1-3 One of the prominent subgroups of pHGG that arises in cerebral hemispheres encodes for G34R/V substitutions in the histone H3F3A, along with ATRX and TP53 inactivating mutations. The current standard of care, consisting of tumor resection followed by radiation and chemotherapy,1-4 only leads to a modest increase in median survival. One of the reasons for the limited therapeutic outcomes is tumor recurrence, caused by the spread of pHGG cells that infiltrate the brain.1-4 Treatment effectiveness for pHGG has also been limited due to the blood-brain barrier (BBB),5 which precludes the efficient delivery of chemotherapeutic compounds to the tumor mass. Therapeutic strategies involving local delivery of chemotherapeutic agents to the tumor are emerging as attractive approaches. To explore novel therapeutic modalities for the G34R/V pHGG subtype, we developed a de novo mouse model harboring the genetic lesions using the Sleeping Beauty (SB) transposase-mediated system.6-8 Our preliminary data demonstrate that the H3.3G34R mutation reduces the expression of genes involved with DNA repair, rendering the cells more susceptible to ionizing radiation in vivo and to DNA damage sensitizers such as Olaparib, a PARP inhibitor. In this application, we propose to deliver Olaparib into the TME using high-density lipoprotein (HDL)-mimicking nanodiscs (NDs) that can be specifically internalized into tumor cells via scavenger receptor class B-1 (SR- B1) and caveolae lipid rafts endocytosis.9 We observed that SR-B1 is expressed in H3.3G34R pHGG neurospheres (NS) derived from the SB model, as well as in H3.3G34R pHGG patient-derived cells. In this study, we will develop chemo-immunotherapy delivery vehicles based on sHDL NDs loaded with CpG, a Toll- like receptor 9 (TLR9) agonist, together with Olaparib, a chemotherapeutic agent, for targeting H3.3G34R pHGG. We demonstrated that local delivery of sHDL NDs loaded with chemo-immunotherapeutics, in an intracranial syngeneic mouse glioma model, elicited tumor regression and anti-tumor CD8+ T cell responses in the brain tumor microenvironment (TME) without overt off-target effects.10 These data indicate that sHDL NDs are an attractive drug delivery platform for pHGG, which we hypothesize will result in tumor regression and long-term survival. The proposed delivery system has significant potential for clinical translation.

抽象的小儿脑肿瘤是美国癌症儿童死亡的主要原因，小儿高级神经胶质瘤（PHGGS）是最常见和侵略性的脑癌形式之一，中位数 9-15个月的生存。1-3大脑半球出现的PHGG的突出亚组之一编码组蛋白H3F3A中的G34R/V取代，以及ATRX和TP53灭活突变。当前的护理标准，包括肿瘤切除，然后进行放疗和化学疗法，仅1-4 导致中位存活率适度增加。有限的治疗结果的原因之一是肿瘤复发，是由浸润大脑的PHGG细胞扩散引起的。1-4治疗效果由于血脑屏障（BBB），PHGG也受到限制，5无法有效地递送化学化合物肿瘤质量。涉及本地交付的治疗策略肿瘤的化学治疗剂正在作为有吸引力的方法出现。探索新颖的治疗 G34R/V PHGG子类型的方式，我们开发了一种携带遗传病变的从头小鼠模型使用“睡美人（SB）转座酶介导的系统”。6-8我们的初步数据表明 H3.3G34R突变降低了与DNA修复有关的基因的表达，使细胞更多容易受到体内电离辐射的影响和DNA损伤敏化剂，例如Olaparib，PARP抑制剂。在我们建议使用高密度脂蛋白（HDL）模仿将Olaparib传递到TME中纳米散发（NDS）可以通过清道夫受体B-1特异性地内化为肿瘤细胞（SR- B1）和小窝脂质筏内吞作用。9我们观察到SR-B1在H3.3G34R PHGG中表达源自SB模型以及H3.3G34R PHGG患者衍生细胞的神经球（NS）。在这个研究，我们将根据加载CpG的SHDL NDS开发化学免疫疗法递送车辆像受体9（TLR9）激动剂一样，与化学治疗剂Olaparib一起用于靶向H3.3G34R phgg。我们证明了局部递送的SHDL NDS在颅内合成小鼠胶质瘤模型，引起肿瘤回归和抗肿瘤CD8+ T细胞反应在脑肿瘤微环境（TME）中，没有明显的脱靶效应。10这些数据表明SHDL NDS是PHGG的有吸引力的药物输送平台，我们假设这将导致肿瘤回归和长期生存。拟议的输送系统具有临床翻译的巨大潜力。