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: 9983047
• 负责人: Linda M Liau
• 金额: $ 35.34万
• 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/9983047
• 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 regulation; T cell response; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; T-cell receptor repertoire; 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 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：胶质母细胞瘤的主动免疫治疗联合检查点调节