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

Th17诱导树突状细胞和派姆单抗联合治疗复发性上皮性卵巢癌患者的 I/II 期研究

• 批准号: 10564386
• 负责人: Matthew Stephen Block
• 金额: $ 63.5万
• 依托单位: MAYO CLINIC JACKSONVILLE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10564386
• 关键词: Adaptive Immune System; Address; Adverse event; Antibodies; Antibody Activation; Antigens; B-Lymphocytes; Cancer Etiology; Cancer Patient; Cellular Immunity; Cessation of life; Characteristics; Clinical; Clinical effectiveness; Combined Modality Therapy; Combined Vaccines; Data; Dendritic Cell Vaccine; Dendritic Cells; Development; Disease Progression; Disease remission; Epithelial ovarian cancer; Evaluable Disease; FOLR1 gene; Funding; Goals; Grant; Human; Humoral Immunities; Hyperthermia; IL17 gene; Immune response; Immune system; Immunity; Immunologic Tests; Immunosuppression; Innate Immune System; Interleukin-15; Macrophage; Malignant Neoplasms; Malignant neoplasm of ovary; Mitogen-Activated Protein Kinase Inhibitor; Mus; Mutation; Myelogenous; Neoadjuvant Therapy; Outcome; Outcome Measure; Pathologic; Patient-Focused Outcomes; Patients; Phagocytes; Phase; Phase I Clinical Trials; Phase I/II Clinical Trial; Phenotype; Poly(ADP-ribose) Polymerase Inhibitor; Production; Recurrence; Recurrent disease; Regulatory T-Lymphocyte; Resistance; Safety; T cell infiltration; T-Lymphocyte; Therapeutically Targetable; Time; Tissues; Vaccinated; Vaccination; Vaccines; Woman; Work; analytical tool; antibody-dependent cell cytotoxicity; bevacizumab; biomarker identification; cancer infiltrating T cells; clinical efficacy; clinical outcome assessment; dendritic cell vaccination; eosinophil; follow-up; immune checkpoint; immune checkpoint blockade; improved; intraperitoneal therapy; mouse model; neoantigens; novel; objective response rate; ovarian neoplasm; p38 Mitogen Activated Protein Kinase; pembrolizumab; pre-clinical; preclinical study; prevent; primary outcome; profiles in patients; prognostic value; programmed cell death ligand 1; programs; recruit; resistance mechanism; response; response biomarker; standard of care; success; therapeutically effective; therapy design; therapy resistant; trafficking; treatment response; tumor; tumor microenvironment; tumor progression; tumor-immune system interactions; vaccine development

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.

抽象的 卵巢癌（OC）每年在美国造成约14,000人死亡。尽管有进步 治疗，进展很常见，治愈率很低。近年来，已经进行了几次试验 单独或与其他药物结合进行测试免疫检查点阻滞（ICB） 复发性疾病的设置。总体响应率没有重视。对ICB反应的生物标志物 治疗，例如突变烧伤，新抗原负荷，PD-L1表达和基线T细胞浸润 与许多癌症中对ICB治疗的反应有关，并表明ICB治疗需要先前 对临床有效性的免疫力。疫苗虽然单独缩小肿瘤效率低下，但可以可靠地产生 包括大多数OC患者在内的必要的先前的免疫力。在以前的NCI资助赠款中（P50- CA136393），我们开发了一种靶向Th17诱导的疫苗的叶酸受体α（FR），该疫苗在 几乎所有OC患者都会产生Th17 T细胞免疫。开发疫苗的前提是基于 在大量工作中显示i）Th17效应与Tregs之间的相互关系，ii） 提高了IL-17表达，并提高了总体存活率，并且III）Th17 T细胞的耐药性 抑制。进行了I期临床试验，其中19名高级OC患者在首次缓解时为 接种疫苗。所有患者均表现出协调的细胞和体液免疫。在18名患者中评估 效率39％（7/18）在数据审查时仍然没有复发，中位随访为49.2 月份，无复发的生存（RFS）优于历史控制（<15％）。平行鼠建模 展示了一种独特的机制，其中Th17 T细胞免疫坐标否则效率低下Th2，Th2 和B细胞免疫通过粒细胞的募集和抗体依赖机制的激活 巨噬细胞和嗜酸性粒细胞。我们观察到TH17 DC疫苗接种超过了对ICB治疗的抗药性 通过产生肿瘤特异性免疫力，修复肿瘤微环境并防止适应性 对ICB的抵抗力。这是我们假设Th17诱导直流疫苗和ICB的组合 在复发性OC的患者中，治疗可能是一种有效的治疗方法。在特定目标1中，我们将 进行新型Th17诱导DC疫苗的I/II期临床试验与Pembrolizumab结合 （由默克提供）在早期疾病复发的32名患者中。主要结果指标 将是安全性和客观响应速度。将对基线肿瘤特征进行询问 生物标志物识别。在特定目标2中，我们将使用经过良好验证的分析工具来检查细胞和 组合治疗后组织和外周的体液免疫反应以识别主要 治疗引起的免疫反应的特征以及它们是否与临床结果相关 评估。将确定对治疗的抗药性机制。如果是积极的，则是新的治疗冰 将建立治疗范例，以改善患有晚期OC的妇女的生存。