Groundbreaking Mass General-designed cancer cell-sorting chip brings liquid biopsies closer to clinic

BOSTON—Liquid, or blood-based, biopsies are one of the most eagerly awaited new technologies in cancer care. It is hoped that doctors will be able to use these, in place of tissue samples, to diagnose cancer, match tumors to treatment regimens, and monitor therapy response in real-time. That would mean more patients could be tested without side effects from invasive needle biopsies.

Now a team at Massachusetts General Hospital (MGH) has devised a new ultrahigh-throughput microfluidic chip (the ^LPCTC-iCHIP) that improves sensitivity of CTC-based assays 100-fold as compared to the existing approaches. The team’s paper appeared recently in Proceedings of the National Academy of Sciences.

Currently, the most limiting aspect of liquid biopsies is retrieving circulating tumor cells (CTCs) from the patient’s blood. These cells break off from tumors, circulate in the blood stream and have been demonstrated to provide a real-time genetic window into the cancer.

However, CTCs are extremely rare. It is estimated that there is only one CTC per billion in the bloodstream. As a result, there may be zero to about a dozen in a typical 10mL clinical blood sample. The very low number of CTCs severely limits the analytic reliability of liquid biopsy.

To address the low recovery of CTCs, the team proposed a two-step process that first entails routine leukapheresis, an hour-or-so long process that enriches white blood cells and CTCs from whole human blood (~5 Liter) while the remaining components of the blood, including plasma, red blood cells and most neutrophils, are returned to the body.

Apheresis is routinely used when treating a number of health conditions and produces an enriched “leukopak” comprising 6 billion white blood cells and CTCs.  

Six billion nucleated cells are still too many to sort through efficiently for CTCs. That is where the ^LPCTC-iCHIP comes in. The white blood cells (WBCs) from the leukopak are labeled with a magnetic tag, next the entire sample is processed on the chip, which uses on-chip magnetic microlenses to remove most of the WBCs.

The entire process takes less than an hour. More importantly, the ^LPCTC-iCHIP works by removing blood cells so it is agnostic to cancer type and works with samples from any solid tumors.

Alternative CTC isolation technologies can only process about three to five percent of a leukopak. The iCHIP can thus recover thousands more CTCs than current competing approaches.

“Drs. Mehmet Toner, Daniel Haber, and Shyamala Maheswaran applied the precision of microfluidics to rare cell sorting and helped establish the field of liquid biopsy research about ten years ago,” says Avanish Mishra, PhD, a research fellow at the Mass General Cancer Center and Harvard Medical School, who was the co-lead author on the ^LPCTC-iCHIP project along with Taronish Dubash, PhD. “With this novel new technology and our unique process using the leukopak, we transform CTC screening from a 10 mL blood sample to whole human blood; hoping to bring highly reliable liquid biopsies into the clinic.” Toner and Haber are co-corresponding authors on the paper.

“I believe that this new generation ^LPCTC-iCHIP will have a transformative impact in the diagnosis and treatment of cancer, Dubash says. “I am very much excited to implement the technology in patient specimens.”

“This was a great collaboration between cancer biologists and engineers, including Drs. Mishra and Dubash,” says Toner. “Tissue biopsies have a lot of side effects,” he adds. “And now, we have a potential approach that can provide true liquid biopsy for noninvasive isolation of cancer cells for clinical applications.”

The study was supported by the National Institute of Biomedical Imaging, the National Cancer Institute, the American Cancer Society, the Howard Hughes Medical Institute, the Shriners Hospital for Children and the Harvard Medical School Eleanor and Miles Shore Faculty Fellowship Award.

About the Massachusetts General Hospital
Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The Mass General Research Institute conducts the largest hospital-based research program in the nation, with annual research operations of over $1 billion and comprises more than 9,500 researchers working across more than 30 institutes, centers and departments. In August 2019, the Mass General was named #2 in the U.S. News & World Report list of "America’s Best Hospitals.