Tests in Development
In January Veridex entered into an agreement with Massachusetts General Hospital (MGH) to establish a center of excellence for research on CTC technologies. The overall goal of the agreement is to develop and commercialize novel, quicker technologies for capturing and characterizing CTCs with improved specificity as well as sensitivity.
MGH scientists along with researchers at Harvard Medical School, Shriners Childrens’ Hospital in Boston, and the National Human Genomics Research Institute had developed a microfluidic in which patient blood samples were processed over a silicon chip covered with antibody-coated microscopic posts. This original chip proved challenging to manufacture reliably and cost effectively. Additionally, the smooth flow of blood around the microposts limited the number of CTCs that came into contact with the antibody-covered surfaces.
The researchers found that passing samples through a chamber lined with a herringbone (HB) pattern of grooves worked better because it allowed for rapid mixing of indpendent fluid streams.
Similarly to Veridex’ approved device, the HB chip employs positive selection of CTCs using the EpCAM antibody to capture the cells. But instead of the magnetic nanoparticles Veridex uses, cells are captured onto antibody-coated microposts arrayed in this herringbone pattern under precisely controlled laminar flow conditions. In its previous incarnation, the chip successfully identified CTCs in the peripheral blood of patients with metastatic lung, prostate, pancreatic, and breast cancers at an approximately 50% purity.
The HB chip that replaces the collaborators’ original CTC chip is expected to provide more comprehensive and easily accessible data from captured tumor cells. “The earlier versions of the CTC chip required hand-counting of thousands of microscopic images, which was sufficient for the initial proof-of-principle studies but far too time-intensive for handling high volumes of patient samples,” explained Shannon Stott, Ph.D., of the MGH Center for Engineering in Medicine. “We also were limited in our ability to analyze cellular factors that could be markers for important properties of the tumors.”
Dr. Stott continued, “We are also working to create a plug-and-play version of the machine that will be easy to use clinically, exploring options for large-scale production of the CTC chip, and continuing to optimize the device to increase its speed and efficiency.”
In another approach, researchers described direct measurement of CTCs in the presence of white blood cells on nanoparticles using surface enhanced Raman spectroscopy (SERS). To differentiate between white blood cells and epithelial cells, the Veridex test and CTC chip test treat patient blood samples with anti-CD45 antibodies, which selectively bind to white blood cells allowing them to be visualized and discounted as CTCs in the final enumeration analysis. In the SERS method, nanoparticles with epidermal growth factor peptide as a targeting ligand were used.
The SERS nanoparticles successfully identified CTCs in the peripheral blood of 19 patients with squamous cell carcinoma of the head and neck, with a range of 1–720 CTCs per milliliter of whole blood. The research was conducted by scientists at Emory University and Quest Diagnostics and published in the journal Cancer Research in a paper appearing January 2011.
To date the Veridex test remains the only FDA-approved diagnostic for CTCs. Dr. McCormack said that in terms of the competitive environment, “what’s important is that analytical validation instrumentation and reagents undergo multiple evaluations. There are 20-plus large biotech companies, small biotechs, and academic labs that are developing technologies to enter into the CTC space. The trick is to go beyond a novel observation or different way of doing it.
“It’s a long, long road to get to an FDA approved test,” Dr. McCormack remarked. While technologies for CTC isolation may take a long time to develop and validate, their increasing application in predicting cancer treatment responses, monitoring tumor progression, and identifying novel drug cancer targets may make it worth developers’ time and effort.