Effects of complement C3/C3b inhibition on control of malignant effusions and neutrophil phenotypes in patients with recurrent epithelial ovarian cancer: Interim analysis of a phase 2 clinical trial

Malignant effusions (ME) can promote metastatic seeding and are challenging to manage. Using ME from patients with epithelial ovarian cancer (OC) and other solid tumors as authentic components of the tumor microenvironment (TME), we observed that ME reprogram neutrophils to acquire complement-depend...

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Veröffentlicht in:Immunobiology (1979) Jg. 230; H. 4; S. 152995
Hauptverfasser: Zsiros, Emese, Nazmul Khan, A.N.M., Giridharan, Thejaswini, Suzuki, Sora, DeJohn, Celia, Hess, Suzanne, Mager, Katherine, Werner, Sarah, McLean, Karen, Gaulin, Nicole, Frederick, Peter, Puzanov, Igor, Kolev, Martin, Deschatelets, Pascal, Segal, Brahm
Format: Journal Article
Sprache:Englisch
Veröffentlicht: Elsevier GmbH 01.07.2025
ISSN:0171-2985
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Zusammenfassung:Malignant effusions (ME) can promote metastatic seeding and are challenging to manage. Using ME from patients with epithelial ovarian cancer (OC) and other solid tumors as authentic components of the tumor microenvironment (TME), we observed that ME reprogram neutrophils to acquire complement-dependent T cell suppressor function characterized by inhibition of T cell proliferation and cytokine and metabolic responses. Pegcetacoplan (APL-2) is a C3 and C3b inhibitor approved for paroxysmal nocturnal hemoglobinuria; its use in cancer is novel. The rationale for C3/C3b inhibition includes abrogation of neutrophil recruitment and suppressor function in TME, inhibition of neutrophil extracellular traps (NETs), and reduction of vascular leak driving ME accumulation. We designed a phase 2 trial of pegcetacoplan-based therapy in patients with recurrent OC and persistent MEs (NCT04919629). This trial is conducted at Roswell Park. It includes 2 sequential safety lead-in cohorts: (i) pegcetacoplan alone for 2 weeks followed by addition of pembrolizumab (n = 3), and (ii) pegcetacoplan + pembrolizumab + bevacizumab (n = 3). Subsequent randomized phase cohorts include: (i) bevacizumab (standard of care), (ii) pegcetacoplan + pembrolizumab, and (iii) pegcetacoplan + pembrolizumab + bevacizumab. Primary endpoints are safety and control of ME. Blood, ME, and tumor tissue are collected at baseline and on therapy. Pegcetacoplan–based regimens were well-tolerated to date. Among nine evaluable patients, the best observed response has been stable disease (SD) in seven, including two patients who have not required therapeutic drainage of MEs for over 40 weeks. Pegcetacoplan had no impact on total white blood cell or absolute neutrophil counts but partially abrogated the capacity of MEs to induce neutrophil suppressor function and significantly reduced serum markers of NETosis. In this interim analysis, complement C3/C3b inhibition with pegcetacoplan demonstrates a favorable safety profile and a preliminary signal of ME control in recurrent OC. Immunologic studies suggest that the clinical benefit may be associated with diminished neutrophil suppressor function and NET formation. Further enrollment and long-term follow-up will clarify the therapeutic potential of this novel approach. This work is supported by NIH R01CA267690. Apellis provided pegcetacoplan and Merck provided pembrolizumab in support of the clinical trial.
ISSN:0171-2985
DOI:10.1016/j.imbio.2025.152995