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

• 批准号: 10689795
• 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
• 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/10689795
• 关键词: Acceleration; Address; Adult; Antibodies; 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; Dedications; 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; manufacture; neoplasm immunotherapy; neoplastic cell; neuro-oncology; notch protein; novel; patient population; personalized medicine; pre-clinical; predictive marker; prevent; programs; prospective; response; synergism; targeted treatment; temozolomide; translational scientist; tumor; tumor heterogeneity; tumor-immune system interactions; ultrasound

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 免疫疗法对治疗胶质母细胞瘤有很大的希望。尽管如此，胶质母细胞瘤的某些特征 当前的固有治疗挑战。在此，两个经验丰富的跨学科实验室和临床团队 在UCSFS Helen Diller家庭综合癌症中心和西北大学的Robert H. Lurie 全面的癌症中心加入努力开发针对的创新免疫疗法方法 胶质母细胞瘤。该提案利用行业和机构支持来解决三个具体目标：1） 为了提高我们对免疫疗法方法在胶质母细胞瘤中的作用的理解； 2）改善我们的 了解如何克服限制血液脑屏障和3）发展创新的 胶质母细胞瘤的免疫疗法治疗，相关的早期临床试验集中于患者 来自复发性胶质母细胞瘤。 从西北航空协调的项目1将以小组脑肿瘤模型的临床前结果为基础 当免疫检查点抑制剂治疗是 在先进的阿霉素剂量之前，这种作用可以通过超声基于超声进一步增强 BBB开放。创新的生物技术公司（Agenus，Astrazeneca，Carthera）提供毒品或 用于临床前和临床研究的设备以及特定的专业知识，测定和技术 这两个机构的调查使这项合作成为非常有力的财团。随后的临床试验 将研究新型的抗PD1检查点抑制剂Balstilimab与阿霉素，与和 没有BBB开放的社会。通过手术前的免疫治疗（诱导治疗， 新辅助治疗）免疫作用使我们能够评估切除的大脑中的体内免疫调节 组织。我们先前已经将PERK/MAPK激活识别为抗PD1治疗中受益的生物标志物 在复发性胶质母细胞瘤中；此和其他标记将被探索。四个前瞻性治疗的队列 将接受有或没有诱导疗法的治疗，并在有和不进行BBB开放的情况下进行治疗。翻译终点 包括免疫反应（肿瘤组织，周围）和药物组织浓度。 从UCSF协调的项目2是一项基于令人兴奋的小说合成档“ Synnotch”接收器的研究 CART系统和开创性的T细胞电路，这些电路基于“原始和杀死”策略识别肿瘤细胞。在 该系统是第一个抗原，仅在GBM细胞（EGFRVIII）上表达，将T细胞刺激为 诱导识别IL-13Rα2和EPHA2的汽车的表达，从而消除表达的GBM细胞 EPHA2或IL-13α2。 Project 2的团队假设Synnotch手推车单元可以革新购物车 通过克服非肿瘤毒性，抗原异质性和推车的挑战来治疗胶质母细胞瘤 细胞耗尽。这是假设这些同步 - 卡特细胞的效率明显高于 常规的，始终表达的IL-13Rα2/epha2 Cart细胞。调查人员将优化 铅剂并在该新型胶质母细胞瘤的新类药物的人类临床试验中的第一个假设中检验了这一假设 患者。 该U19提案还为支持明显重要的Trans-GTN试点项目提供资金，并 对于两个核心（行政，免疫监测和生物循环），将支持这两个项目的努力。 通过解决所描述的总体特定目标，本应用程序中提出的研究具有很高的 在胶质母细胞瘤中理解和利用免疫疗法的方式改变了免疫疗法的可能性。创新 该提案中描述的研究将利用福祉的卓越资源 在UCSF和Northwestern建立了临床和基础科学家的合作小组。