Massachusetts General Hospital, Harvard Medical School
Harvard-MIT Division of Health Sciences & Technology
Viable tumor-derived circulating tumor cells (CTCs) have been identified in peripheral blood from cancer patients and are probably the origin of intractable metastatic disease. The reliable isolation of CTCs using the microfluidic chip in metastatic cancer offers the possibility of monitoring patient response and changes in tumor genotypes during the course of treatment. However, the ability to isolate CTCs as a potential alternative to invasive biopsies as a source of tumor tissue for detection, characterization and monitoring of cancer patients have proven to be difficult due to the exceedingly low frequency of CTCs in circulation.
We previously demonstrated the effectiveness of a microfluidic device, the CTC-Chip, in capturing rare CTCs using antibody-coated micro-posts under laminar flow conditions. More recently, we developed a second-generation chip based on high throughput microfluidic mixing approach, the herringbone-chip, or ‘HB-chip’, which provides an enhanced platform for CTC isolation. The HB-chip design applies passive mixing of blood cells through the generation of micro-vortices to dramatically increase the number of interactions between target CTCs and the antibody-coated chip surface.
We applied the microfluidic platforms to blood samples obtained from metastatic lung, prostate, breast, colon, and pancreatic cancer patients. These studies with patient blood showed very high sensitivity and specificity of the microchip. We also tested the microchip in a cohort of patients with metastatic cancer undergoing systemic treatment and showed the temporal changes in CTC numbers correlated well with the clinical course of disease as measured by standard radiographic methods.
To further show the utility of the CTC-chip, we isolated CTCs from patients with metastatic non-small-cell-lung cancer and identified the expected EGFR activating mutation in CTCs. We also detected the T790M mutation, which confers drug resistance, in CTCs collected from patients with EGFR mutations who had received tyrosine kinase inhibitors. More recently, we applied microchip to isolate CTCs from blood specimens of patients with either metastatic or localized prostate cancer.
Remarkably, the low shear design of the HB-chip revealed micro-clusters of CTCs in a subset of patient samples. Microscopic CTC aggregates may contribute to the hematogenous dissemination of cancer. Currently, the work is focused on dissemination of the technology to multiple clinical centers as well as the development of novel tools for high sensitivity detection of CTCs for early detection of cancer.