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: 10689822
• 负责人: Brahm H Segal
• 金额: $ 64.57万
• 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/10689822
• 关键词: Anaphylatoxins; Ascites; Biology; Blood; Blood Vessels; Cancer Patient; Cause of Death; Chemotactic Factors; Circulation; 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; 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; Morphology; 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; Proliferating; Quality of life; Randomized; Recurrence; Refractory; Regimen; Relapse; Research; Response Generalization; Safety; Sampling; Signal Pathway; Signal Transduction; Specific qualifier value; Suppressor-Effector T-Lymphocytes; T cell infiltration; T memory cell; T-Cell Activation; T-Lymphocyte; Testing; Therapeutically Targetable; Time; Tumor Immunity; United States; Work; anti-PD-1; arm; bevacizumab; cancer immunotherapy; cell injury; chemokine; cohort; cytokine; disorder control; efficacy evaluation; efficacy testing; effusion; glucose uptake; granulocyte; immunogenic; immunoregulation; inhibitor; neutrophil; novel; novel strategies; nuclear factors of activated T-cells; 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; 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.

摘要