Abstract 4956: CD34bright/CD133neg candidate circulating endothelial progenitor cells (ccEPCs) are a potential biomarker during treatment with sunitinib or bevacizumab
Authors: Vroling Laura , van der Veldt Astrid A.M. , de Haas Richard R , Schuurhuis Gerrit Jan , van Cruijsen Hester , van den Eertwegh Alfons J.M. , Hoekman Klaas , van Hinsbergh Victor W.M. , Boven Epie , Smit Egbert F. , Broxterman Henk J. 
Published: May 2019

An ongoing effort in the clinical application of anti-angiogenic cancer therapy is to identify and validate molecular and/or cellular biomarkers that could predict response as well as enhance our insight in the pharmacodynamics of these agents. Here we study therapy-induced changes in the frequency of a novel rare circulating cell population, characterized by a CD45neg / CD34bright / CD133neg marker profile, which was recently shown to be the source of highly proliferative endothelial outgrowth cells. These candidate cEPCs (ccEPCs) were measured during treatment of 23 renal cell cancer patients with the receptor tyrosine kinase inihibitor, sunitinib and 19 non-small cell lung cancer patients with the monoclonal antibody bevacizumab together with the EGFR inhibitor erlotinib. In addition plasma VEGF was monitored. Tumor response was assessed with Computed Tomography (CT)-scans according to RECIST criteria. In patients treated with sunitinib an opposite change in the frequency of CD34bright/ CD45dim/CD133pos (hematopoetic progenitor cells, HPCs) and CD34bright/CD45neg /CD133neg (ccEPCs) was seen. The median of ccEPCs increased from 69 before treatment (C1Day1) to 180 cells/ml on C1Day14 (P= 0.001) and to 229 (n=14, P=0.013) on C1Day28, while the HPCs decreased from 1350 on C1Day1 to 372 cells/ml on C1Day14 (n= 23, P=0.000) to 409 on C1Day28 (n=14, P= 0.001). Plasma VEGF levels showed an increase during treatment, parallel to the ccEPC numbers. These effects were treatment-related as both cell populations and plasma VEGF levels returned to pretreatment levels after the 2 weeks rest period (C2Day1). The responders group (PR+SD) showed an increase of ccEPCs ( median 82 to 188, P=0.001), while no significant increase was found in the non-responders group (PD) but this group (n=5) was limited in size (median 69 to 145, P=0.686). In patients treated with bevacizumab and erlotinib, but not with erlotinib alone (controls) ccEPCs also increased, whereas the HPCs remained stable during treatment and the free plasma VEGF levels decreased. The relation to tumor response is being analyzed.

In conclusion, two CD34bright populations, ccEPCs and HPCs, which both are partly VEGFR2pos, showed a different response to anti-VEGF(R) treatment. This study therefore implicates that in future analysis of CD34bright/VEGFR2pos cEPCs, a distinction has to be made between CD45neg and CD45dim cells. Since, recent studies in mice have shown that human highly proliferative EPC outgrowth cells are functionally important in neovascularization, the potential role of ccEPCs in human tumor angiogenesis and their increased numbers upon anti-VEGF therapy warrants further study. Larger studies are needed to define the predictive potential of these cells for the outcome of anti-angiogenic therapies.