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.

总结/摘要 免疫疗法对胶质母细胞瘤的治疗有很大的希望;尽管如此，胶质母细胞瘤的某些特征 存在固有的治疗挑战。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。Lurie 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实现三个具体目标： 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 了解如何克服血脑屏障的限制和3）开发创新 胶质母细胞瘤的免疫治疗，相关的早期临床试验集中在患有 复发性胶质母细胞瘤 来自西北大学的项目1将建立在该团队在小鼠脑肿瘤模型中的临床前结果的基础上 证明了当免疫检查点抑制剂治疗是 在免疫原性剂量的阿霉素之前， BBB开放。在创新生物技术公司（AstraZeneca，Carthera）的支持下， 用于临床前和临床研究的器械，以及特定的专业知识、分析和技术， 这两个机构的调查，使这种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PD 1检查点抑制剂balstilimab与多柔比星联合使用， 不进行超声处理以打开BBB。通过在手术前给予免疫治疗（诱导治疗， 新辅助治疗）的免疫效应使我们能够评估在切除的脑中的体内免疫应答 组织.我们以前已经确定pERk/MAPK活化作为抗PD 1治疗获益的生物标志物 在复发性胶质母细胞瘤中;将进一步探讨该标记物和其他标记物。4个前瞻性治疗队列 将接受和不接受诱导治疗，以及接受和不接受BBB开放治疗。翻译终点 包括免疫应答（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“引发和杀死”策略识别肿瘤细胞。在 该系统，即仅在GBM细胞上表达的第一抗原（EGFRvIII），引发T细胞， 诱导识别IL-13 R α2和EphA 2的CAR的表达，从而根除表达IL-13 R α2和EphA 2的GBM细胞， EphA 2或IL-13α2。Project 2的团队假设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的挑战治疗胶质母细胞瘤 细胞衰竭因此，这些synNotch-CART细胞被假设为比其他细胞显著更有效。 常规的组成型表达IL-13 R α2/EphA 2 CART细胞。研究者将优化以下药物的疗效： 并在胶质母细胞瘤中进行这类新药物的首次人体临床试验中验证这一假设 患者 这项U19提案还预留了资金用于支持非常重要的trans-GTN试点项目， 两个核心（行政、免疫监测和生物标本）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 改变免疫疗法在胶质母细胞瘤中的理解和利用方式的可能性。创新 本提案中所述的研究将利用井- 在加州大学旧金山分校和西北大学建立了临床和基础科学家合作小组。