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死亡的主要原因。 States.虽然OC是免疫原性的，并且细胞毒性T淋巴细胞（CTL）浸润的增加与 更长的存活期，单药检查点抑制剂在复发/难治性环境中基本上无效。我们 长期目标是开发新的方法来克服持久抗肿瘤免疫的障碍， 免疫治疗更有效。我们的研究结果指出了以前未被认识到的成熟的机制， 中性粒细胞在肿瘤微环境（TME）中获得抑制表型。中性粒 抑制剂抑制循环幼稚T细胞、中枢记忆T细胞和效应记忆T细胞的刺激增殖， 和肿瘤相关淋巴细胞（TAL）从新诊断的OC患者。中性粒细胞的诱导 抑制表型需要补体信号传导和NADPH氧化酶激活。类似的补充- 依赖性中性粒细胞抑制表型是由复发性OC患者的腹水和 一些转移性癌症患者的恶性积液，强调了我们的普遍性， 调查结果。这些在人类样本中的结果和其他人在荷瘤小鼠中的工作支持靶向 补充以增强抗肿瘤免疫力。我们将评估APL-2，一种肽C3抑制剂，在一个随机的， 在复发性OC和持续性恶性积液患者中进行的II期临床试验。APL-2是安全的 在阵发性睡眠性血红蛋白尿症（PNH）方面上级依库珠单抗，并已获得FDA批准 适应症;它在癌症中应用是新的。安全性导入后，患者将随机分配至以下组 队列：（i）贝伐单抗（抗VEGF）;（ii）APL-2 +派姆单抗（抗PD 1）;和（iii）APL-2 +派姆单抗 + 贝伐单抗。具体目的1：评价恶性积液作为主要终点的安全性和控制 和无进展生存期（PFS）、客观缓解率（ORR）、疾病控制率（DCR）、总体 生存期（OS）和生活质量（QoL）作为次要终点。具体目标2：确定 基于APL-2的治疗在TME中调节免疫应答。患者样本（血液、积液、肿瘤） 将在基线和试验期间预先规定的时间点采集。我们将测试APL-2 将消除嗜中性粒细胞抑制活性并扩增TME中的活化T细胞。的组合 循环和腹水中性粒细胞和T细胞的功能研究以及转录和质谱分析 细胞将被执行。我们的建议的影响是获得APL-2的安全性和初步疗效数据， 复发性OC伴恶性积液的基础方案，并详细了解这些方案 调节TME中的免疫状况。这项研究有望为更大规模的研究奠定基础。 随机试验，以明确测试C3抑制在增强癌症免疫治疗中的功效。

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.