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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：
10599231
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 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10599231
关键词：
Alternative Splicing Animals Antigen Targeting 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 Infiltration 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 antigen-specific T cells bioinformatics pipeline bioinformatics tool candidate identification design exome innovation insight mRNA Precursor melanoma mouse model nanoparticle neoantigens neoplasm immunotherapy neoplastic cell neuro-oncology neurosurgery 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/文摘