First-In-Human Rapid Removal of Circulating Tumor Cells in Solid Metastatic Neoplasia by Microbind Affinity Blood Filter

Primary tumors with metastatic potential release circulating tumor cells (CTCs) into the blood stream. In vitro experiments previously demonstrated that the Seraph^® 100 Microbind^® Affinity Blood Filter (Seraph, ExThera, Martinez, CA, USA), an extracorporeal hemoadsorption filter with functional media composed of ultrahigh molecular weight polyethylene and heparane sulfate receptors (shown in Fig. 1a), is capable of removing pathogens and CTCs from blood at high clearance rates [1‒3]. To determine Seraph’s therapeutic and diagnostic potential, we conducted a first-in-human trial evaluating safety and the potential for combined pathogen and CTC removal in patients with solid metastatic cancers.

The study protocol was approved by the IRB Ethical Committee at UHC Zagreb, Croatia (EC/IRB Protocol #02/013AG), and patients gave written informed consent before study enrollment. The Seraph procedure was performed at a hemodialysis clinic on 10 consecutive patients with metastatic cancer whose liquid biopsy was positive for the epithelial cell adhesion molecule as determined by automated microfluorimetric image analysis of epithelial cell adhesion molecule-positive cells with visual control (MAINTRAC) [4, 5]. All of the patients exerted positive bacterial or fungal isolates. The Seraph device was inserted in-series with the dialyzer of a multiFitrate hemodialysis machine (Fresenius, Bad Homburg, Germany – shown in Fig. 1b). Blood flow rate averaged 200 mL/min and duration of the treatment averaged 120 min. After treatment completion, Seraph functional filtration media was removed and evaluated by cell isolation, culture, and identification.

Microbiological investigations prior to procedure yielded presence of various pathogens in all of the 10 patients (i.e., Candida tropicalis, Aspergillus fumigatus, Staphylococcus aureus, Escherichia coli, Klebsiella aerogenes). Hemo cultures obtained 4 h after Seraph therapy were all negative. Pre-procedure CTCs levels ranged from 50 to 2,600 cells/mL (shown in Fig. 1c). Post treatment CTCs ranged from undetectable to 450 cells/mL. The median reduction in CTCs within the 120 min was 71% (IQR 67%–100%). Post procedure, the immunohistochemistry of cells cultured from the Seraph functional media showed positive staining for cytokeratin 19, marker for CTCs of epithelial origin in the blood, which confirmed its CTC binding ability (shown in Fig. 1d). Furthermore, cultured functional media also showed strong staining for Twist1, a marker for epithelial to mesenchymal transition (shown in Fig. 1e). No patient experienced treatment related adverse effects.

The results of this small observational trial demonstrate the ability of Seraph to remove both pathogens and CTCs from patient blood. High yield CTCs clearance could potentially benefit patients in diagnostic and personalized treatment of cancer to be elucidated in further research.

The authors would like to thank Robert Ward, PhD(h), NAE (ExThera Medical Corporation), for his support in this clinical study.

This study protocol was reviewed and approved by the IRB Ethical Committee at University Hospital Center Zagreb, Croatia (EC/IRB Protocol Approval No. [#02/013AG]). Written informed consent was obtained from participants to participate in the study.

While Sanja Ilic is an employee of the Exthera Medical Corporation, the company that has invented Seraph functional media; she have completed collaboration on this article in her personal time. Seraph filters were donated by Exthera Medical Corporation.

The provider of Seraph filters, Exthera Medical Corporation, had no role in the design, data collection, data analysis, and reporting of this study.

S.I. has contributed to the conceptualization, data curation, formal analysis, investigation, methodology, project administration, resources, writing – original draft, and writing– review and editing of the manuscript. V.P. is the corresponding author and has contributed to the conceptualization, data curation, formal analysis, investigation, methodology, validation, visualization, writing – original draft, and writing – review and editing of the manuscript.

Trial registration ID: IRB Ethical Committee at University Hospital Center Zagreb, Croatia (EC/IRB Protocol Approval No. [#02/013AG]).

The data that support the findings of this study are not publicly available due to their containing information that could compromise the privacy of research participants but are available from the corresponding author (V.P.) or Data Sharing Committee (IRB UHC Zagreb, email: [email protected]) upon reasonable request.