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) 的免疫反应已被反复证明，并且具有显着的效果与生存相关；然而，对于大多数患者来说，OvCa 的免疫控制是暂时的，并且我们和其他人已经证明了肿瘤细胞持续存在、生长并最终导致患者死亡。 OvCa 逃避宿主免疫反应在很大程度上是由于调节性 T 细胞 (Treg) 和抑制性骨髓细胞和抑制性骨髓细胞都会导致 OvCa 反应性 T 辅助细胞无反应。 Tregs 1 (Th1) 和 CD8 T 细胞不仅在内源性抗 OvCa 免疫反应中被诱导，而且还被诱导。也在抗 OvCa 免疫疗法的背景下，多个小组做出了努力，从而限制了疗效。使用化疗药物和毒素靶向 OvCa 中的抑制细胞，但这些药物的作用是相比之下，T 辅助细胞 17 (Th17) 细胞是短暂的，并且还会耗尽有益细胞类型。下调这些抑制细胞，同时促进促炎细胞我们最近描述了一种离体 DC 成熟的新策略。在 OvCa 模型中，用 Th17 诱导 DC 治疗的小鼠会产生强烈的抗原特异性 Th17 反应。强大的抗 OvCa Th17 免疫反应、Treg 显着减少和持久的 OvCa 除了我们的研究证明使用 Th17 免疫反应产生的希望之外。 DCs 离体成熟，我们还鉴定了一种新的 OvCa 抗原，叶酸受体 α (FRα)。该蛋白在绝大多数人类（和小鼠）OvCa 肿瘤中过度表达，并与更糟糕的情况相关因此，我们从 FRα 中鉴定出抗原肽并完成了一项临床研究。根据这些结果，我们建议 1) 确定治疗性疫苗中的这些肽。免疫效应物支撑 Th17 诱导癌症疫苗的抗肿瘤功效，2) 确定是否针对卵巢癌抗原的 Th17 免疫反应的诱导将克服局部肿瘤免疫通过抑制 Treg 生成和调节浸润性骨髓细胞功能来抑制，3) 执行确定是否可以安全地产生 FRα 特异性 Th17 T 细胞反应的 1 期临床试验总的来说，这些目标将有助于阐明接受常规治疗的 OvCa 患者的机制。 Th17 诱导 DC 疫苗接种可抑制肿瘤生长，并将提供安全性和该策略对人类 OvCa 患者的免疫原性，促进 Mayo SPORE 的延续用于预防 OvCa 疾病复发的创新免疫方法计划。