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：
10373241
负责人：
Dolores Hambardzumyan
金额：
$ 27.09万
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/10373241
关键词：
Address Adult Affect 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 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 Neurocognitive Deficit Non-Small-Cell Lung Carcinoma Outcome PD-L1 blockade PMS2 gene Pathway interactions Patients Phenotype 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 base 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 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 treatment response 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：小儿脑肿瘤是儿童与癌症相关死亡的主要原因1。小儿的整体生存淋巴细胞白血病在5年2年超过90％。在鲜明的对比中，儿童的总体存活率高级神经胶质瘤（PHGG）在5年时不到20％。最后取得了显着的进步阐明儿童脑肿瘤的起源和基因组景观的十年3。 PHGG大多是无法治愈的，因为当前的疗法很少能比当前提供更大的生存益处护理标准，焦点辐射。少数具有PHGG的幸存者通常会遭受毁灭性的副作用，包括内分泌发病率，精神病和神经认知障碍，发育障碍，神经疾病，次级肿瘤的高发病率为4-6。这些副作用进一步突出了需要开发新的治疗方式，理想情况下，具有最小的毒性，同时保持显着 PHGG儿童的预后结果。免疫检查点抑制（ICI）导致了前所未有的许多癌症类型的缓解率，包括在晚期转移性阶段的癌症，例如黑色素瘤和非小细胞肺癌7-9。不幸的是，ICI在很大程度上未能在PHGG中产生好处携带宪法不匹配修复（MMR）缺陷综合征（CMMRD）的患者例外为10-13。基于文献和我们的初步观察的有限数据，我们假设双重生殖器 PHGG中的MMR突变导致ICI响应增强，而体细胞MMR突变则没有。我们进一步假设基质MMR突变通过逆转免疫抑制来增强ICI响应先天免疫细胞的表型称为肿瘤微环境中的肿瘤相关巨噬细胞（TAM）（TME）。 TAM是TME中最丰富的非肿瘤细胞浸润，并表达最高水平 PD-L114,15，效应T细胞的编程细胞死亡-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MR突变体PHGG的遗传模型，并建议将这些模型用于将其表达谱与CMMRD和非CMMRD患者的人类PHGG样品进行比较。我们将还使用这些模型来确定种系双质MMR突变与对抗PD-L1治疗的反应。这种高风险高回报应用的临床益处是两倍。第一的，它将确定pHGG中的双重MMR突变与免疫疗法之间是否存在因果关系回复。如果存在链接，它将有助于我们理解对检查点抑制剂的主要抵抗力在患有PHGG以及随后的儿童中，如何针对此类机制。其次，CMMRD肿瘤具有抗性进行常规疗法，因为几种常见的化学治疗剂（包括替莫唑胺）需要足够的不匹配修复以发挥其细胞毒性作用。因此，CMMRD肿瘤患者需要新颖治疗策略，我们的研究将机械地确定ICI是否引起了增强的抗反抗这些肿瘤中的肿瘤反应。