Dynamic Microenvironments: Finding the Right Cancer Therapy
With so many promising cancer therapies emerging from research labs, a key challenge for biomedical researchers is to develop tools that accurately predict treatment efficacy against a patient’s specific cancer, thereby avoiding subjecting the patient to a trial and error process to find the best drug. Current practice to determine how a particular drug or drug combination will work on a particular patient’s tumour is to administer the drug for weeks to months and to observe tumour progression over time.
Patients can be fortunate and find success on the first drug prescribed, or they may waste valuable time on a treatment that proves ultimately ineffective. Finding the right therapy is a gruelling, expensive and time-consuming process – in a patient population with extremely limited time.
As a biomedical engineer who develops technology to recapitulate the tissue and organ microenvironment to advance drug development, I have felt for a long time that these technologies could be applied toward a rapid, high-throughput laboratory tool to identify the right cancer drug for patient-specific tumours.
This approach is commonly known as personalised therapeutics or precision medicine. Our tool is based on a microfluidic platform, a tumour microenvironment that mimics conditions in the human body in a dynamic manner. A key advantage of this platform is the ability to recapitulate the interaction between a patient’s immune cells and their tumour and to investigate this interaction as a function of candidate drug therapies in a dynamic and physiologically relevant microenvironment. The platform is designed to test multiple cancer drugs directly on human organ tissue before testing clinically. As the name implies, the Personalised Predictive Assay for Cancer Treatment (PPACT) brings the individual patient into the therapeutic compound discovery process.
Draper’s microfluidics system is a test bed complete with an engineered vascular-like system containing nutrients and lymphocytes, providing the exact conditions to sustain a 3D fragment of the patient’s biopsied tumour tissue. The circulating fluid system delivers different drugs or combinations of drugs along with lymphocytes treated with various compounds, to determine which are most effective at killing the patient’s cancer. If a drug is observed to kill tissues within the PPACT platform, it provides predictive evidence of clinical efficacy against the patient’s cancer.
PPACT can replicate human body functions
Reproducing a human organ system in the lab is the marriage of several emerging and established capabilities. In the case of PPACT, these include microfluidic design and fabrication, imaging and image analytics, systems integration and advances in tumour and immune cell biology.
- Tissue in a 3D format or matrix responds like tissue in the human body, with interactions in three dimensions, unlike simplified 2D models. 3D models significantly increase the ability to model components of the tumour microenvironment and capture the dynamics of tumour and immune cell response.
- Microfluidic channels that can be as small as human capillaries are able to replicate the abnormal conditions of fluid flow and shear stresses found in tumours and blood vessels surrounding a cancerous tumour, flows and stresses that alter cell sensitivity and response to therapeutics. Microfluidic platform materials are selected to avoid problems related to absorption of drugs.
- Microscale pumps circulate blood-like fluid and control delivery of different drugs, or combinations of drugs, with the precision necessary to simulate processes in the human body. These pumps may use micro-electromechanical systems (MEMS) technology in their design or may use scalable pressure control approaches that can be easily scaled to high throughput.
- Image analytic tools combined with high-resolution real-time microscopy are leveraged to provide cellular-level response information over periods of hours to weeks. Clinicians using the image analytics to visualise tumor-immune interactions in three-dimensions can quantify drug responses in ways that extend well beyond conventional imaging approaches.
What does this mean?
PPACT is ideally suited to test the efficacy of immunotherapy drugs, which unleash the body’s own immune system to fight cancer. With the right immune checkpoint inhibitor, the ability to block the immune response is turned off, and the patient’s T-cells are able to attack the cancer. When immune checkpoint inhibitors work, they are remarkably successful, producing long remissions, as experienced by Jimmy Carter in 2015. There are currently more than 20 immune checkpoint inhibitor drugs on the market, but not every cancer responds to each one, and conventional tools to predict the best one are inadequate.
PPACT provides the capability to predict whether and how a particular immune checkpoint inhibitor enables a particular patient’s T-cells to attack a tumour. The precision and scalability of the PPACT microfluidic design enables testing of a large number of therapeutic combinations simultaneously within time frames as short as one week so that patients can start with the right treatment, right away.
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