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.

Catherine J. Wu，医学博士和 David A. Reardon，医学博士项目1：胶质母细胞瘤个性化新抗原疫苗接种和抗PD-1治疗概括胶质母细胞瘤（GBM）是最常见的恶性原发性脑癌，目前的治疗方法保持姑息治疗。这些肿瘤对单药免疫疗法反应不佳由于多种因素的影响，包括 GBM 是一种免疫冷肿瘤这一事实缺乏浸润肿瘤微环境的效应 T 细胞。我们开发了一个基于稳健分析的个性化肿瘤新抗原靶向疫苗策略（NeoVax）测序流程，并已证明 CD4+ 和 CD8+ T 细胞对高危黑色素瘤患者接种新表位肽（Ott & Hu，Nature，2017）以及新诊断的 GBM（Reskin 等人，Nature 2019）。此外，与合作来自项目 3 的研究人员，我们证明 NeoVax 诱导了显着的涌入瘤内免疫效应细胞，包括具有免疫特异性的 CD4+ T 细胞新表位进入 GBM 肿瘤微环境。我们现在通过开展一项活动来扩展这项工作第二项试验基于 NeoVax 与抗 PD-1 疗法联合治疗 GBM 患者我们观察到抗 PD-1 疗法扩大了我们的抗肿瘤免疫反应接受 NeoVax 治疗的黑色素瘤患者。我们设计试验是为了解决关键问题 PD-1 阻断相对于 NeoVax 启动新抗原的时间是否会影响 T 细胞记忆响应，基于 Sharpe 博士（项目 2）最近的工作，证明 PD-1 信号传导关键调节长期 T 细胞记忆。我们假设抗 PD-1 疗法会有所改善接受 NeoVax 治疗的 GBM 患者的结果以及 PD-1 阻断的时机相对于用 NeoVax 引发的肿瘤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分为三个具体目标。在目标 1 中，我们将评估 PD-1 的给药在新诊断 GBM 的 1b 期试验中，在 NeoVax 启动之前或之后进行封锁接受标准放射治疗的患者。我们将评估强度、广度和循环新抗原特异性 T 细胞反应状态与 PD-1 阻断时间的关系包括在目标 2 中接受本试验治疗的患者中的长期 T 细胞记忆反应。我们将类似地询问肿瘤浸润免疫细胞的组成和功能状态在目标 3 中使用 NeoVax 加抗 PD-1 治疗后。目标 2 和 3 的 T 细胞免疫反应将在核心 1 中进行分析，而核心 2 将执行计算和统计分析这些数据。