Targeting complement to enhance antitumor immunity and control malignant effusions in patients with recurrent epithelial ovarian cancer

靶向补体增强复发性上皮性卵巢癌患者的抗肿瘤免疫并控制恶性积液

• 批准号: 10530911
• 负责人: Brahm H Segal
• 金额: $ 69.39万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-24 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10530911
• 关键词: Anaphylatoxins; Ascites; Biology; Blood; Blood Circulation; Blood Vessels; Cancer Patient; Cause of Death; Chemotactic Factors; Complement; Complement 3a; Complement 5a; Complement component C4a; Cyclophosphamide; Cytometry; Cytotoxic T-Lymphocytes; Data; Diagnosis; Disease; Disseminated Malignant Neoplasm; Epithelial ovarian cancer; Exposure to; FDA approved; FRAP1 gene; Foundations; Genetic Transcription; Goals; Granulopoiesis; Guidelines; Human; Hybrids; Immune; Immune checkpoint inhibitor; Immune response; Immunosuppression; Immunotherapy; Infiltration; Inflammatory; Lead; Liquid substance; Lymphocyte; Malignant - descriptor; Malignant Female Reproductive System Neoplasm; Malignant Neoplasms; Malignant neoplasm of ovary; Memory; Mitochondria; Modeling; Mus; Myeloid-derived suppressor cells; NADPH Oxidase; National Comprehensive Cancer Network; Neutrophil Infiltration; Newly Diagnosed; Oral; Pathway interactions; Patients; Peptides; Phase II Clinical Trials; Phenotype; Progression-Free Survivals; Quality of life; Randomized; Recurrence; Refractory; Regimen; Relapse; Research; Safety; Sampling; Signal Pathway; Signal Transduction; Specific qualifier value; Suppressor-Effector T-Lymphocytes; T memory cell; T-Cell Activation; T-Lymphocyte; Testing; Time; Tumor Immunity; Tumor-infiltrating immune cells; United States; Vascular Endothelial Growth Factors; Work; anti-PD-1; arm; base; bevacizumab; cancer immunotherapy; cell injury; chemokine; cohort; cytokine; disorder control; efficacy testing; effusion; glucose uptake; granulocyte; immunogenic; immunoregulation; inhibitor; neutrophil; novel; novel strategies; objective response rate; paroxysmal nocturnal hemoglobinuria; pembrolizumab; phase II trial; primary endpoint; randomized trial; response; response to injury; secondary endpoint; standard of care; survival prediction; therapeutic target; tumor; tumor microenvironment; tumor progression

Abstract Epithelial ovarian cancer (OC) is the leading cause of death from gynecological malignancies in the United States. While OC is immunogenic and increased infiltration of cytotoxic T lymphocytes (CTL) correlates with longer survival, single agent checkpoint inhibitors are largely ineffective in the relapsed/refractory setting. Our long-term goal is to develop novel approaches to overcome obstacles to durable antitumor immunity to make immunotherapy more effective. Our results point to previously unrecognized mechanisms for mature neutrophils acquiring a suppressor phenotype within the tumor microenvironment (TME). Neutrophil suppressors inhibited stimulated proliferation of circulating naïve, central memory, and effector memory T cells, and of tumor-associated lymphocytes (TAL) from patients with newly diagnosed OC. Induction of the neutrophil suppressor phenotype required complement signaling and NADPH oxidase activation. A similar complement- dependent neutrophil suppressor phenotype was induced by ascites from patients with recurrent OC and from malignant effusions from patients with a number of metastatic cancers, underscoring the generalizability of our findings. These results in human samples and work by others in tumor-bearing mice support targeting complement to enhance anti-tumor immunity. We will evaluate APL-2, a peptide C3 inhibitor, in a randomized phase 2 clinical trial in patients with recurrent OC and persistent malignant effusions. APL-2 was safe and superior to eculizumab for paroxysmal nocturnal hemoglobinuria (PNH) and is FDA-approved for this indication; it’s use in cancer is novel. Following a safety lead-in, patients will be randomized to the following cohorts: (i) bevacizumab (anti-VEGF); (ii) APL-2 + pembrolizumab (anti-PD1); and (iii) APL-2 + pembrolizumab + bevacizumab. Specific Aim 1: To evaluate safety and control of malignant effusions as primary endpoints and progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), overall survival (OS), and quality of life (QoL) as secondary endpoints. Specific Aim 2: To determine the effects of APL-2-based therapy in modulation of immune responses in the TME. Patient samples (blood, effusion, tumor) will be collected at baseline and at pre-specified time points during the trial. We will test the extent that APL-2 will abrogate neutrophil suppressor activity and expand activated T cells in the TME. A combination of functional studies and transcriptional and mass cytometry profiling of circulating and ascites neutrophils and T cells will be performed. The impact of our proposal is to gain safety and preliminary efficacy data on APL-2- based regimens in recurrent OC with malignant effusions and a detailed understanding of how these regimens modulate the immune landscape in the TME. This research is expected to establish the foundation for larger randomized trials to definitively test the efficacy of C3 inhibition in enhancing cancer immunotherapy.

抽象的 上皮卵巢癌（OC）是联合妇科恶性肿瘤死亡的主要原因 国家。虽然OC具有免疫原性，并且会增加细胞毒性T淋巴细胞（CTL）的浸润与 在继电器/难治设置中，单药检查点抑制剂在很大程度上无效。我们的 长期目标是开发新的方法，以克服耐用的抗肿瘤免疫的障碍以使 免疫疗法更有效。我们的结果指出了以前未被认可的成熟机制 中性粒细胞在肿瘤微环境（TME）内获得抑制表型。中性粒细胞 补充剂抑制了循环幼稚，中央记忆和效应记忆T细胞的刺激增殖， 来自新诊断的OC患者的肿瘤相关淋巴细胞（TAL）。诱导中性粒细胞 抑制剂表型需要完成信号传导和NADPH氧化物激活。类似的完成 - 复发性OC的患者的腹水诱导依赖性嗜中性粒细胞抑制作用，并 来自多种转移性癌症患者的恶性积液，强调了我们的普遍性 发现。这些结果是人类样本，其他人在承重肿瘤的小鼠中的作用 补充以增强抗肿瘤免疫力。我们将在随机的 反复发生OC和持续性恶性积液患者的2阶段临床试验。 APL-2很安全， 优于eculizumab，用于阵发性夜间血红蛋白尿症（PNH），并为此批准了FDA 指示；它用于癌症是新颖的。安全引导后，患者将随机分配到以下 队列：（i）贝伐单抗（抗VEGF）; （ii）APL-2 + Pembrolizumab（抗PD1）; （iii）APL-2 + pembrolizumab + bevacizumab。特定目的1：评估恶性排出素作为主要终点的安全和控制 和无进展生存期（PFS），客观反应率（ORR），疾病控制率（DCR），总体 生存（OS）和生活质量（QOL）作为次要终点。特定目的2：确定 基于APL-2的治疗，用于调节TME的免疫复杂。患者样品（血液，积液，肿瘤） 将在基线和试验期间预先指定的时间点收集。我们将测试APL-2的程度 将废除中性粒细胞抑制活性并扩大TME中活化的T细胞。组合 循环和腹水中性粒细胞和t的功能研究以及转录和质量细胞仪分析 细胞将进行。我们的建议的影响是获得安全性和初步效率数据对APL-2- 具有恶性积液的复发性OC中的基于基于的方案，并详细了解这些方案 调节TME中的免疫景观。这项研究有望为更大的基础奠定基础 随机试验可确定测试C3抑制在增强癌症免疫疗法方面的效率。