Experimental Therapy for Brain Tumors

项目总结--总体 恶性原发脑瘤，如胶质母细胞瘤(GBM)，是最常见的癌症死亡原因 儿童和年轻人的死亡人数超过了肾癌或黑色素瘤患者。此外， 目前的治疗方法是无能为力，并受到非特异性毒性的限制。尽管进行了数百次临床试验，但很少有 药物已被批准用于临床，本申请中涉及的肿瘤保持统一。 致命的。PPG的总体目标是开发全新的治疗方法或改进现有的新药 通过更好地了解患者对两种疾病的免疫生物学反应的治疗方法 肿瘤和治疗可延长GBM患者的生存期而不伴随毒性。在 在这一总体目标中，我们的重点是消除迄今制约成功的关键障碍 针对脑肿瘤的免疫治疗。在三项拟议的临床试验中，我们将重点加强 通过更有效的平台进行免疫治疗，通过减少免疫抑制，通过调节 肿瘤微环境，并通过了解免疫介导的机制激活 不同的平台。重要的是，这一PPG利用了一群非凡的资深科学家，他们拥有长期的 合作历史和成功的翻译研究，以实现这些目标。项目1，由 John Sampson将根据他最近公布的试点试验进行第二阶段试验，该试验证明 在肿瘤靶向DC之前用破伤风/白喉(TD)召回抗原对疫苗部位进行预处理 针对巨细胞病毒(CMV)抗原的疫苗接种被证明在肿瘤内显著地重新激活 GBM患者的扩展OS。该第二阶段试验将在一个更大的小组中验证这些试验结果 病人。此外，这项试验还将加入一种新型的、完全人类的、临床批准的抗CD27单抗。 这同时减少了免疫抑制并通过伴随的调节性T细胞加强了疫苗接种 细胞耗竭和CD27共刺激。由Michael Gunn领导的项目2评估了一部全新的小说和 非常有效的细胞疫苗策略，并检查单核细胞疫苗在人类中是否安全和 将导致强大的抗肿瘤抗原特异性T细胞反应。项目3，由Darell Bigner领导，将进行 基于有希望的第一阶段的第二阶段临床试验与重组溶瘤脊髓灰质炎病毒合作，以阐明 这种疗法产生抗肿瘤免疫反应的机制，并检查其协同作用 联合应用化疗药物洛莫司汀。这些项目将由一个 管理核心，以及提供生物统计和生物信息学的三个共享资源核心 资源(核心1)、临床试验和成像基础设施(核心2)以及相关研究和 免疫监测专门知识(核心3)。虽然建议的个体化疗法多种多样，但我们的中心 脑瘤免疫治疗的主题，我们小组专注于隔离和解决关键限制 预防成功的GBM免疫治疗，创建了一个高度协同和综合的计划，作为一个 统一的计划将比单独执行的每个项目取得更大的成果。

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.