Abstract B036: Complement C3 inhibition as a novel immunotherapy strategy in recurrent ovarian cancer with malignant effusions: Interim results from a phase 2 trial of pegcetacoplan

Abstract Malignant effusions (MEs) in ovarian cancer are associated with substantial morbidity, impaired quality of life, and frequently preclude eligibility for clinical trials due to diffuse peritoneal disease and poor performance status. Beyond its clinical burden, ascites contributes to an immunosuppressive tumor microenvironment (TME). We previously showed that MEs reprogram neutrophils into T cell suppressor cells through complement signaling, and that ascitic fluid independently impairs T cell effector function. These findings provided the rationale for the first clinical trial of complement C3 inhibition in cancer (NCT04919629), evaluating pegcetacoplan, a C3/C3b inhibitor approved for paroxysmal nocturnal hemoglobinuria. Here, we present interim clinical and translational results from this ongoing phase 2 trial in patients with recurrent epithelial ovarian cancer and persistent, symptomatic MEs. The trial includes three treatment arms: (i) bevacizumab alone, (ii) pegcetacoplan + pembrolizumab, and (iii) pegcetacoplan + pembrolizumab + bevacizumab. A safety lead-in (n=6) preceded randomization. As of June 2025, 13 patients were enrolled (6 in lead-in, 7 randomized). Pegcetacoplan-based regimens were well-tolerated with no treatment-limiting toxicities. Eleven patients were evaluable; nine achieved stable disease, and two remained without need for therapeutic drainage for over 40 weeks with improved quality of life. Although white blood cell and neutrophil counts remained unchanged, pegcetacoplan therapy significantly reduced serum markers of neutrophil extracellular traps and partially reversed the ability of MEs to induce neutrophil suppressor function. To further investigate immune effects, mechanistic studies were conducted in parallel using ascites supernatants from patients with newly diagnosed ovarian cancer. Ascites suppressed CD3/CD28-stimulated T cell cytokine production (interleukin-2, interferon-γ, interleukin-10), NFAT activation, glycolysis and mitochondrial function, and phosphorylation of key proteins in TCR-NFAT-IL2 and CD28-PI3K-mTOR signaling pathways. These effects were reversed by C3/C3b inhibition but not by blockade of downstream complement proteins. Recombinant complement receptor-1 (rCR-1), a receptor for C3b, inhibited C3b/iC3b binding to T cells following ascites exposure and rescued stimulated IL-2 responses. RNA sequencing of T cells confirmed suppression of activation and metabolic genes by ascites and their rescue with C3/C3b inhibition. These findings identify complement C3 activation as a novel immune checkpoint that disrupts T cell function and contributes to immune evasion in ovarian cancer. Pegcetacoplan-based regimens show preliminary safety and clinical benefit, including durable control of malignant effusions and reversal of key immunosuppressive mechanisms. By restoring T cell function and abrogating neutrophil suppressor activity, complement inhibition offers a promising new avenue for immunotherapy in ovarian cancer and potentially other solid tumors. Citation Format: Emese Zsiros, Thejaswini Giridharan, ANM Nazmul H. Khan, Sora Suzuki, Peter Frederick, Kathrine LaVigne Mager, Karen McLean, Nicole Gaulin, Audrey Rawleigh, Suzanne M. Hess, Celia DeJohn, Maximilian Smidt, Brian A. Joughin, Martin Kolev, Pascal Deschatelets, Michael B. Yaffe, Brahm H. Segal. Complement C3 inhibition as a novel immunotherapy strategy in recurrent ovarian cancer with malignant effusions: Interim results from a phase 2 trial of pegcetacoplan [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Ovarian Cancer Research; 2025 Sep 19-21; Denver, CO. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl):Abstract nr B036.