Generating a Systemic Immune Response Using Localized Delivery of Chemotherapy in Brain Tumors

使用脑肿瘤局部化疗产生全身免疫反应

基本信息

批准号：
10653808
负责人：
Michael Lim
金额：
$ 35.93万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-06-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10653808
关键词：
Acceleration Address Adult Antigen Presentation Antigen-Presenting Cells Antigenic Diversity Antigens Apoptosis Automobile Driving Brain Neoplasms Carmustine Cell Communication Cell Migration Induction Cervical lymph node group Chemoresistance Chemotherapy-Oncologic Procedure Clinical Clinical Trials Clone Cells Complement Conflict (Psychology)DNA DNA Damage Data Deep Cervical Lymph Node Dendritic Cells Dependence Failure Flow Cytometry Foundations Gliadel Glioblastoma Glioma Goals Immune Evasion Immune response Immune system Immunosuppression Immunotherapeutic agent Immunotherapy Infiltration Institution Investigation Knowledge Laboratories Location Lymphopenia MGMT gene Malignant Neoplasms Malignant neoplasm of brain Malignant neoplasm of lung Measures Mediating Mismatch Repair Modality Modeling Mus Mutation Myelosuppression Newly Diagnosed Nivolumab Outcome Patient Care Patients Peripheral Phase II Clinical Trials Phenotype Population Positioning Attribute Pre-Clinical Model Prognosis Radiation Recurrence Regimen Renal Cell Carcinoma Reporting Role Solid Neoplasm Specimen T memory cell T-Cell Receptor T-Lymphocyte TAP1 gene Testing Therapeutic Transfection Treatment Efficacy Treatment Protocols Tumor Antigens Tumor Cell Necrosis Tumor Immunity anti-CTLA4 anti-PD-1 anti-PD1 antibodies anti-PD1 therapy anti-tumor immune response antigen detection biomarker identification cancer immunotherapy cancer type checkpoint inhibition chemokine chemotherapy clinical practice clinically relevant detection assay efficacy testing experimental study gene repair immune checkpoint blockade immune function improved insight melanoma migration mouse model neoantigens neoplastic cell novel novel strategies phase II trial potential biomarker pre-clinical preclinical study predicting response preservation responders and non-responders response response biomarker standard care standard of care synergism temozolomide tumor

项目摘要

Glioblastoma (GBM) is the most common primary malignant brain tumor in adults and is associated with a dismal prognosis. Immunotherapy has demonstrated potential to generate durable antitumor activity in other types of cancer. In particular, agents that selectively target checkpoint molecules, such as anti-CTLA-4 and anti-PD-1 antibodies, have accelerated the field of cancer immunotherapy by directly combating the tumor's mechanisms of immune evasion. Notable results with these agents have already been reported in advanced melanoma, renal cell carcinoma, and lung cancer and trials are underway in GBM. Chemotherapy, which is part of the standard of care for patients with GBM, has been associated with immunosuppressive effects and with myeloablative results. Recent data from our laboratory shows that local chemotherapy may be a better alternative to systemic chemotherapy given that it avoids these untoward effects. The main goal of this proposal is to understand the main mechanisms by which GBM evades the immune system and how to thwart these mechanisms with local chemotherapy and checkpoint blockade to enhance an effective immune response against GBM. Our data demonstrates that local chemotherapy in combination with anti-PD-1 increases survival and provides an increase in memory T cells in an orthotopic glioma model and protects against tumor re-challenge. We propose to study: 1. Potential biomarkers of response in patients with GBM treated with LC and anti-PD-1 therapy as part of an ongoing clinical trial at our institution. 2. The neoantigen profile generated by LC in intracranial chemosensitive and chemoresistant murine gliomas, to determine the impact on TCR diversity and anti-tumor immune response. 3. The location and identity of APCs responsible for antigen presentation induced by LC. These data will have direct clinical relevance for the findings and can be translational into clinical trials and patient care. We expect that the data generated from these studies will provide novel insights into a previously unexplored aspect of chemotherapy and serve as a foundation for optimizing the efficacy of therapy and host immune function against GBM. The knowledge obtained from this study will undoubtedly result in better therapeutic alternatives for current unsuccessful treatment for patients with GBM.

胶质母细胞瘤（GBM）是成年人中最常见的原发性恶性脑肿瘤，与A有关令人沮丧的预后。免疫疗法表明，在其他癌症类型。特别是，选择性靶向检查点分子的药物，例如抗CTLA-4和抗PD-1抗体，通过直接对抗肿瘤的癌症加速了癌症免疫疗法的领域免疫逃避机制。这些代理的显着结果已经在高级报告中报道黑色素瘤，肾细胞癌和肺癌以及试验正在GBM中进行。化学疗法，就是 GBM患者的一部分护理标准与免疫抑制作用和有骨髓性的结果。我们实验室的最新数据表明，局部化疗可能会更好鉴于它避免了这些不良影响，因此可以替代全身化疗。主要目标建议是了解GBM逃避免疫系统的主要机制以及如何阻止这些机制具有局部化疗和检查点阻滞，以增强有效的免疫对GBM的响应。我们的数据表明，局部化疗与抗PD-1结合提高生存率并在原位神经胶质瘤模型中增加记忆T细胞的增加并保护反对肿瘤重新挑战。我们建议研究：1。GBM患者的反应潜在生物标志物用LC和抗PD-1治疗作为我们机构正在进行的临床试验的一部分。 2。新抗原 LC在颅内化学敏感和化学疗法的鼠神经胶质瘤中产生的特征，以确定对TCR多样性和抗肿瘤免疫反应的影响。 3。负责APC的位置和身份 LC诱导的抗原表现。这些数据将与调查结果具有直接的临床相关性，并且可以是转化为临床试验和患者护理。我们希望从这些研究中产生的数据将提供对化疗的先前未开发方面的新见解，并作为基础优化治疗和宿主免疫功能对GBM的功效。从中获得的知识研究无疑会为患者提供当前失败治疗的更好的治疗方法与GBM。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Overcoming EGFR inhibitor resistance in Glioblastoma by targeting co-amplified genes.

DOI：
10.1073/pnas.2312277120
发表时间：
2023-09-19
期刊：
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
影响因子：
11.1
作者：
Pant, Ayush;Lim, Michael
通讯作者：
Lim, Michael