Project 8 - TH17 Dendritic Cell Vaccine

项目概要-项目8 卵巢癌（OvCa）的宿主免疫反应已被反复证明，并具有显着的 然而，对于大多数患者，OvCa的免疫控制是暂时的， 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， OvCa逃避宿主免疫应答在很大程度上是由于调节性T细胞（TcB）的影响， 抑制性骨髓细胞T淋巴细胞和抑制性髓系细胞均引起OvCa反应性T辅助细胞无能 1（Th 1）和CD 8 T细胞。不仅在内源性抗OvCa免疫应答过程中诱导T细胞， 在抗OvCa免疫疗法的情况下也是如此，从而限制了功效。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，也可以消耗有益的细胞类型。与此相反，辅助性T细胞17（Th 17）已经被发现。 证明下调这些抑制细胞，同时促进促炎性细胞因子的表达。 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， 导致强的抗原特异性Th 17应答。在OvCa模型中，用Th 17诱导的DC处理的小鼠 证明了强大的抗OvCa Th 17免疫应答，TcR的显著降低，和持久的OvCa 缓解。除了我们的研究证明了使用免疫球蛋白产生Th 17免疫应答的前景之外， DC离体成熟后，我们还鉴定了一种新的OvCa抗原，叶酸受体α（FRα）。这 蛋白质在绝大多数人类（和小鼠）OvCa肿瘤上过表达，并与恶化有关。 临床结果。因此，我们鉴定了FRα的抗原肽，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 支持Th 17诱导的癌症疫苗的抗肿瘤功效的免疫效应物，2）确定是否 诱导靶向卵巢癌抗原的Th 17免疫应答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进行抑制，和3）进行 1期临床试验，以确定FRα特异性Th 17 T细胞应答是否可以安全地在 常规治疗后的OvCa患者。总的来说，这些目标将有助于阐明机制， Th 17诱导DC疫苗接种可抑制肿瘤生长，并将提供安全性和安全性评估 该策略对人类OvCa患者的免疫原性，促进了马约孢子的延续 创新的免疫为基础的方法，以防止OvCa疾病复发的计划。

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.