Advancing treatment and understanding of immunotherapy in glioblastoma

摘要/摘要 免疫疗法对治疗胶质母细胞瘤大有可为；然而，胶质母细胞瘤的某些特征 提出了固有的治疗挑战。在这里，两个经验丰富的跨学科实验室和临床团队 在加州大学旧金山分校海伦·迪勒家庭综合癌症中心和西北大学的罗伯特·H·卢里 综合癌症中心共同努力开发创新的免疫治疗方法 胶质母细胞瘤。该提案利用行业和机构的支持来解决三个具体目标：1) 提高我们对免疫治疗方法在胶质母细胞瘤中的作用的了解；2)改善我们的 认识如何克服血脑屏障的局限性；3)开拓创新 胶质母细胞瘤的免疫治疗，相关的早期临床试验集中在患者身上 死于复发的胶质母细胞瘤。 由西北大学协调的项目1将以该团队在小鼠脑瘤模型上的临床前结果为基础 当免疫检查点抑制剂治疗时表现出免疫调节和致敏效应 在免疫剂量阿霉素之前，这种效果可以通过基于超声波的进一步增强 BBB开启。由创新型生物技术公司(Agenus、阿斯利康、CarThera)提供支持，提供药物或 用于临床前和临床研究的设备以及特定的专门知识、分析和技术 这两个机构都进行了调查，使这一合作成为一个非常强大的财团。随后的临床试验 将研究新型抗PD1检查点抑制剂balstilimab与阿霉素联合使用， 没有为BBB打开而发出声响。通过在手术前给予免疫疗法(诱导疗法， 新辅助治疗)免疫效果使我们能够评估切除的大脑中的体内免疫反应 组织。我们之前已经确定PERK/MAPK激活是从抗PD1治疗中受益的生物标志物 在复发的胶质母细胞瘤中；这个和其他标记物将被进一步探索。四个前瞻性治疗的队列 将接受和不接受诱导治疗，以及接受和不接受血脑屏障开放治疗。转换端点 包括免疫反应(肿瘤组织、外周血)和药物组织浓度。 项目2是由加州大学旧金山分校协调进行的，是一项基于令人兴奋的新型合成Notch“synNotch”受体的研究 CART系统和开创性的T细胞电路，基于“先启动后杀死”的策略识别肿瘤细胞。在……里面 这个系统是第一个抗原，它只在GBM细胞(EGFRvIII)上表达，使T细胞启动 诱导识别IL-13Rα2和EphA2的CAR表达，从而根除表达 要么是EphA2，要么是IL-13α2。项目2的S团队假设SynNotch CART细胞可以使CART细胞发生革命性变化 克服肿瘤外毒性、抗原异质性和CART挑战的胶质母细胞瘤治疗 细胞耗尽。因此，这些SynNotch-Cart细胞被假设为比 常规、组成性表达IL-13Rα2/EphA2的CART细胞。调查人员将优化药效 先导剂并在首次人类临床试验中验证这一假说，这类新的药物治疗胶质母细胞瘤 病人。 这项U19提案还拨出资金，用于支持非常重要的跨GTN试点项目，以及 两个核心(行政、免疫监测和生物监测)将支持这两个项目的努力。 通过解决所描述的总体具体目标，本U19申请中提出的研究具有很高的 改变免疫治疗在胶质母细胞瘤中被理解和使用的可能性。创新的 这项建议中描述的研究将利用油井- 加州大学旧金山分校和西北大学建立了由临床和基础科学家组成的协作小组。

SUMMARY/ABSTRACT Immunotherapy holds great promise for the treatment of glioblastoma; still, certain characteristics of glioblastoma present inherent therapeutic challenges. Herein, two experienced interdisciplinary laboratory and clinical teams at UCSFs Helen Diller Family Comprehensive Cancer Center and Northwestern University's Robert H. Lurie Comprehensive Cancer Center join efforts to develop innovative immunotherapy approaches against glioblastoma. This proposal leverages industry and institutional support to address three specific objectives: 1) to improve our understanding of the role of immunotherapy approaches in glioblastoma; 2) to improve our understanding of how to overcome the limitation the blood brain barrier and 3) to develop innovative immunotherapy treatments for glioblastoma, with associated early clinical trials focused on patients suffering from recurrent glioblastoma. Project 1, coordinated from Northwestern, will build on the team's preclinical results in mouse brain tumor models demonstrating an immunomodulatory and sensitization effect when immune checkpoint inhibitor therapy is preceded by a immunogenic dose of doxorubicin, an effect that can be further enhanced by ultrasound-based BBB opening. Support by innovative biotech companies (Agenus, AstraZeneca, Carthera) provide drugs or devices for preclinical and clinical investigation as well as specific expertise, assays and technology for investigations at both institutions, making this collaboration a very powerful consortium. The ensuing clinical trial will investigate the novel anti-PD1 checkpoint inhibitor balstilimab in conjunction with doxorubicin, with and without sonication for BBB opening. By administration of immune therapy prior to surgery (induction therapy, neoadjuvant treatment) the immune effect enables us to evaluate in vivo immune response in the resected brain tissue. We have previously identified pERk/MAPK activation as a biomarker for benefit from anti-PD1 treatment in recurrent glioblastoma; this and other markers will be explored furthermore. Four prospectively treated cohorts will be treated with and without induction therapy, and with and without BBB opening. Translational endpoints include immune response (tumor tissue, peripheral) and drug tissue concentration. Project 2, coordinated from UCSF, is a study based on the exciting novel synthetic Notch “synNotch” receptor CART system and pioneering T cell circuits that recognize tumor cells based on a “prime-and-kill” strategy. In this system, the first antigen, which is expressed exclusively on GBM cells (EGFRvIII), primes the T cells to induce expression of a CAR that recognizes IL-13Rα2 and EphA2, thereby eradicating GBM cells expressing either EphA2 or IL-13α2. Project 2's team hypothesizes that synNotch CART cells can revolutionize the CART therapy for glioblastoma by overcoming the challenges of off-tumor toxicity, antigen heterogeneity, and CART cell exhaustion. Thus, these synNotch-CART cells are hypothesized to be significantly more efficacious than conventional, constitutively expressed IL-13Rα2/EphA2 CART cells. Investigators will optimize the efficacy of the lead agent and test this hypothesis in the first in human clinical trial of this new class of agents in glioblastoma patients. This U19 proposal also has set aside funds for support of the distinctly important trans-GTN pilot projects, and for two cores (Administrative, Immune Monitoring & Biospecimen) that will support the efforts of the two projects. By addressing the overall specific objectives described, the research proposed in this U19 application has a high likelihood of changing the way immunotherapy is understood and utilized in glioblastoma. The innovative research described in this proposal will take advantage of the exceptional resources assembled by the well- established, collaborative group of clinical and basic scientists at UCSF and Northwestern.