Understanding and Overcoming Immunotherapy Resistance in Pediatric High-Grade Glioma

了解并克服儿童高级别胶质瘤的免疫治疗耐药性

基本信息

批准号：
10529330
负责人：
Dolores Hambardzumyan
金额：
$ 21.13万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
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：
2021-12-01 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10529330
关键词：
Address Adult Affect Alleles Animals Antitumor Response Automobile Driving Base Pair Mismatch Brain Brain Neoplasms Brain Stem CD8-Positive T-Lymphocytes Cells Cessation of life Child Childhood Childhood Brain Neoplasm Childhood Glioma Childhood Malignant Brain Tumor Clinical Clinical Trials Complement Constitution Constitutional Data Diagnosis Disease Endocrine Flow Cytometry Future Genes Genetic Models Genomics Goals Histologic Human Immune Immune checkpoint inhibitor Immune system Immunologic Surveillance Immunophenotyping Immunotherapeutic agent Immunotherapy Incidence Infiltration Knowledge Left Link Literature Location Lymphoblastic Leukemia MLH1 gene MSH2 gene MSH6 gene Malignant Childhood Neoplasm Malignant Neoplasms Microsatellite Instability Mismatch Repair Mismatch Repair Deficiency Modality Modeling Morbidity - disease rate Mus Mutation Neoplasm Metastasis Neurocognitive Deficit Non-Small-Cell Lung Carcinoma Outcome PD-L1 blockade PMS2 gene Pathway interactions Patients Phenotype Prediction of Response to Therapy Prognosis Property Radiation Recurrence Resistance Role Sampling Somatic Mutation Survival Analysis Survivors Syndrome T-Lymphocyte Testing Therapeutic Toxic effect Tumor-associated macrophages aggressive therapy anti-PD-L1 antibodies anti-PD-L1 therapy autosome cancer type checkpoint inhibition chemotherapeutic agent clinical predictors conventional therapy cytotoxic design developmental disease diffuse midline glioma effector T cell efficacy testing fighting gene repair genome integrity high reward high risk immune cell infiltrate in vitro Assay ineffective therapies insertion/deletion mutation loss of function mutation melanoma mouse model mutant nervous system disorder novel novel therapeutic intervention pediatric patients prognostic programmed cell death ligand 1 public health relevance receptor response side effect standard of care temozolomide therapy resistant transcriptome transcriptome sequencing tumor tumor microenvironment tumor progression tumor-immune system interactions

项目摘要

Abstract: Pediatric brain tumors are the leading cause of childhood cancer-related death1. The overall survival for pediatric lymphoblastic leukemia is over 90% at 5 years 2. In stark contrast, the overall survival of children with pediatric high-grade gliomas (pHGG) is less than 20% at 5-years. Remarkable progress has been made over the last decade in elucidating the origin and genomic landscape of childhood brain tumors 3. Despite these advances, pHGGs are mostly incurable, as current therapies rarely provide a greater survival benefit over the current standard of care, focal radiation. The few survivors with pHGG are often left with devastating side effects, including endocrine morbidity, psychiatric and neurocognitive impairments, developmental disorders, neurological disease, and a high incidence of secondary tumors4-6. These side effects further highlight the necessity of developing novel treatment modalities, ideally with minimal toxicity while maintaining significant prognostic outcomes for children with pHGG. Immune checkpoint inhibition (ICI) resulted in an unprecedented response rate in many cancer types, including cancers in advanced metastatic stages such as melanoma and non-small cell lung cancer 7-9. Unfortunately, ICI has largely failed to produce benefits in pHGG, with the exception of patients harboring constitutional mismatch repair (MMR) deficiency syndrome (CMMRD) 10-13. Based on limited data from literature and our preliminary observations, we hypothesize that biallelic germline MMR mutations in pHGG result in enhanced ICI response while somatic MMR mutations do not. We further hypothesize that stromal MMR mutations drive enhanced ICI response by reversing the immunosuppressive phenotype of innate immune cell called tumor-associated macrophages (TAMs) in the tumor microenvironment (TME). TAMs are the most-abundant non-neoplastic cell infiltrates in the TME and express the highest levels of PD-L114,15, a ligand for the programmed cell death-1 receptor (PD-1) on effector T-cells. To test our hypothesis, we developed genetic models of germline and somatic MMR mutant pHGG and propose to use these models to compare their expression profiles to human pHGG samples from CMMRD and non-CMMRD patients. We will also use these models to determine whether there is a casual link between germline biallelic MMR mutation and response to anti-PD-L1 therapy. The clinical benefits of this high-risk high-reward application are two-fold. First, it will establish whether there is a causal link between biallelic MMR mutation in pHGG and immunotherapy response. If the link exists it will contribute to our understanding of the primary resistance to checkpoint inhibitors in children with pHGG and subsequently, how to target such mechanisms. Second, CMMRD tumors are resistant to conventional therapies, since several common chemotherapeutic agents, including temozolomide, require adequate mismatch repair to exert their cytotoxic effects. Patients with CMMRD tumors thus require novel therapeutic strategies, and our studies will mechanistically establish whether or not ICI elicits an enhanced anti- tumor response in these tumors.

抽象的：儿童脑肿瘤是儿童癌症相关死亡的主要原因1。儿科的总生存率 5 岁时，淋巴细胞白血病的发病率超过 90% 2。形成鲜明对比的是，儿科儿童的总体生存率 5 年时，高级别胶质瘤 (pHGG) 的发生率低于 20%。过去一年取得了显着进展十年来阐明儿童脑肿瘤的起源和基因组景观 3。尽管取得了这些进展， pHGG 大多无法治愈，因为目前的疗法很少能比目前的疗法提供更大的生存益处标准护理，焦点辐射。 pHGG 的少数幸存者往往会留下毁灭性的副作用，包括内分泌疾病、精神和神经认知障碍、发育障碍、神经系统疾病，以及继发性肿瘤的发生率很高4-6。这些副作用进一步凸显了有必要开发新的治疗方式，理想情况下毒性最小，同时保持显着的效果 pHGG 儿童的预后结果。免疫检查点抑制（ICI）导致前所未有的许多癌症类型的缓解率，包括晚期转移阶段的癌症，如黑色素瘤和非小细胞肺癌7-9。不幸的是，ICI 基本上未能在 pHGG 中产生效益，患有体质错配修复 (MMR) 缺陷综合征 (CMMRD) 的患者除外 10-13。根据文献中的有限数据和我们的初步观察，我们假设双等位基因种系 pHGG 中的 MMR 突变会导致 ICI 反应增强，而体细胞 MMR 突变则不会。我们进一步假设基质 MMR 突变通过逆转免疫抑制来增强 ICI 反应肿瘤微环境中称为肿瘤相关巨噬细胞（TAM）的先天免疫细胞的表型（TME）。 TAM 是 TME 中最丰富的非肿瘤细胞浸润，表达最高水平的 PD-L114,15，效应 T 细胞上程序性细胞死亡 1 受体 (PD-1) 的配体。为了检验我们的假设，我们开发了种系和体细胞 MMR 突变体 pHGG 的遗传模型，并建议使用这些模型将它们的表达谱与来自 CMMRD 和非 CMMRD 患者的人类 pHGG 样本进行比较。我们将还使用这些模型来确定种系双等位基因 MMR 突变与对抗 PD-L1 治疗的反应。这种高风险高回报的应用的临床益处是双重的。第一的，它将确定 pHGG 中的双等位错配修复突变与免疫治疗之间是否存在因果关系回复。如果这种联系存在，它将有助于我们了解检查点抑制剂的主要耐药性在患有 pHGG 的儿童中，以及随后如何针对此类机制。二、CMMRD肿瘤具有耐药性与传统疗法相比，因为包括替莫唑胺在内的几种常见化疗药物需要充分的错配修复以发挥其细胞毒性作用。因此，患有 CMMRD 肿瘤的患者需要新的治疗策略，我们的研究将机械地确定 ICI 是否会引发增强的抗- 这些肿瘤中的肿瘤反应。