Project 8 - TH17 Dendritic Cell Vaccine

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，并有戏剧性的 然而，对于大多数患者来说，OvCa的免疫控制是暂时的，而 肿瘤细胞持续生长，并最终导致病人死亡。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 抑制性髓系细胞。树突状细胞和抑制性髓系细胞均可引起卵巢反应性辅助性T细胞无能 1(Th1)和CD8T细胞。Treg不仅在内源性抗OvCa免疫反应中诱导，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来靶向OvCa中的抑制细胞，但这些药物的效果是 暂时性的，也可能耗尽有益的细胞类型。相比之下，T辅助17(Th17)细胞 证明了在下调这些抑制细胞的同时促进促炎 抗原特异性免疫反应。我们最近描述了一种新的体外DC成熟策略 导致强大的抗原特异性Th17反应。在OvCa模型中，Th17诱导的DC治疗小鼠 表现出强大的抗OvCa Th17免疫反应，Tregs显著减少，Ovca持久 减刑。除了我们的研究表明有希望产生Th17免疫反应外， 在DCs体外成熟的基础上，我们还发现了一种新的OvCa抗原--叶酸受体α(FRα)。这 蛋白质在绝大多数人(和小鼠)OvCa肿瘤上过度表达，并与更糟糕的 临床结果。因此，我们已经从FRα中鉴定出抗原肽并完成了一项临床研究 在治疗性疫苗中测试这些多肽。在这些结果的基础上，我们建议1)确定 支持Th17诱导的肿瘤疫苗抗肿瘤效果的免疫效应分子，2)决定了 针对卵巢癌抗原的Th17免疫应答的诱导将克服局部肿瘤免疫 通过抑制Treg的生成和调节浸润性髓系细胞的功能来抑制，以及3)执行 第一阶段临床试验，以确定FRα特异性Th17T细胞反应是否可以安全地在 OvCa患者接受常规治疗。总而言之，这些目标将有助于通过以下方式阐明机制 哪种Th17诱导的DC疫苗可抑制肿瘤生长，并将提供安全性和 这一策略对人卵巢癌患者的免疫原性，促进了梅奥孢子的延续 Ovca预防疾病复发的基于免疫的创新方案。

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.