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Tuesday, August 7, 2018

Draper Advances Immuno-Oncology with Microfluidic Model of Dynamics of Tumor-Immune Interactions

CAMBRIDGE, MA—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 utilize the body’s immune system in new ways to treat cancer, and the global market for I-O therapies is expected to exceed $45 billion 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 tumor 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 tumor 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 tumor.

“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 percent. “A microdevice that can mimic the body’s own tumor environment, however, enables researchers to probe the dynamics of interactions between immune cells and patient tumor 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 tumors. The credit card-sized device features 12 parallel and independent channels, each capable of running an independent test of a tumor biopsy fragment interacting with flowing tumor-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 tumor in a range of possible configurations. The platform can sustain tumor 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 tumor killing, enabling mapping of how the drugs work on specific tumors.

Called EVIDENT, for Ex Vivo Immuno-oncology Dynamic ENvironment of Tumor 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 customizable 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 tumors in a high-throughput, scalable configuration.

Draper recently used the EVIDENT platform to demonstrate significantly greater tumor 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.

In tests Draper demonstrated that it could closely mimic the body’s own tumor environment outside the body—and drive and measure tumor-immune interactions—a boon for cancer researchers. An illustration of Draper’s EVIDENT microfluidic platform trapping a tumor sample and keeping it alive during experiments that can last several days. Modified immune cells are introduced to the tumor in Draper's EVIDENT device. Modified immune cells begin attacking the tumor. Researchers can map the death of a tumor over 72 hours or longer using data derived from the EVIDENT microdevice and an image analytic algorithm developed by Draper.
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Image & Data Analytics

Draper combines specific domain expertise and knowledge of how to apply the latest analytics techniques to extract meaningful information from raw data to better understand complex, dynamic processes. Our system design approach encompasses effective organization and processing of large data sets, automated analysis using algorithms and exploitation of results. To facilitate user interaction with these processed data sets, Draper applies advanced techniques to automate understanding and correlation of patterns in the data. Draper’s expertise encompasses machine learning (including deep learning), information fusion from diverse and heterogeneous data sources, optimized coupling of data acquisition and analysis and novel methods for analysis of imagery and video data.

Biomedical Solutions

Draper’s Biomedical Solutions capability centers on the application of microsystems, miniaturized electronics, computational modeling, algorithm development and image and data analytics applied to a range of challenges in healthcare and related fields. Draper fills that critical engineering niche that is required to take research or critical requirements and prototype or manufacture realizable solutions.  Some specific examples are MEMS, microfluidics and nanostructuring applied to the development of wearable and implantable medical devices, organ-assist devices and drug-delivery systems. Novel neural interfaces for prosthetics and for treatment of neurological conditions are being realized through a combination of integrated miniaturized electronics and microfabrication technologies.

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Draper continues to develop its expertise in designing, characterizing and processing materials at the macro-, micro- and nanoscales. Understanding the physical properties and behaviors of materials at these various scales is vital to exploit them successfully in designing components or systems. This enables the development and integration of biomaterials, 3D printing and additive manufacturing, wafer fabrication, chemical and electrochemical materials and structural materials for application to system-level solutions required of government and commercial sponsors.

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