Project 1: Active immunotherapy combined with checkpoint modulation for glioblastoma

项目1：主动免疫疗法联合检查点调节治疗胶质母细胞瘤

• 批准号: 10225550
• 负责人: Linda M Liau
• 金额: $ 34.58万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-11 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10225550
• 关键词: Active Immunotherapy; Animal Model; Animals; Antigen-Presenting Cells; Attenuated; Blood; Brain; Brain Neoplasms; Cancer Vaccines; Cell physiology; Cells; Cellular Immunity; Cellular biology; Chronic; Clinical; Clinical Trials; Clofarabine; Data; Dendritic Cell Vaccine; Dendritic Cells; Development; Effectiveness; Elements; Enrollment; Genes; Glioblastoma; Glioma; Goals; Health; Human; Immigration; Immune; Immune Evasion; Immune response; Immunologic Markers; Immunologics; Immunosuppression; Immunotherapeutic agent; Immunotherapy; In Vitro; Infiltration; Inflammatory; Interleukin-10; Lead; Malignant neoplasm of brain; Mediating; Modeling; Monoclonal Antibodies; Mus; Nivolumab; PD-1/PD-L1; Pathway interactions; Patients; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Phase III Clinical Trials; Phenotype; Physiologic pulse; Positron-Emission Tomography; Pre-Clinical Model; Randomized; Recurrence; Research Project Grants; Sampling; T cell receptor repertoire sequencing; T cell regulation; T cell response; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; Testing; Therapeutic; Tracer; Translational Research; Treatment Failure; Treatment outcome; Tumor Immunity; Tumor Markers; Tumor-Infiltrating Lymphocytes; Tumor-infiltrating immune cells; Vaccination; Virus Diseases; Work; anti-PD-1; anti-tumor immune response; base; checkpoint inhibition; checkpoint modulation; clinically relevant; dendritic cell vaccination; design; effective therapy; efficacy evaluation; efficacy testing; imaging biomarker; immunoregulation; improved outcome; in vivo; in vivo Model; inflammatory milieu; inhibitor/antagonist; innovation; insight; mouse model; neoplasm immunotherapy; neoplastic cell; next generation sequencing; non-invasive imaging; novel; pre-clinical; preclinical study; programmed cell death ligand 1; programmed cell death protein 1; prophylactic; response; response biomarker; synthetic peptide; tumor; tumor microenvironment; vaccination strategy

Project 1: Active immunotherapy combined with checkpoint modulation for glioblastoma SUMMARY/ABSTRACT The lack of effective treatments for glioblastoma (GBM) patients remains a significant health problem and highlights the need for novel and innovative approaches. Immunotherapy is an appealing strategy because of the potential ability for immune cells to traffic to and destroy infiltrating tumor cells in the brain. Pre-clinical studies and clinical trials of dendritic cell (DC) vaccination for GBM have shown some promising results, but also some treatment failures. The broad overall goals of this research project are to investigate mechanisms of immune evasion following active immunotherapy, and to develop rational combinations of immunotherapeutic strategies to overcome the immunosuppressive milieu of the brain tumor microenvironment. Our new preliminary data strongly suggests that active immunotherapy with DC vaccination may create a pro-inflammatory tumor microenvironment that induces the immigration of immunosuppressive antigen presenting cells (iAPC), which express high levels of PD-L1 and IL-10. We show that these cells are phenotypically similar to the iAPC that dominantly influence the T-cell response to chronic viral infection, and may act to counteract effective T-cell responses induced by DC vaccination via a mechanism involving PDL1/PD-1. Furthermore, inhibition of iAPC using an anti-PD1 mAb (Nivolumab, BMS) or a CNS penetrant inhibitor of CSF-1R (PLX-3397, Plexxikon), in conjunction with tumor lysate-pusled DC vaccination (DC-Vax-L), resulted in significantly prolonged survival in tumor-bearing animals with well-established intracranial (i.c.) gliomas. We therefore postulate that clinically relevant anti-tumor immunity to glioblastoma (GBM) must have two cellular components: 1) significant infiltration of tumor-specific tumor-infiltrating lymphocytes (TIL); and 2) blockade of immune-regulatory antigen presenting cell (iAPC) function within the tumor microenvironment. As such, our hypothesis is that the local cellular interactions between iAPC and T lymphocytes within the brain tumor microenvironment is a critical factor influencing the efficacy of immunotherapies in glioblastoma patients. A better understanding of the biology of these cellular interactions will provide insight into more effective ways to induce therapeutic anti-tumor immune responses for this deadly type of brain tumor. In Aim 1, we will study the mechanisms by which iAPC limit glioma- specific anti-tumor immune responses in vitro and in vivo. In Aim 2, we will evaluate the efficacy of combining tumor lysate-pulsed DC vaccination (to induce T-cell infiltration into tumors) with immune checkpoint inhibition and other novel immunoregulatory targets (to block iAPC function) in pre-clinical syngeneic animal models of glioblastoma, and explore the use of a novel PET tracers as non-invasive imaging biomarkers of immune response. Finally, in Aim 3, we will develop and validate predictive tumor, immunological and imaging biomarkers of response in recurrent glioblastoma patients enrolled in a Phase II clinical trial of DCVax-L +/- Nivolumab. These studies span the continuum of translational research in brain tumor immunotherapy, and will likely provided informative new insights for the development of new, rational immune-based strategies for brain tumor patients.

项目1：主动免疫疗法与胶质母细胞瘤的检查点调制结合 摘要/摘要 缺乏针对胶质母细胞瘤（GBM）患者的有效治疗方法仍然是一个重大的健康问题， 强调了对新颖和创新方法的需求。免疫疗法是一种吸引人的策略 免疫细胞流动和破坏大脑中浸润的肿瘤细胞的潜在能力。临床前研究 GBM的树突状细胞（DC）疫苗接种的临床试验已显示出一些有希望的结果，但也显示了一些 治疗失败。该研究项目的广泛总体目标是调查免疫机制 主动免疫疗法后逃避，并发展免疫治疗策略的合理组合 为了克服脑肿瘤微环境的免疫抑制环境。我们的新初步数据 强烈建议通过直流疫苗接种主动免疫疗法可能会产生促炎性肿瘤 诱导免疫抑制抗原呈递细胞（IAPC）移民的微环境，该环境 表达高水平的PD-L1和IL-10。我们表明，这些细胞在表型上与IAPC相似 主要影响T细胞对慢性病毒感染的反应，并可能作用以抵消有效的T细胞 DC疫苗接种通过涉及PDL1/PD-1的机制引起的反应。此外，抑制IAPC 使用抗PD1 mAb（Nivolumab，BMS）或CSF-1R的CNS渗透抑制剂（PLX-3397，Plexxikon） 与肿瘤裂解液螺旋的直流疫苗接种（DC-VAX-L）的结合，导致了显着延长的生存率 具有公认的颅内（I.C.）神经胶质瘤的肿瘤动物。因此，我们假设临床 相关的抗肿瘤免疫对胶质母细胞瘤（GBM）必须具有两个细胞成分：1）显着浸润 肿瘤特异性肿瘤浸润的淋巴细胞（TIL）；和2）免疫调节抗原的阻塞 肿瘤微环境中的细胞（IAPC）功能。因此，我们的假设是局部细胞 脑肿瘤微环境中的IAPC和T淋巴细胞之间的相互作用是关键因素 影响免疫疗法在胶质母细胞瘤患者中的功效。对生物学的更好理解 这些细胞相互作用将为诱导治疗性抗肿瘤免疫提供更有效的方法提供洞察力 对这种致命类型的脑肿瘤的反应。在AIM 1中，我们将研究IAPC限制神经胶质瘤的机制 特定的抗肿瘤免疫反应在体外和体内。在AIM 2中，我们将评估组合的功效 肿瘤裂解物脉冲直流疫苗（以诱导T细胞浸润到肿瘤中），并具有免疫检查点抑制 以及其他新型免疫调节靶标（阻止IAPC功能） 胶质母细胞瘤，并探索使用新型宠物示踪剂作为免疫的非侵入性成像生物标志物 回复。最后，在AIM 3中，我们将发展和验证预测性肿瘤，免疫学和成像 在DCVAX-L +/-的II期临床试验中，复发性胶质母细胞瘤患者的反应生物标志物 Nivolumab。这些研究跨越了脑肿瘤免疫疗法中转化研究的连续性，并将 可能为开发新的，理性免疫的大脑策略提供了信息丰富的新见解 肿瘤患者。