Project 8 - TH17 Dendritic Cell Vaccine

项目8——TH17树突状细胞疫苗

• 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
• 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

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 与生存的联系；然而，对于大多数患者来说，OvCa 的免疫控制是暂时的，并且 肿瘤细胞持续存在、生长并最终导致患者死亡。我们和其他人已经证明了这种能力 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。 Tregs 和抑制性骨髓细胞都会导致 OvCa 反应性 T 辅助细胞无反应 1 (Th1) 和 CD8 T 细胞。 Tregs 不仅在内源性抗 OvCa 免疫反应中被诱导，而且 也在抗 OvCa 免疫疗法的背景下，从而限制了疗效。多个团体做出了努力 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 短暂的，也可以耗尽有益的细胞类型。相比之下，辅助 T 17 (Th17) 细胞 被证明可以下调这些抑制细胞，同时促进促炎细胞 抗原特异性免疫反应。我们最近描述了一种离体 DC 成熟的新策略 导致强烈的抗原特异性 Th17 反应。在 OvCa 模型中，用 Th17 诱导 DC 治疗小鼠 表现出强大的抗 OvCa Th17 免疫反应、Treg 显着减少和持久的 OvCa 缓解。除了我们的研究证明使用 Th17 产生免疫反应的前景 DCs 离体成熟，我们还鉴定了一种新的 OvCa 抗原，叶酸受体 α (FRα)。这 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 临床结果。因此，我们从 FRα 中鉴定出抗原肽并完成了临床研究 在治疗性疫苗中测试这些肽。基于这些结果，我们建议 1) 确定 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 接受常规治疗的 OvCa 患者。总的来说，这些目标将有助于阐明其机制： 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。