Draper’s Tumor-on-a-Chip Parallels In Vivo Findings of Checkpoint Inhibitor Efficacy in Mice
Draper, in one of the latest lab-on-a-chip advances, has shown that its dynamic, in vitro tumor microenvironment can be used to distinguish tumor responses against two different checkpoint inhibitors in three mouse lines.
The system, named EVIDENT™ (Ex Vivo Immuno-oncology Dynamic ENvironment for Tumor biopsies), “enables both precision-controlled perfusion across biopsied tumor fragments and the introduction of checkpoint-inhibitor-treated tumor-infiltrating lymphocytes in a single experiment,” according to a recent report in the International Journal of Molecular Science.
Experiments performed in parallel using the EVIDENT™ system at Draper and in mouse models at Charles River Laboratories compared results using two different ICI therapies (anti-CTLA4 and anti-PD-1) against three different syngeneic mouse lines (MC38, CT26, and B16F10). The results from the EVIDENT system were consistent with the in vivo mouse studies.
Specifically, “Charles River Labs found that the checkpoint inhibitors stopped the tumor from growing in mice in one mouse model, while Draper’s tumor-on-a-chip showed that the same checkpoint inhibitors killed the tumor (in the same mouse line),” Jeff Borenstein, Ph.D., a group leader in the bioengineering division at Draper, told BioSpace. “In another mouse model, neither drug elicited a response.”
In the other, there was a mixed response. The results correlated with those from Draper’s EVIDENT system.
“Our tests show that EVIDENT can accommodate dynamic interactions between lymphocytes and tumors and is compatible with real-time imaging and quantification of tumor killing and lymphocyte infiltration in response to ICI treatments,” he said in a statement. Importantly, the tumor fragments remain viable for at least a week.
The difference between the two approaches was the time it took to return results.
“The EVIDENT system returned results in five days, whereas the mouse-based research took four to six weeks,” Borenstein said.
Part of the speed can be attributed to the relative sizes of the tissues. The fragments in the EVIDENT system were approximately 150 μm diameter, while the mouse tumors were approximately 10mm in diameter. The “tumor-infiltrating lymphocytes were not required to home and infiltrate very deeply into the tumor fragments,” the paper noted.
The tumor-on-a-chip approach reduced the need for large numbers of mice, and the individual testing of the tumors, and the care of the mice. In contrast, taking a small number of mice, excising fragments of the tumors, putting them on a plate, and performing the experiment is faster.
Labs-on-a-chip have been available, at least at the research stage, for years but are just now gaining traction among drug developers. “Most of the work in the microfluidics evaluation of cancer drugs is done with organoids or spheroids – culture-grown systems,” he elaborated. Those are synthesized and fail to capture the true complexity of the tumor microenvironment in the body. For example, the paper points out, “…most are non-perfused systems that do not capture the dynamics of lymphocyte migration and drug transport , and their study is often of limited duration due to a rapid decline in viability beyond 24–72 hours.”
Thus, as Borenstein said, “To recapitulate what happens in the body, there’s no better way than to take an actual tumor.” Unlike those systems, “The EVIDENT system uses actual biopsies of tumors from mice rather than lab-created models of tumors.”
The EVIDENT system used a 12-channel plate. Draper wants to scale that to 96-well plates. “Tumors are very heterogeneous,” Borenstein pointed out, “so you don’t want to base drug selection, for example, on just one tumor. You want replicates. Fragmenting a tumor (or tumors) provides more evidence,” that leads to more accurate results.
Increasing the plate’s multiplexing capabilities could significantly benefit drug developers, enabling them to simultaneously screen more compounds against a tumor.
As evidence mounts, he expects the system to also be used to determine patient-specific therapies for personalized medicine. For clinicians, increasing the multiplexing capabilities will allow multiple therapeutics to be screened against a patient’s tumor, thereby identifying the one most likely to be effective without the need for the patient to endure a series of failed therapies. Combining information gained from EVIDENT with the growing body of research into biomarkers, genetics, and epigenetics provides a powerful set of tools for both drug developers and oncologists.
Additionally, in the lab, the EVIDENT system lets researchers watch what’s happening to the tumor under a microscope.
“You can monitor activity in real time, and can label the tumor and immune cells to develop a mechanistic understanding of what’s occurring,” Borenstein said.
Draper, as a not-for-profit institution, is collaborating with companies to develop this and tools for drug development and precision medicine. It is working on a variety of programs for diagnostics, devices, and platform technologies. Before they can be rolled out, “We need to partner to increase availability, to enable scale up to bring the device to drug companies and hospitals.
“What’s next,” Borenstein said, “is to use this tumor-on-a-chip system in parallel with mouse studies. As a bridge between high throughput screening and animal studies, Draper’s EVIDENT system can provide fast, statistically significant results early on, allowing researchers to reserve animal studies for confirmation or later stages of development.”