Project 8 - TH17 Dendritic Cell Vaccine

项目8——TH17树突状细胞疫苗

基本信息

批准号：
9149472
负责人：
Keith L. Knutson
金额：
$ 28.06万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-01 至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/9149472
关键词：
Address Affect Animal Model Antigens Biological Response Modifiers Biostatistics Core CD4 Positive T Lymphocytes CD8B1 gene Cancer Etiology Cancer Patient Cancer Remission Cancer Vaccines Cell Maturation Cell physiology Cells Cessation of life Characteristics Clinic Clinical Clinical Research Clinical Trials Collaborations Combined Vaccines Coupled Cyclophosphamide Cytotoxic T-Lymphocytes Data Dendritic Cell Vaccine Dendritic Cells Development Disease Disease remission Employee Strikes FOLR1 gene Failure Fostering Generations Genetic Models Goals Helper-Inducer T-Lymphocyte Human IL2RA gene Immune Immune response Immune system Immunity Immunosuppression Immunosuppressive Agents Immunotherapeutic agent Immunotherapy Individual Infiltration Interferon Type II Interleukin-15 Interleukin-17 Lead Link MAP Kinase Gene MAPK14 gene Malignant neoplasm of ovary Memory Modeling Mus Myelogenous Myeloid Cells No Evidence of Disease Outcome Ovarian Paralysed Pathogenesis Pathologic Patient-Focused Outcomes Patients Peptides Phase Phase I Clinical Trials Phenotype Population Pre-Clinical Model Proteins Recurrence Regulatory T-Lymphocyte Resistance Role Safety Signal Transduction Staging Stem cells Suppressor-Effector T-Lymphocytes T cell response T-Lymphocyte Testing Toxin Tumor Antigens Vaccination Vaccine Design Vaccines Work anergy base cancer immunotherapy cell type chemotherapy conventional therapy immunogenicity improved inhibitor/antagonist innovation insight interest meetings mouse model neoplastic cell novel novel strategies ovarian neoplasm overexpression pre-clinical preclinical efficacy prevent programs response therapeutic vaccine trafficking tumor tumor growth tumor microenvironment vaccine development vaccine evaluation vaccine trial

项目摘要

PROJECT SUMMARY – Project 8 The host immune response to ovarian cancer (OvCa) has been repeatedly demonstrated and has a dramatic association with survival; however, for the majority of patients, immune control of OvCa is temporary, and the tumor cells persist, grow, and ultimately lead to patient death. We and others have shown that this ability of OvCa to evade host immune responses is due in large part to the influence of regulatory T cells (Tregs) and suppressive myeloid cells. Both Tregs and suppressive myeloid cells cause anergy of OvCa-reactive T helper 1 (Th1) and CD8 T cells. Tregs are induced not only during endogenous anti-OvCa immune responses, but also in the context of anti-OvCa immunotherapies, thereby limiting efficacy. Multiple groups have made efforts to target suppressor cells in OvCa using chemotherapy agents and toxins, but the effects of these agents are transient and can also deplete beneficial cell types. In contrast, T helper 17 (Th17) cells have been demonstrated to downregulate these suppressor cells while simultaneously promoting a proinflammatory antigen-specific immune response. We have recently described a novel strategy of ex vivo DC maturation that leads to a robust antigen-specific Th17 response. In a model of OvCa, mice treated with Th17-inducing DCs demonstrated robust anti-OvCa Th17 immune responses, a dramatic reduction in Tregs, and durable OvCa remissions. In addition to our studies demonstrating the promise of generating Th17 immune responses using DCs matured ex vivo, we have also identified a novel OvCa antigen, the folate receptor alpha (FRα). This protein is overexpressed on the vast majority of human (and mouse) OvCa tumors and is linked to worse clinical outcomes. We have, therefore, identified antigenic peptides from FRα and completed a clinical study testing these peptides in a therapeutic vaccine. Building on these results, we propose to 1) identify the immune effectors underpinning the anti-tumor efficacy of Th17-inducing cancer vaccines, 2) determine whether the induction of Th17 immune responses targeting ovarian cancer antigens will overcome local tumor immune suppression by inhibiting Treg generation and modulating infiltrating myeloid cell function, and 3) perform a phase 1 clinical trial to determine whether FRα-specific Th17 T cell responses can be safely generated in OvCa patients following conventional therapy. Collectively, these aims will help elucidate the mechanisms by which Th17-inducing DC vaccination suppresses tumor growth, and will provide an assessment of safety and immunogenicity of this strategy for human OvCa patients, fostering the continuation of a Mayo SPORE program of innovative immune-based approaches for preventing disease recurrence in OvCa.

项目摘要 - 项目8 宿主对卵巢癌（OVCA）的免疫反应已反复证明，并具有戏剧性与生存相关；但是，对于大多数患者，OVCA的免疫控制是暂时的，并且肿瘤细胞持续，生长并最终导致患者死亡。我们和其他人表明了这种能力 OVCA逃避宿主免疫反应在很大程度上归功于调节性T细胞（Tregs）和抑制髓样细胞。 Tregs和抑制性髓样细胞都会引起OVCA反应T助手的反应 1（TH1）和CD8 T细胞。不仅在内源性抗抗反抗管免疫复杂期间诱导了Treg，而且还被诱导同样在反抗抗乳液的免疫疗法的背景下，从而限制了效率。多个小组付出了努力使用化学疗法剂和毒素靶向OVCA中的抑制细胞，但这些药物的作用是瞬态，也可以有益细胞类型。相反，T辅助器17（Th17）细胞已经证明可以下调这些抑制细胞，同时促进促炎性细胞抗原特异性免疫反应。我们最近描述了一种新型的Ex Vivo DC成熟策略导致强大的抗原特异性TH17响应。在OVCA模型中，用Th17诱导的DC处理的小鼠表现出强大的抗抗抗菌Th17免疫反应，Treg的急剧减少和持久的OVCA 恢复。除我们的研究外，还证明了使用使用Th17免疫反应的希望 DCS成熟的离体，我们还确定了一种新型的OVCA抗原，叶酸受体α（FRα）。这蛋白质在绝大多数人（和小鼠）OVCA肿瘤上过表达，并且与恶化有关临床结果。因此，我们已经确定了来自FRα的抗原性胡椒剂并完成了临床研究在治疗性疫苗中测试这些肽。在这些结果的基础上，我们建议1）确定受Th17诱导癌症疫苗的抗肿瘤效率的免疫作用，2）确定是否是否确定是否是否靶向卵巢癌抗原的Th17免疫反应的诱导将克服局部肿瘤免疫通过抑制treg的产生并调节渗透髓样细胞功能，并执行抑制第1阶段的临床试验，以确定是否可以在常规治疗后的OVCA患者。总的来说，这些目标将有助于通过 Th17诱导的直流疫苗接种会抑制肿瘤的生长，并将评估安全性和这种策略对人OVCA患者的免疫原性，促进了蛋黄酱的持续创新的基于免疫的方法预防OVCA疾病复发的方法。