Leveraging Temozolomide to Improve Treatment Efficacy of Immune Checkpoint Blockade in Glioblastoma

利用替莫唑胺提高胶质母细胞瘤免疫检查点阻断的治疗效果

• 批准号: 9224807
• 负责人: Maryam Rahman
• 金额: $ 18.2万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-12-15 至 2021-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9224807
• 关键词: Adult; Aftercare; Antibodies; Apoptosis; Award; Brain Neoplasms; Cancer Center; Cells; Cessation of life; Clinical; Clinical Sciences; Clinical Trials; Clonality; Cytotoxic T-Lymphocyte-Associated Protein 4; Cytotoxic T-Lymphocytes; DNA Sequence Alteration; Data; Dose; Drug usage; Environment; Equilibrium; Extramural Activities; Failure; Fellowship; Florida; Funding; Glioblastoma; Glioma; Goals; Growth; Immune; Immune checkpoint inhibitor; Immune response; Immune system; Immunity; Immunologic Monitoring; Immunologics; Immunosuppressive Agents; Immunotherapeutic agent; Immunotherapy; Institutes; Intervention; Lead; Learning; Ligands; Lymphopenia; MGMT gene; Malignant Glioma; Malignant Neoplasms; Malignant neoplasm of brain; Master' s Degree; Measures; Mediating; Mentors; Modeling; Modification; Morbidity - disease rate; Mus; Mutation; Neurologic; Neurosurgeon; Newly Diagnosed; PDCD1LG1 gene; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Pharmacotherapy; Phenotype; Primary Brain Neoplasms; Program Development; Protocols documentation; Quinones; Radiation Therapy Oncology Group; Recovery; Regimen; Regulatory T-Lymphocyte; Research; Research Methodology; Research Project Grants; Research Proposals; Resistance; Resources; Role; Schedule; Scientist; Solid; T cell response; T-Cell Activation; T-Lymphocyte; Testing; Therapeutic; Training; Translational Research; Treatment Efficacy; Tumor Antigens; Tumor Burden; Tumor Stem Cells; Tumor Tissue; Tumor-Infiltrating Lymphocytes; United States National Institutes of Health; Universities; Work; career; career development; cell killing; chemotherapy; clinical investigation; clinically significant; combinatorial; conditioning; efficacy testing; experience; experimental study; immune checkpoint; immune checkpoint blockade; immune function; immunoregulation; improved; improved outcome; inhibitor/antagonist; innovation; interest; killings; medical specialties; meetings; neoplasm immunotherapy; neoplastic cell; neuro-oncology; neurosurgery; novel; novel therapeutic intervention; novel therapeutics; oncology; overexpression; peptide vaccination; programs; response; success; synergism; temozolomide; therapy resistant; tumor

PROJECT SUMMARY Glioblastoma (GBM) is the most common primary brain tumor in adults and is characterized by aggressive growth, significant neurologic morbidity and eventually death. Temozolomide (TMZ) is the most widely accepted chemotherapy drug used to treat GBM, although its efficacy is limited in almost 50% of GBM patients. Therefore, novel treatment approaches, such as immune checkpoint inhibitors are being investigated for GBM. Immune checkpoints are immune inhibitory responses that are co-opted by tumor cells to down regulate T cell targeting of tumor antigens. Antibodies to programmed cell death 1 (PD-1) allow for T cell activation against tumor neoantigens. This approach has had tremendous success in the treatment of solid tissue tumors and are now being tested for efficacy in GBM. This research proposal will investigate the mechanisms by which dose-modified TMZ may prime host T cells and tumor neoantigen expression to improve response to PD-1 immune checkpoint blockade. The rationale for this proposal include several factors. First, TMZ has been found to be advantageous when used in combination with immunotherapy for GBM due to conditioning of host immunity during the recovery from TMZ-induced lymphopenia. Second, immune checkpoint inhibitors enhance anti-tumor T cell responses against tumor neoantigens. This phenomenon can be leveraged since TMZ is known to be mutagenic and result in an increase burden of tumor neoantigens in malignant glioma. Third, combination TMZ and PD-1 blockade has a unique role for resistant phenotypes of GBM since these tumors have an increase in PD-L1 expression. This proposal will test the hypothesis that TMZ induces host immunologic and tumor genetic changes that will result in increased response to PD-1 blockade. This hypothesis will be tested by completing three aims. The first aim will determine the effects of TMZ dose and timing on host immunologic changes and the impact on PD-1 blockade efficacy for GBM. This aim will be tested by evaluating PD-1 and PD-L1 expression on host immune cells after various TMZ dosing strategies, and evaluating the effects of combining TMZ with PD-1 blockade on host immunologic function and tumor infiltrating lymphocytes in a syngeneic murine GBM model. The second aim will evaluate the utility of combining dose-modified TMZ and PD-1 blockade for resistant GBM tumors. This aim will utilize an MGMT-mediated TMZ resistant tumor model to determine the efficacy of combinatorial treatment for resistant phenotypes of GBM. The final aim will explore the mechanism by which dose-modified TMZ alters the tumor mico-environment and changes response to PD-1 blockade. The experiments will test the differences tumor genetic mutations and T cell clonality in tumors that respond to PD- 1 blockade compared to those that are resistant. Tumors that have been pre-treated with TMZ will also be tested to determine how post-treatment tumors may differ in response to immune checkpoint blockade independent of TMZ's effects on host immunity. At the completion of this proposal, the role of PD-1 blockade in combination with dose-modified TMZ for GBM and its efficacy for resistant phenotypes of GBM will be understood. These results have the potential for immediate impact for GBM patients as there are ongoing trials. The proposed research will be conducted by Dr. Rahman at the University of Florida Brain Tumor Immunotherapy Program (UFBTIP). She is well-suited to successfully complete the proposed research as an academic neurosurgeon with sub-specialty training in neuro-oncology. She has completed research fellowships under the direction of Dr. Brent Reynolds and Dr. Quinones-Hinojosa in studying tumor stem cells in malignant glioma and overcoming treatment resistance. She has completed an NIH funded program in clinical investigation and obtained her Master's degree from the Clinical and Translational Science Institute. Her primary mentor, Dr. Duane Mitchell, is the director of the UFBTIP, and has a strong record of extra-mural funding and success in investigating novel immunotherapeutic platforms for malignant brain tumors. Her co- mentors are Dr. Mark Gilbert and Dr. Amy Heimberger. Dr. Gilbert is chief of the Neuro-Oncology divison of the NCI. He has considerable clinical trial experience and lead an RTOG trial investigating dose-intensified TMZ for GBM and is currently leading a clinical trial exploring immune checkpoint blockade for GBM. Dr. Heimberger is a neurosurgeon-scientist at MD Anderson Cancer Center with expertise in immunotherapy for brain tumors and training young scientists. In addition to guiding her research, Dr. Heimberger will help Dr. Rahman learn to balance a clinical neurosurgical practice with translational research endeavors. Dr. Rahman has considerable funding and ample resources to accomplish her research goals through the UFBTIP. During the award period, Dr. Rahman will complete a comprehensive program to develop as a clinician scientist. This program will include completing the experimental protocols outlined in the proposal, completing course work in research methods and conduct, and regular scheduled meetings with her advisory panel which includes highly accomplished clinician scientists in neurosurgery, neuro-oncology and oncology. Her career goals include developing novel therapies for malignant glioma, understanding how to overcome tumor treatment resistance and improving outcomes for glioma patients. This career development program will be an important first step in achieving these goals.

项目摘要 胶质母细胞瘤（GBM）是成年人中最常见的原发性脑肿瘤，其特征是侵略性 生长，明显的神经系统发病率和最终死亡。 Temozolomide（TMZ）是最广泛的 接受的化学疗法药物用于治疗GBM，尽管其疗效在几乎50％的GBM中受到限制 患者。因此，正在研究新型治疗方法，例如免疫检查点抑制剂 对于GBM。免疫检查点是免疫抑制反应，由肿瘤细胞采用 调节肿瘤抗原的T细胞靶向。编程细胞死亡1（PD-1）的抗体允许T细胞 针对肿瘤新抗原的激活。这种方法在固体的治疗方面取得了巨大的成功 组织肿瘤，现在正在测试GBM的功效。 该研究建议将调查剂量改性TMZ的机制 和肿瘤新抗原表达以改善对PD-1免疫检查点阻滞的反应。理由 该建议包括几个因素。首先，在组合使用时发现TMZ是有利的 通过从TMZ诱导的恢复期间宿主免疫的调理，对GBM进行免疫疗法 淋巴细胞减少症。第二，免疫检查点抑制剂增强了针对肿瘤的抗肿瘤T细胞反应 新抗原。由于已知TMZ是诱变的，因此可以利用这种现象 增加恶性神经胶质瘤中肿瘤新抗原的负担。第三，组合TMZ和PD-1封锁具有 由于这些肿瘤的PD-L1表达增加，因此GBM耐药表型的独特作用。 该提案将检验以下假设：TMZ诱导宿主的免疫和肿瘤遗传变化，这将 导致对PD-1封锁的反应增加。该假设将通过完成三个目标来检验。这 第一个目标将确定TMZ剂量和时机对宿主免疫变化的影响以及对 GBM的PD-1封锁功效。该目标将通过评估主机上的PD-1和PD-L1表达来测试 各种TMZ剂量策略后的免疫细胞，并评估将TMZ与PD-1结合的影响 宿主免疫功能和肿瘤浸润淋巴细胞的封锁。 第二个目标将评估耐药性GBM的剂量改性TMZ和PD-1阻滞的实用性 肿瘤。该目标将利用MGMT介导的TMZ抗性肿瘤模型来确定 GBM耐药表型的组合治疗。最终目标将探讨 剂量改性的TMZ改变了肿瘤微型环境并改变对PD-1阻滞的反应。这 实验将测试对PD-反应的肿瘤遗传突变和T细胞克隆性的差异 与耐药性相比，有1个封锁。已预处理TMZ的肿瘤也将是 经过测试以确定治疗后肿瘤的响应方式可能有何不同 独立于TMZ对宿主免疫的影响。该提案完成时，PD-1封锁的作用 与剂量改性的TMZ结合使用GBM及其对GBM耐药表型的功效将是 理解。这些结果可能会对GBM患者产生立即影响 试验。 拟议的研究将由佛罗里达大学脑肿瘤的拉赫曼博士进行 免疫疗法计划（UFBTIP）。她非常适合成功完成拟议的研究 学术神经外科医生和神经肿瘤学的亚专业培训。她已经完成了研究 在研究肿瘤干细胞的Brent Reynolds和Quinones-Hinojosa博士的指导下奖学金 在恶性神经胶质瘤和克服治疗耐药性中。她已经完成了NIH资助的计划 临床研究并从临床和转化科学研究所获得了硕士学位。 她的主要导师杜安·米切尔（Duane Mitchell）博士是UFBTIP的董事，并且有壁外记录 用于调查恶性脑肿瘤的新型免疫治疗平台的资金和成功。她的共同 导师是马克·吉尔伯特（Mark Gilbert）博士和艾米·海姆伯格（Amy Heimberger）博士。吉尔伯特博士是神经肿瘤的负责人 NCI。他拥有丰富的临床试验经验，并领导了RTOG试验，调查了剂量强化的TMZ 对于GBM，目前正在领导一项临床试验，该试验探讨了GBM的免疫检查点封锁。博士 Heimberger是MD Anderson癌症中心的神经外科医生，在免疫疗法方面具有专业知识 脑肿瘤和培训年轻科学家。除了指导她的研究外，Heimberger博士还将帮助博士。 拉赫曼学会平衡临床神经外科实践与转化研究的努力。拉赫曼博士 拥有大量资金和充足的资源，可以通过UFBTIP实现她的研究目标。期间 奖项期，拉赫曼博士将完成一项综合计划，以发展为临床医生。这 计划将包括完成提案中概述的实验协议，完成课程工作 研究方法和行为，以及与她的咨询小组的定期安排会议，其中包括高度 神经外科，神经肿瘤学和肿瘤学的临床医生有成熟的科学家。她的职业目标包括 开发新型恶性神经胶质瘤的疗法，了解如何克服肿瘤治疗抗性 并改善神经胶质瘤患者的结局。该职业发展计划将是重要的第一步 实现这些目标。