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 在美国，卵巢癌 (OC) 每年导致约 14,000 人死亡，尽管在这方面取得了进展。 近年来，已经进行了多项试验，但进展常见且治愈率较低。 单独或与其他药物联合测试免疫检查点阻断（ICB），主要是在 复发性疾病的总体反应率并不理想。 治疗，如突变负荷、新抗原负荷、PD-L1 表达和基线 T 细胞浸润， 与许多癌症对 ICB 治疗的反应相关，并表明 ICB 治疗需要预先存在 疫苗虽然单独作用于缩小肿瘤效果不佳，但可以可靠地产生临床效果。 必要的预先存在的免疫力，包括大多数 OC 患者 在先前 NCI 资助的拨款中（P50-）。 CA136393），我们开发了一种针对 Th17 诱导疫苗的叶酸受体 α (FRα)，该疫苗可有效 在几乎所有 OC 患者中产生 Th17 T 细胞免疫是开发疫苗的前提。 大量工作表明 i) Th17 效应子和 Tregs 之间存在相互关系，ii) IL-17 表达增加，总体存活率提高；iii) Th17 T 细胞对免疫的抵抗力 进行了一项 I 期临床试验，其中 19 名首次缓解的晚期 OC 患者接受了治疗。 所有患者均表现出协调的细胞和体液免疫力，其中 18 名患者可进行评估。 疗效，39% (7/18) 在数据审查时保持无复发，中位随访率为 49.2 月，无复发生存（RFS）优于历史对照（<15%）。 Th17 T 细胞免疫协调低效 Th1、Th2 的独特机制 和 B 细胞免疫通过骨髓募集和抗体依赖性机制的激活 我们观察到 Th17 DC 疫苗接种克服了对 ICB 治疗的耐药性。 通过产生肿瘤特异性免疫、重建肿瘤微环境、预防适应性 因此，我们寻求将诱导 Th17 的 DC 疫苗接种与 ICB 相结合。 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，我们将进行治疗。 进行新型 Th17 诱导 DC 疫苗与 pembrolizumab 联合的 I/II 期临床试验 （由默克公司提供）在 32 名 OC 患者中进行了早期疾病复发的主要结果测量。 将进行安全性和客观反应率的基线肿瘤特征询问。 在具体目标 2 中，我们将使用经过充分验证的分析工具来检查细胞和生物标志物。 联合治疗后组织和外周的体液免疫反应以确定显性免疫反应 治疗引起的免疫反应的特征及其是否与临床结果相关 如果呈阳性，将确定治疗耐药机制。 将建立治疗模式以提高患有晚期 OC 的女性的生存率。