Sub Topic | Secondary Topic: Biotherapeutics and Biotechnology - Biomarkers | Analytical Qualification and Validation
Authors: Ja Hye Myung, University of Illinois (Main Author, Presenting Author); Joseph Caster, University of North Carolina at Chapel Hill; Michael Eblan, University of North Carolina at Chapel Hill; Sin-jung Park, University of Wisconsin, Madison; Kevin Tam, University of Illinois; Andrew Wang, University of North Carolina at Chapel Hill; Seungpyo Hong, University of Wisconsin, Madison
Presenting Author: Ja Hye Myung
Purpose: Although circulating tumor cells (CTCs) can be potentially used as excellent biomarkers for diagnosis and prognosis of many types of cancers, effective detection and isolation of CTCs still remain a tremendous challenge due to their extreme rarity and intrinsic heterogeneity. Our group has developed a CTC-detection platform via a unique combination of biomimetic cell rolling and dendrimer-mediated multivalent binding effect (<B>Fig. 1</B>). This study aims to assess this device using clinical blood samples from cancer patients of various cohorts.
Methods: To exploit the concurrent rolling and binding behaviors of CTCs, our platform was functionalized using recombinant human E-selectin and poly(amidoamine) dendrimers with tumor cell-specific antibodies, respectively (<B>Fig. 1a</B> and <B>1b</B>). An antibody cocktail against CTC surface markers, such as epithelial cell adhesion molecule (anti-EpCAM), human epidermal growth factor-2 (anti-HER-2), and epidermal growth factor receptor (anti-EGFR), were conjugated to the dendrimers on the platform (OncoSense CTCTM, <B>Fig. 1c</B>). Using a control substrate solely functionalized with anti-EpCAM, the CTC capture sensitivity and specificity of OncoSense CTCTM was assessed by comparing the captured CTC numbers from the blood specimens of a cancer patient cohort undergoing radiotherapy (RT). In addition, the potential of OncoSense CTCTMfor therapeutic effect monitoring was evaluated in a human clinical pilot study by collecting peripheral blood at several time points: prior to, throughout, and after completion of RT.
Results: In this human pilot study of 24 confirmed cancer patients, OncoSense CTCTM detected CTCs from all 24 patients upon diagnosis (100% detection rate). Compared to the control surface, the CTC counts on OncoSense CTCTM was highly sensitive (mean ± SE of 1,450 ± 350 CTCs per 7.5 mL of whole blood, range 150 - 6364 CTCs, n = 20) and specific (0.66 - 37.54%, up to 170-fold enhancement). As for the therapeutic monitoring, median CTC counts throughout RT treatment were well correlated to clinical outcomes: among the 20 patients who completed their RT treatment, CTCs declined throughout RT in the 18 patients with complete clinical and/or radiographic response; but an elevation in CTCs in the 2 patients with pathologic residual disease. Our results demonstrate that the kinetic changes in CTC counts measured using OncoSense CTCTM can be utilized as a biomarker for cancer prognosis.
Conclusion: This study using the blood specimens from cancer patients clearly demonstrated the advantages and effectiveness of cell rolling and multivalent binding in improving the sensitivity and specificity of CTC capture, respectively. Although more extensive clinical studies are still required, OncoSense CTCTM has great potential to accurately count CTCs of individual patients and monitor responses of the patients to cancer therapy, which will ultimately allow personalized medicine of cancer treatments and surveillance.
See attached abstract pdf for images.