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

摘要 上皮性卵巢癌(OC)是美国妇科恶性肿瘤的主要死亡原因 各州。而OC是免疫原性的，细胞毒性T淋巴细胞(CTL)的浸润增加与 存活时间较长的单一药物检查点抑制剂在复发/难治环境中大多无效。我们的 长期目标是开发新的方法来克服持久抗肿瘤免疫的障碍，以使 免疫治疗更有效。我们的结果指出了以前未知的成熟机制 中性粒细胞在肿瘤微环境(TME)中获得抑制表型。中性粒细胞 抑制因子抑制循环中的幼稚T细胞、中央记忆T细胞和效应记忆T细胞的增殖。 以及新诊断OC患者的肿瘤相关淋巴细胞(TAL)。中性粒细胞的诱导 抑制表型需要补体信号和NADPH氧化酶的激活。类似的补充- 复发OC患者的腹水诱导依赖的中性粒细胞抑制表型 来自许多转移性癌症患者的恶性积液，强调了我们的 调查结果。这些在人类样本中的结果和其他人在荷瘤小鼠上的工作支持靶向 补充，增强抗肿瘤免疫力。我们将在一项随机的研究中评估APL-2，一种C3多肽抑制剂 复发性OC和持续性恶性积液患者的2期临床试验。APL-2是安全的 优于eculizumab治疗阵发性睡眠性血红蛋白尿(PNH)，并得到FDA的批准 适应症；它在癌症中的应用是新颖的。在安全引导后，患者将被随机分为以下几组 队列：(I)贝伐单抗(抗血管内皮生长因子)；(Ii)APL-2pembrolizumab(抗PD1)；以及(Iii)apl-2pembrolizumab 贝伐单抗。具体目标1：评价恶性积液作为主要终点的安全性和可控性 和无进展生存率(PFS)、客观应答率(ORR)、疾病控制率(DCR)、总体 生存(OS)和生活质量(QOL)作为次要终点。具体目标2：确定 基于APL-2的治疗对TME免疫反应的调节作用。病人样本(血液、积液、肿瘤) 将在试验期间的基线和预先指定的时间点收集。我们将测试APL-2的程度 将消除中性粒细胞抑制活性，并扩大激活的T细胞在TME。一种组合 循环和腹水中性粒细胞和T细胞的功能研究及转录和质量细胞分析 将执行单元格。我们建议的影响是获得APL-2的安全性和初步疗效数据- 复发性OC伴恶性积液的基本治疗方案以及对这些方案的详细了解 调节TME中的免疫格局。这项研究有望为更大规模的 明确测试C3抑制在增强癌症免疫治疗中的有效性的随机试验。

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.