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.

抽象的儿童脑肿瘤是美国儿童癌症死亡的主要原因。高级别胶质瘤 (pHGG) 是最常见和最具侵袭性的脑癌形式之一，中位数为存活 9-15 个月。1-3 大脑半球出现的 pHGG 的重要亚群之一编码组蛋白 H3F3A 中的 G34R/V 替换，以及 ATRX 和 TP53 失活突变。目前的护理标准仅包括肿瘤切除，然后进行放疗和化疗1-4 导致中位生存期略有增加。治疗效果有限的原因之一是肿瘤复发，由浸润大脑的 pHGG 细胞扩散引起。1-4 治疗效果 pHGG 也受到血脑屏障 (BBB) 的限制，5 阻碍了药物的有效输送对肿瘤块进行化疗化合物。涉及局部给药的治疗策略肿瘤化疗药物正在成为有吸引力的方法。探索新疗法针对 G34R/V pHGG 亚型的模式，我们开发了一种含有遗传损伤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 突变减少了与 DNA 修复相关的基因的表达，使细胞更加对体内电离辐射和 DNA 损伤敏化剂（如 PARP 抑制剂奥拉帕尼）敏感。在在此应用中，我们建议使用高密度脂蛋白（HDL）模拟将奥拉帕尼输送到 TME 中纳米圆盘 (ND) 可以通过 B-1 类清道夫受体 (SR- B1) 和小窝脂筏内吞作用。9 我们观察到 SR-B1 在 H3.3G34R pHGG 中表达源自 SB 模型的神经球 (NS) 以及源自 H3.3G34R pHGG 患者的细胞。在这个研究中，我们将开发基于装载 CpG（一种 Toll- 类似受体 9 (TLR9) 激动剂与化疗药物奥拉帕尼 (Olaparib) 一起用于靶向 H3.3G34R pHGG。我们证明了装载化学免疫治疗药物的 sHDL ND 的局部递送颅内同基因小鼠神经胶质瘤模型，引发肿瘤消退和抗肿瘤 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 ND 是 pHGG 的一个有吸引力的药物递送平台，我们假设这将导致肿瘤消退和长期生存。所提出的输送系统具有临床转化的巨大潜力。