Advancing treatment and understanding of immunotherapy in glioblastoma

促进胶质母细胞瘤免疫疗法的治疗和理解

基本信息

批准号：
10487522
负责人：
Nicholas A Butowski
金额：
$ 82.2万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-10 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10487522
关键词：
Address Adult Antibody Therapy Antigens Back Biological Assay Biological Markers Biotechnology Blood - brain barrier anatomy Brain Brain Neoplasms Cell Therapy Cells Characteristics Clinic Clinical Clinical Investigator Clinical Treatment Clinical Trials Collaborations Combination immunotherapy Comprehensive Cancer Center Cytotoxic Chemotherapy Development Devices Dose Doxorubicin Drug Kinetics Failure Family Fostering Funding Genetic Glioblastoma Goals Grant Hematologic Neoplasms Heterogeneity Homing Immune Immune checkpoint inhibitor Immune response Immunologic Monitoring Immunotherapy Industry Institution International Investigation Knowledge Laboratories Lead MAP Kinase Gene Malignant Neoplasms Mediating Modeling Mus Neoadjuvant Therapy Operative Surgical Procedures Organ Patient-Focused Outcomes Patients Peripheral Pharmaceutical Preparations Pharmacotherapy Pilot Projects Population Pre-Clinical Model Primary Brain Neoplasms Prior Therapy Prognostic Marker Quality of life Radiation Recurrence Research Research Personnel Research Project Grants Resected Resources Role Safety Scientist Site Solid Neoplasm Sonication Structure System T-Lymphocyte Technology Testing Therapeutic Tissues Toxic effect Translating Translational Research Treatment Efficacy Tumor Tissue United States National Institutes of Health Universities anti-PD-1 anti-PD1 therapy base bevacizumab blood-brain barrier disruption brain tissue checkpoint therapy chemotherapy chimeric antigen receptor chimeric antigen receptor T cells clinical development clinical investigation clinical translation cohort combinatorial design early phase clinical trial electric field epidermal growth factor receptor VIII exhaustion experience first-in-human immune checkpoint blockade immunogenic immunoregulation immunotherapy clinical trials improved in vivo in vivo evaluation innovation neoplasm immunotherapy neoplastic cell neuro-oncology notch protein novel oncology program patient population personalized medicine pre-clinical predictive marker prevent prospective response targeted treatment temozolomide translational scientist tumor tumor heterogeneity tumor-immune system interactions ultrasound

项目摘要

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.

摘要/摘要免疫疗法对于治疗胶质母细胞瘤有着巨大的前景；但胶质母细胞瘤的某些特征仍然存在。在此，两个经验丰富的跨学科实验室和临床团队提出了固有的治疗挑战。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罗伯特·H·卢里综合癌症中心携手开发创新免疫疗法该提案利用行业和机构的支持来实现三个具体目标：1) 提高我们对免疫治疗方法在胶质母细胞瘤中的作用的理解；2) 提高我们的认识；了解如何克服血脑屏障的限制以及3）开发创新胶质母细胞瘤的免疫疗法，以及针对患有胶质母细胞瘤的患者的相关早期临床试验来自复发性胶质母细胞瘤。项目 1 由西北大学协调，将以该团队在小鼠脑肿瘤模型中的临床前结果为基础证明免疫检查点抑制剂治疗时具有免疫调节和敏化作用先给予免疫原性剂量的阿霉素，这种效果可以通过超声进一步增强 BBB 开放。由创新生物技术公司（Agenus、阿斯利康、Carthera）提供药物或支持用于临床前和临床研究的设备以及特定的专业知识、分析和技术两个机构的调查使这次合作成为一个非常强大的联盟随后的临床试验。将研究新型抗 PD1 检查点抑制剂巴司替利单抗 (balstilimab) 与多柔比星 (doxorubicin) 的结合，以及无需超声处理即可打开血脑屏障通过在手术前进行免疫治疗（诱导治疗、新辅助治疗）免疫效应使我们能够评估切除大脑的体内免疫反应我们之前已将 pERk/MAPK 激活确定为抗 PD1 治疗获益的生物标志物。在复发性胶质母细胞瘤中；将进一步探索四个前瞻性治疗队列。将使用或不使用诱导治疗，以及使用或不使用 BBB 打开进行治疗。包括免疫反应（肿瘤组织、外周）和药物组织浓度。项目 2 由 UCSF 协调，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 细胞回路基于“启动并杀死”策略来识别肿瘤细胞。该系统是唯一在 GBM 细胞 (EGFRvIII) 上表达的第一个抗原，它使 T 细胞做好准备诱导识别 IL-13Rα2 和 EphA2 的 CAR 表达，从而消除表达的 GBM 细胞 EphA2 或 IL-13α2 的团队重新认识到 synNotch CART 细胞可以彻底改变 CART。通过克服肿瘤外毒性、抗原异质性和 CART 的挑战来治疗胶质母细胞瘤因此，这些 synNotch-CART 细胞被认为比 synNotch-CART 细胞更有效。传统的、组成型表达的 IL-13Rα2/EphA2 CART 细胞的研究人员将优化其功效。主导药物，并在此类新型胶质母细胞瘤药物的首次人体临床试验中检验了这一假设患者。该 U19 提案还预留了资金来支持极其重要的跨 GTN 试点项目，以及两个核心（管理、免疫监测和生物样本）将支持这两个项目的工作。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准确性。改变胶质母细胞瘤免疫疗法的理解和使用方式的可能性。本提案中描述的研究将利用由有能力的人聚集的特殊资源。由加州大学旧金山分校和西北大学的临床和基础科学家组成的合作小组。