Proj. 1 Targeting Tumor-Specific Neoepitopes for Glioblastoma Immunotherapy

项目。

基本信息

批准号：
10684012
负责人：
DAVID A REARDON
金额：
$ 56.49万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-03 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10684012
关键词：
Address Affect Antigen Targeting Antigens CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes Cells Clinical Clinical Trials Clonality Collaborations Combined Modality Therapy Computer Analysis Dana-Farber Cancer Institute Data Development Diagnosis Effector Cell Exhibits Gene Expression Generations Glioblastoma Immune Immune response Immunize Immunofluorescence Immunologic Immunologic Adjuvants Immunologics Immunosuppression Immunotherapeutic agent Immunotherapy Impact evaluation Malignant - descriptor Malignant Neoplasms Malignant neoplasm of brain Manuscripts Memory Mutation Nature Newly Diagnosed Oncology Operative Surgical Procedures Outcome PD-1 blockade Patient-Focused Outcomes Patients Peptides Peripheral Blood Mononuclear Cell Phase Ib Clinical Trial Phase Ib Trial Phenotype Pilot Projects Poly ICLC Population Production Radiation Radiation therapy Recurrence Research Personnel Resources Rest Safety Sampling Schedule Signal Transduction Specificity Statistical Data Interpretation T cell infiltration T cell response T memory cell T-Cell Immunologic Specificity T-Lymphocyte Therapeutic Tumor Antigens Tumor Tissue Tumor-infiltrating immune cells Up-Regulation Vaccinated Vaccination Vaccines Work anti-PD-1 anti-PD1 therapy anti-tumor immune response antigen-specific T cells cancer infiltrating T cells central tolerance cohort design effector T cell exhaustion high risk immunogenic immunogenicity immunoregulation improved outcome long term memory melanoma mutant neoantigen vaccination neoantigen vaccine neoantigens novel palliative peripheral blood preservation programmed cell death protein 1 response transcriptome tumor tumor heterogeneity tumor microenvironment tumor specificity vaccine platform vaccine strategy

项目摘要

Catherine J. Wu, MD and David A. Reardon, MD Project 1: Personalized Neoantigen Vaccination and Anti-PD-1 Therapy for Glioblastoma Summary Current therapies for glioblastoma (GBM), the most common malignant primary brain cancer, remain palliative. These tumors have responded poorly to single agent immunotherapy approaches due to several factors including the fact that GBM is an immunologically cold tumor with a paucity of effector T cells infiltrating the tumor microenvironment. We have developed a personalized tumor neoantigen-targeting vaccine strategy (NeoVax) based on robust analytic sequencing pipelines and have demonstrated marked CD4+ and CD8+ T cell responses to vaccinated neoepitope peptides among patients with high-risk melanoma (Ott & Hu, Nature, 2017) and with newly diagnosed GBM (Reskin et al., Nature 2019). Furthermore, in collaboration with investigators from Project 3, we demonstrated that NeoVax induced a marked influx of intratumoral immune effector cells, including CD4+ T cells with specificity to an immunizing neoepitope into the GBM tumor microenvironment. We now extend this work by conducting a second trial in which NeoVax will be combined with anti-PD-1 therapy for GBM patients based on our observation that anti-PD-1 therapy broadened anti-tumor immune responses among our melanoma patients treated with NeoVax. We have designed our trial to address the key question whether timing of PD-1 blockade relative to neoantigen priming with NeoVax affects T cell memory responses, based on recent work by Dr. Sharpe (Project 2) demonstrating that PD-1 signaling critically regulates long-term T cell memory. We hypothesize anti-PD-1 therapy will improve outcome for GBM patients undergoing NeoVax therapy and that timing of PD-1 blockade relative to tumor neoantigen priming with NeoVax will critically influence the generation of polyfunctional, long-term memory T cell responses. We will evaluate these hypotheses in work organized into three specific aims. In Aim 1, we will evaluate the administration of PD-1 blockade either before or after NeoVax priming in a phase 1b trial for newly diagnosed GBM patients who are treated with standard radiotherapy. We will evaluate the strength, breadth and state of circulating neoantigen-specific T cell responses relative to timing of PD-1 blockade including long-term T cell memory responses among patients treated on this trial in Aim 2. We will similarly interrogate the composition and functional states of tumor infiltrating immune cells before and after NeoVax plus anti-PD-1 therapy in Aim 3. T cell immune responses for Aims 2 and 3 will be analyzed in Core 1, while Core 2 will perform the computational and statistical analyses of these data.

凯瑟琳·J·吴（Catherine J. 项目1：胶质母细胞瘤的个性化新抗原疫苗和抗PD-1疗法概括胶质母细胞瘤（GBM）的当前疗法，最常见的原发性脑癌，保持姑息性。这些肿瘤对单药免疫疗法的反应很差由于几个因素，方法包括GBM是一种免疫学冷肿瘤的事实由于效应T细胞缺乏渗透肿瘤微环境。我们已经开发了个性化肿瘤新抗原靶向疫苗策略（Neovax）基于强大的分析测序管道，并证明了明显的CD4+和CD8+ T细胞对高风险黑色素瘤患者中接种的新皮肽肽（Ott＆Hu，Nature，2017年）并有了新诊断的GBM（Reskin等人，自然，2019年）。此外，与来自项目3的调查人员，我们证明了Neovax引起了明显的涌入肿瘤内免疫效应细胞，包括具有特异性的CD4+ T细胞 NeoEpitope进入GBM肿瘤微环境。现在，我们通过执行第二次试验将基于GBM患者的Neovax与抗PD-1治疗结合我们认为抗PD-1治疗扩大了我们的抗肿瘤免疫反应黑色素瘤患者接受了新诺法治疗。我们设计了试验来解决关键问题 PD-1封锁的时间相对于新抗原启动的Neovax是否会影响T细胞记忆根据Sharpe博士（项目2）的最新工作，回答证明了PD-1信号传导批判性调节长期T细胞记忆。我们假设抗PD-1治疗将改善接受Neovax治疗的GBM患者的结果和PD-1阻滞的时间相对于肿瘤新抗原引发新抗原，将严重影响多功能，长期记忆T细胞反应。我们将评估这些假设工作成三个特定目标。在AIM 1中，我们将评估PD-1的管理在新诊断的GBM的1B期试验中，Neovax启动之前或之后的封锁接受标准放疗治疗的患者。我们将评估强度，广度和相对于PD-1封锁的时间，循环新抗原特异性T细胞反应的状态在AIM 2中，在此试验中接受治疗的患者中包括长期T细胞记忆反应。我们将类似地询问肿瘤浸润的免疫细胞的组成和功能态在AIM 3中Neovax加抗PD-1治疗后。目标2和3将在Core 1中进行分析，而Core 2将执行计算和统计分析这些数据。