Experimental Therapy for Brain Tumors

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，比肾癌或黑色素瘤的死亡人数更多。此外，委员会认为， 目前的治疗是失能性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， 药物已被批准用于临床使用，并且本申请中涉及的肿瘤仍然是一致的。 致命的本PPG的总体目标是开发全新的疗法或改善现有的新疗法。 通过更好地了解患者对免疫和免疫应答的免疫生物学， 肿瘤和治疗，以实现GBM患者的生存期延长，而没有伴随的毒性。内 为了实现这一总体目标，我们集中精力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。在三项拟议的临床试验中，我们将重点加强 免疫治疗通过更有效的平台，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的 不同的平台。重要的是，这个PPG利用了一个由资深科学家组成的非凡团队， 历史的合作和成功的转化研究，以实现这些目标。项目1，由 约翰·桑普森将根据他最近发表的试点试验进行第二阶段试验， 在肿瘤靶向DC之前用破伤风/白喉（Td）回忆抗原预处理疫苗部位 针对巨细胞病毒（CMV）抗原的疫苗接种显示在肿瘤内显著地重新活化， GBM患者的OS延长。这项2期试验将在一个更大的群体中验证这些初步发现， 患者此外，本试验还将纳入一种新型的、全人源的、临床批准的抗CD 27 mAb 同时减少免疫抑制，并通过伴随的调节性T 细胞耗竭和CD 27共刺激。项目2，由迈克尔古恩，评估一个完全小说， 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， 将导致稳健的抗肿瘤抗原特异性T细胞应答。由Darell Bigner领导的项目3将进行一次 基于重组溶瘤脊髓灰质炎病毒的有前景的1期工作的2期临床试验，以阐明 这种疗法产生抗肿瘤免疫应答的机制，并检查这种疗法的协同作用。 与化学治疗剂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），临床试验和成像基础设施（核心2），以及相关研究和 免疫监测专业知识（核心3）。虽然提出的个别疗法是多种多样的，我们的中心 脑肿瘤免疫治疗的主题，我们的小组专注于隔离和解决关键的局限性 预防GBM的成功免疫治疗，创建一个高度协同和综合的计划， 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.