A phase I/II study of combined therapy with Th17-inducing dendritic cells and pembrolizumab in patients with recurrent epithelial ovarian cancer

摘要 卵巢癌（OC）在美国每年导致约14，000人死亡。虽然在这方面取得了进展， 治疗，进展是常见的，治愈率低。近年来，已经做了几次试验 测试免疫检查点阻断（ICB），无论是单独或与其他药物组合，主要是在 复发性疾病的设置。总的答复率不高。ICB应答的生物标志物 治疗，如突变负荷、新抗原负荷、PD-L1表达和基线T细胞浸润， 在许多癌症中与ICB治疗的反应相关，并表明ICB治疗需要预先存在 临床有效性的免疫力。疫苗虽然在缩小肿瘤方面效率低下，但可以可靠地产生 必要的预先存在的免疫力，包括大多数OC患者。在先前的国家癌症研究所资助的赠款（P50- CA 136393），我们开发了一种叶酸受体α（FR α）靶向Th 17诱导疫苗， 在几乎所有OC患者中产生Th 17 T细胞免疫。研制疫苗的前提是 广泛的工作表明i）Th 17效应物和TcB之间的相互关系，ii） IL-17表达增加，总存活率提高，和iii）Th 17 T细胞对免疫应答的抗性， 镇压进行了一项I期临床试验，其中19名晚期OC患者首次缓解， 接种疫苗。所有患者均表现出协调的细胞和体液免疫。在18例可评价的患者中， 在有效性方面，39%（7/18）在数据删失时保持无复发，中位随访时间为49.2 月，无复发生存率（RFS）优于历史对照（<15%）上级。平行小鼠模型 证明了一种独特的机制，其中Th 17 T细胞免疫协调否则无效的Th 1，Th 2 和B细胞免疫通过骨髓募集和激活抗体依赖性机制， 巨噬细胞和嗜酸性粒细胞。我们观察到Th 17 DC疫苗接种克服了对ICB治疗的抗性， 通过产生肿瘤特异性免疫，重建肿瘤微环境， 抗ICB。因此，我们假设Th 17诱导的DC疫苗接种和ICB的组合， 治疗可能是复发性OC患者的有效治疗方法。在具体目标1中， 开展新型Th 17诱导DC疫苗联合派姆单抗的I/II期临床试验 （由Merck提供）在32名处于早期疾病复发背景下的OC患者中进行。主要结局指标 是安全性和客观反应率。将询问基线肿瘤特征， 生物标志物鉴定在具体目标2中，我们将使用经过验证的分析工具来检查细胞和 联合治疗后组织和外周的体液免疫应答，以鉴定显性 治疗诱导的免疫应答特征及其是否与临床结果相关 评估。将确定耐药机制。如果阳性，则进行新的治疗ICB 将建立一个治疗范例，以提高晚期OC妇女的生存率。

ABSTRACT Ovarian cancer (OC) causes ~14,000 deaths each year in the USA. While there have been advances in treatment, progression is common and cure rates are low. In recent years, several trials have been done testing immune checkpoint blockade (ICB), either alone or in combination with other agents, largely in the setting of recurrent disease. Overall response rates have been unimpressive. Biomarkers of response to ICB therapy, such as mutational burden, neoantigen load, PD-L1 expression, and baseline T cell infiltration, are associated with response to ICB therapy in many cancers and suggest that ICB therapy requires pre-existent immunity for clinical effectiveness. Vaccines, while inefficient alone at shrinking tumor, can reliably generate the necessary pre-existing immunity, including in most OC patients. In a prior NCI-funded grant (P50- CA136393), we developed a folate receptor alpha (FR) targeting Th17-inducing vaccine that is effective at generating Th17 T cell immunity in nearly all OC patients. The premise for developing the vaccine was based on extensive work showing i) a reciprocal relationship between Th17 effectors and Tregs, ii) association of increased IL-17 expression with improved overall survival, and iii) resistance of Th17 T cells to immune suppression. A phase I clinical trial was conducted in which 19 advanced OC patients, in first remission, were vaccinated. All patients demonstrated coordinated cellular and humoral immunity. Of 18 patients evaluable for efficacy, 39% (7/18) remained recurrence-free at the time of data censoring, with a median follow-up of 49.2 months, a recurrence-free survival (RFS) superior to historical controls(<15%). Parallel murine modeling demonstrated a unique mechanism in which Th17 T cell immunity coordinates otherwise inefficient Th1, Th2 and B cell immunity through myeloid recruitment and activation of antibody-dependent mechanisms in macrophages and eosinophils. We observed that Th17 DC vaccination overcomes resistance to ICB therapy by generating tumor-specific immunity, restructuring the tumor microenvironment, and preventing adaptive resistance to ICB. Thus, we hypothesize that the combination of Th17-inducing DC vaccination and ICB therapy may be an effective therapeutic approach in patients with recurrent OC. In specific Aim 1 we will conduct a phase I/II clinical trial of the novel Th17-inducing DC vaccine in combination with pembrolizumab (provided by Merck) in 32 OC patients in the setting of early disease recurrence. Primary outcome measures will be safety and the rate of objective responses. Interrogation of baseline tumor features will be done for biomarker identification. In Specific Aim 2 we will use well validated analytical tools to examine cellular and humoral immune responses in tissue and the periphery following combination treatment to identify dominant features of the immune response induced by treatment and whether they are correlate with clinical outcome assessments. Mechanisms of resistance to therapy will be identified. If positive, a new treatment ICB treatment paradigm will be established to improve the survival of women afflicted with advanced OC.