Identification and cloning of neoantigen-specific T cells for GBM immunotherapy

用于 GBM 免疫治疗的新抗原特异性 T 细胞的鉴定和克隆

基本信息

批准号：
10375387
负责人：
Robert M Prins
金额：
$ 40.25万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
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：
2019-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10375387
关键词：
Alternative Splicing Animals Antigens Bar Codes Bioinformatics Blood Brain Brain Neoplasms CD8-Positive T-Lymphocytes Cell Separation Cells Clinical Clinical Trials Cloning Code Custom Data Dendritic Cells Development Disease Effectiveness Engineering Epitopes Frequencies Glioblastoma Glioma Health Human Immune Immune response Immunocompetent Immunologics Immunology Immunotherapeutic agent Immunotherapy Individual Lead Malignant Glioma Malignant Neoplasms Modeling Monoclonal Antibodies Mus Mutation Neoadjuvant Therapy Nucleic Acids Oncology Operative Surgical Procedures Patients Phase I Clinical Trials Phase III Clinical Trials Physiologic pulse Population Pre-Clinical Model RNA Splicing Randomized Recurrence Sampling Somatic Mutation Specimen T cell response T-Lymphocyte Testing Translational Research Tumor Antigens Tumor Biology Tumor Immunity Vaccination Vaccines Variant anti-PD1 antibodies anti-tumor immune response base bioinformatics pipeline bioinformatics tool design exome innovation insight mRNA Precursor melanoma mouse model nanoparticle neoantigens neoplasm immunotherapy neoplastic cell neuro-oncology next generation sequencing novel peripheral blood preclinical study programmed cell death protein 1 synthetic peptide transcriptome sequencing transcriptomics tumor vaccination strategy

项目摘要

SUMMARY/ABSTRACT The lack of effective glioblastoma treatments poses a significant health problem and highlights the need for novel and innovative approaches. Immunotherapy is an appealing strategy because of the potential ability for immune cells to traffic to and destroy infiltrating tumor cells in the brain. New information suggests that patients mounting immune responses after immunotherapy preferentially recognize novel neoantigens created by tumor-specific mutations. Our data, and that from other immunotherapeutic strategies for patients with cancer, suggest that the vast majority of tumor-specific T cells induced by such personalized, patient-specific immunotherapies do NOT recognize well-characterized, known antigens. Such information is consistent with recent data from other immune-responsive cancers, such as melanoma, in which the percentage of tumor-specific T cells recognizing known antigens was less than 1%. In order to design the most effective immunotherapeutic strategies for glioblastoma, we believe that it is critical to understand which antigens tumor-specific T cells recognize in this disease. Our hypothesis is that glioblastoma patients treated with immunotherapy will mount anti-tumor immune responses against specific mutations and splice variants in their individual tumors. Similarly, our other recent findings strongly suggest that the addition of PD-1 antibody (mAb) blockade to DCVax enhances both the intra-tumoral CD8+ T cell response and clinical benefit in pre-clinical studies. Furthermore, the timing of PD-1 mAb blockade is immunologically relevant; our unpublished, recent clinical trial results highlight how the neoadjuvant (prior to surgery) treatment with PD-1 mAb blockade induces enhanced anti-tumor immune responses and clinical benefit. We hypothesize that the addition of PD-1 mAb blockade should amplify the neoantigen-specific T cell response induced by DC vaccination, both in the blood and the tumor. To test these important questions, In Aim 1, we will develop a new bioinformatics pipeline to predict neoantigens that arise specifically from the types of genetic alterations that occur in GBM. In Aim 2, will create immunocompetent murine glioma models to test the importance of neoantigens. Finally, in Aim 3, we will identify neoantigen-specific T cells from both the TIL population and peripheral blood of GBM patients treated with immunotherapy. These studies span the continuum of translational research in brain tumor immunotherapy and will likely provide informative new insights for the development of new, rational immune-based strategies for brain tumor patients.

摘要/摘要缺乏有效的胶质母细胞瘤治疗带来了重大的健康问题，并突出了对新颖的需求和创新的方法。免疫疗法是一种有吸引力的策略，因为潜在的免疫能力细胞以交通并破坏大脑中浸润的肿瘤细胞。新信息表明患者安装免疫疗法后的免疫反应优先识别由肿瘤特异性产生的新型新抗原突变。我们的数据，以及来自癌症患者的其他免疫治疗策略的数据，表明这种个性化的，患者特定的免疫疗法诱导的绝大多数肿瘤特异性T细胞不要识别特征良好的已知抗原。此类信息与来自的最新数据一致其他免疫反应性癌症，例如黑色素瘤，其中肿瘤特异性T细胞的百分比识别已知的抗原小于1％。为了设计最有效的免疫治疗性胶质母细胞瘤的策略，我们认为了解哪些抗原肿瘤特异性T细胞至关重要认识到这种疾病。我们的假设是，接受免疫疗法治疗的胶质母细胞瘤患者将针对特定突变和剪接变体的抗肿瘤免疫反应安装抗肿瘤免疫反应肿瘤。同样，我们最近的其他发现强烈表明添加了PD-1抗体（MAB）阻滞为了达到DCVAX，在临床前研究中增强了肿瘤内CD8+ T细胞反应和临床益处。此外，PD-1 MAB阻滞的时机在免疫学上是相关的。我们未发表的最近临床试验结果强调了新辅助（手术前）如何使用PD-1 MAB封锁治疗如何诱导增强抗肿瘤免疫反应和临床益处。我们假设添加了PD-1 MAB封锁应在血液中扩增DC疫苗接种诱导的新抗原特异性T细胞反应和肿瘤。为了测试这些重要问题，在AIM 1中，我们将开发新的生物信息学管道预测GBM中发生的遗传改变类型的新抗原。在AIM 2中，将创建免疫能力的鼠神经胶质瘤模型来测试新抗原的重要性。最后，在AIM 3中，我们将鉴定已治疗的GBM患者的TIL群体和外周血的新抗原特异性T细胞免疫疗法。这些研究涵盖了脑肿瘤免疫疗法转化研究的连续性并可能为开发新的，理性免疫的策略提供信息的新见解脑肿瘤患者。