Experimental Therapy for Brain Tumors

脑肿瘤的实验治疗

• 批准号: 10005980
• 负责人: David M. Ashley
• 金额: $ 253.68万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10005980
• 关键词: Address; Antigens; Basic Science; Bioinformatics; Biological; Biometry; Brain; Brain Neoplasms; CCL3 gene; Cancer Etiology; Cancer Vaccines; Cessation of life; Clinical; Clinical Data; Clinical Research; Clinical Trials; Clinical assessments; Collaborations; Communication; Correlative Study; Cytomegalovirus; Data; Dendritic Cells; Development; Diagnosis; Diagnostic radiologic examination; Diphtheria; Diphtheria Toxoid; Doctor of Medicine; Doctor of Philosophy; Dose; Ensure; Experimental Designs; Focus Groups; Generations; Glioblastoma; Goals; Harvest; Human; Immune; Immune response; Immunobiology; Immunologic Monitoring; Immunologics; Immunosuppression; Immunotherapeutic agent; Immunotherapy; Individual; Infrastructure; Investigational Therapies; Leadership; Link; Lomustine; Malignant - descriptor; Malignant Glioma; Malignant neoplasm of brain; Mediating; Monitor; Monoclonal Antibodies; Office of Administrative Management; Oncolytic poliovirus; Patients; Phase; Phase II Clinical Trials; Phase II/III Trial; Physiologic pulse; Primary Brain Neoplasms; Protocols documentation; Publishing; Randomized; Randomized Clinical Trials; Recombinants; Recording of previous events; Recurrence; Regulatory T-Lymphocyte; Renal carcinoma; Reporting; Research; Research Personnel; Resource Sharing; Safety; Sampling; Scientist; Senior Scientist; Site; Standardization; T cell response; T-Cell Depletion; Testing; Tetanus; Therapeutic; Therapeutic Trials; Tissues; Toxic effect; Translational Research; Tumor Antigens; Universities; Vaccination; Vaccines; Work; anti-tumor immune response; base; bioinformatics resource; cell motility; childhood cancer mortality; clinical imaging; clinical translation; dendritic cell vaccination; design; experience; improved; innovation; melanoma; monocyte; neoplasm immunotherapy; novel; novel strategies; novel therapeutic intervention; novel therapeutics; operation; patient population; patient response; phase II trial; pilot trial; preconditioning; prevent; programs; success; synergism; translational physician; tumor; tumor microenvironment; vaccine safety; young adult

PROJECT SUMMARY – Overall Malignant primary brain tumors, like glioblastoma (GBM), are the most frequent cause of cancer death in children and young adults and account for more deaths than cancer of the kidney or melanoma. Moreover, current therapy is incapacitating and limited by non-specific toxicity. Despite hundreds of clinical trials, few agents have been approved for clinical use, and the tumors addressed in this application remain uniformly lethal. The OVERALL GOAL of this PPG is to develop completely new therapies or to improve existing novel therapeutic approaches through a better understanding of the immunobiology of patient's response to both the tumor and the therapy to achieve prolonged survival in patients with GBM without concomitant toxicity. Within this overall goal, we have focused on eliminating the key barriers that have thus far restricted successful immunotherapy against brain tumors. In the three proposed clinical trials, we will focus on enhancing immunotherapy through more potent platforms, through reducing immunosuppression, through modulating the tumor microenvironment, and through understanding the immune-mediated mechanisms activated by the different platforms. Importantly, this PPG leverages an extraordinary group of senior scientists with a long history of collaboration and successful translational research to accomplish these goals. Project 1, led by John Sampson, will conduct a Phase 2 trial based on his recently published pilot trial demonstrating that preconditioning the vaccine site with tetanus/diphtheria (Td) recall antigens prior to tumor-targeted DC vaccination against Cytomegalovirus (CMV) antigens shown to be re-activated within the tumor dramatically extended OS in patients with GBM. This Phase 2 trial will validate these pilot findings in a larger group of patients. Furthermore, this trial will also incorporate a novel, fully human, clinically approved anti-CD27 mAb that simultaneously reduces immunosuppression and potentiates vaccination through concomitant regulatory T cell depletion and CD27 costimulation. Project 2, led by Michael Gunn, evaluates a completely novel and extraordinarily potent cellular vaccine strategy and examines if monocyte vaccination in humans is safe and will result in robust anti-tumor antigen-specific T cell responses. Project 3, led by Darell Bigner, will conduct a Phase 2 clinical trial based on the promising Phase 1 work with a recombinant oncolytic poliovirus, to elucidate mechanisms by which this therapy generates an anti-tumor immune response, and to examine the synergistic therapeutic combination with the chemotherapeutic lomustine. These projects will be supported by an Administrative Core, as well as three shared resource cores to provide Biostatistics and Bioinformatics resources (Core 1), Clinical Trials and Imaging infrastructure (Core 2), and Correlative Studies and Immune Monitoring expertise (Core 3). While the individual therapies proposed are diverse, our central theme of brain tumor immunotherapy, and our group focus on isolating and addressing the key limitations preventing successful immunotherapy for GBM, creates a highly synergistic and integrated Program that as a unified program will achieve greater results than each project performed in isolation.

项目概要——总体 恶性原发性脑肿瘤，如胶质母细胞瘤 (GBM)，是癌症死亡的最常见原因。 儿童和年轻人的死亡人数比肾癌或黑色素瘤还要多。而且， 目前的治疗是失能的并且受到非特异性毒性的限制。尽管进行了数百次临床试验，但很少 药物已被批准用于临床，并且本申请中涉及的肿瘤保持一致 致命。该 PPG 的总体目标是开发全新的疗法或改进现有的新疗法 通过更好地了解患者对两种药物反应的免疫生物学来制定治疗方法 肿瘤和实现 GBM 患者延长生存期且无伴随毒性的治疗方法。之内 为实现这一总体目标，我们重点消除迄今为止限制成功的关键障碍 针对脑肿瘤的免疫疗法。在拟议的三项临床试验中，我们将重点加强 通过更有效的平台、减少免疫抑制、调节 肿瘤微环境，并通过了解肿瘤细胞激活的免疫介导机制 不同的平台。重要的是，这个 PPG 拥有一群杰出的资深科学家，他们拥有长期的研究经验。 实现这些目标的合作历史和成功的转化研究。项目1，由 约翰·桑普森 (John Sampson) 将根据他最近发表的试点试验进行第二阶段试验，该试验表明 在肿瘤靶向 DC 之前用破伤​​风/白喉 (Td) 记忆抗原预处理疫苗位点 针对巨细胞病毒 (CMV) 抗原的疫苗接种显示在肿瘤内显着重新激活 GBM 患者的 OS 延长。该第二阶段试验将在更大的群体中验证这些试点结果 患者。此外，该试验还将纳入一种新型、全人源、临床批准的抗 CD27 mAb 通过伴随的调节 T 同时减少免疫抑制并加强疫苗接种 细胞耗竭和 CD27 共刺激。项目 2 由 Michael Gunn 领导，评估一部完全小说和 非常有效的细胞疫苗策略，并检查人类单核细胞疫苗接种是否安全 将导致强烈的抗肿瘤抗原特异性 T 细胞反应。由 Darell Bigner 领导的项目 3 将进行 2 期临床试验基于重组溶瘤脊髓灰质炎病毒的有希望的 1 期工作，以阐明 该疗法产生抗肿瘤免疫反应的机制，并检查协同作用 与化疗洛莫司汀的治疗组合。这些项目将得到一个 管理核心，以及三个共享资源核心，提供生物统计学和生物信息学 资源（核心 1）、临床试验和影像基础设施（核心 2）以及相关研究和 免疫监测专业知识（核心 3）。虽然提出的个体疗法多种多样，但我们的核心 脑肿瘤免疫治疗的主题，我们小组专注于隔离和解决关键局限性 阻止 GBM 免疫治疗的成功，创建了一个高度协同和综合的计划，作为 统一的计划将比单独执行的每个项目取得更好的成果。