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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）是成人中最常见的原发性恶性脑肿瘤，与脑癌相关