Microfluidic model of dynamics of tumour-immune interactions

10th August 2018
Enaie Azambuja

Recent successes with immune checkpoint inhibitors (ICIs), such as anti-PD-1 antibodies, continue to fuel interest in immuno-oncology (I-O), one of the most competitive and fastest-growing areas of pharmaceutical R&D. Immuno-oncology therapies utilise the body’s immune system in new ways to treat cancer, and the global market for I-O therapies is expected to exceed $45bn by 2025. Researchers aiming to advance the science, however, are confronting several challenges and limitations in the drug development process.

A sticking point for cancer researchers has been the inability to develop drug therapies in systems that closely mimic the body’s own tumour environment. Typically, pharmaceutical companies rely on a range of animal models and in vitro models.

These latter systems are typically static in nature, comprising multiwell plates containing tumour fragments or spheroids that degrade over periods of hours to days while being tested against candidate compounds.

Further limitations with these in vitro models are that researchers have little control of the interactions with immune cells, and the culture systems do not capture the heterogeneity of the in vivo tumour.

“Current oncology and immuno-oncology models are often poor predictors of clinical performance, can be very expensive and do not permit mechanistic studies,” said Jeff Borenstein, a biomedical engineer at Draper. One estimate puts the clinical success rate for securing Food and Drug Administration approval for a drug in oncology to be only 3.4%.

“A microdevice that can mimic the body’s own tumour environment, however, enables researchers to probe the dynamics of interactions between immune cells and patient tumour fragments, an aspect not anticipated in the original design of many in vitro cancer models.”

In response, Draper has developed a multiplexed microfluidic device for drug development with the aim of improving the predictability of the tests and to further understand how and which immunotherapies work on specific tumours.

The credit card-sized device features 12 parallel and independent channels, each capable of running an independent test of a tumour biopsy fragment interacting with flowing tumour-infiltrating lymphocytes (TILs) in a dynamic microenvironment.

The system permits testing of the effects of immunotherapies individually or in various combinations, and their efficacy when administered to the TILs and the tumour in a range of possible configurations.

The platform can sustain tumour tissue viability outside the body for several days—a significant improvement over static systems—and enable real-time, high-resolution imaging of immune cell infiltration and tumour killing, enabling mapping of how the drugs work on specific tumours.

Called EVIDENT, for Ex Vivo Immuno-oncology Dynamic ENvironment of tumour biopsies, the system features organ-on-a-chip technology, flow-control using a single pump, low-absorption materials and the ability to connect to Draper’s customisable image analytic algorithms to provide automated and quantitative assessment of experimental results.

EVIDENT enables cancer researchers to evaluate how ICIs and other drugs arm the immune system to kill tumours in a high-throughput, scalable configuration.

Draper recently used the EVIDENT platform to demonstrate significantly greater tumour killing in a mouse MC38 model exposed to TILs and treated with ICI therapy versus a control antibody alone, establishing a high correlation with in vivo mouse studies.

The test was intended as a proof-of-concept demonstration of the EVIDENT system, and the research results were published in the journal Lab on a Chip. Authors are Nathan Moore, Daniel Doty, Alla Gimbel, Nathan Lowry, Jose Santos, Vienna Mott, Louis Kratchman and Jeff Borenstein of Draper, and Mark Zielstorff, Ilona Kariv, Lily Moy, George Addona and Hongmin Chen of Merck Research Laboratories.

The EVIDENT multiplex microfluidic system is part of an integrated portfolio of resources at Draper intended to help government, industry and academia make better use of biomedicine.

The company is working with pharmaceutical companies on drug discovery and development; medical device developers to provide clinicians with quantitative diagnostic data at bedside to help them diagnose their patients’ illnesses more accurately and quickly; and biomanufacturing companies on increasing the speed and reducing the cost of processing cell therapies.

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