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Flow Cytometry: A powerful tool in drug discovery

Flow cytometry is a powerful tool in drug discovery because it provides a way to understand the drug’s mechanism of action. In order to stratify a better target for patients, you often need to know where the drug is working, and what kind of pathway it is operating along.

For example, at BMS we have ongoing trials where it is crucial to understand what different subsets of cells are doing. One of the ways to track this is through different biomarkers, such as activation or proliferation markers on specific cell types.

We can identify if the drug is causing the proliferation of effector cells, which are pivotal in the response against different tumours or can impact the regulatory T cells. Often, you can look at a substance like myeloid-derived suppressor cells and see a correlation between drug response to treatment and various biomarker expressions.

To meet the different needs of different trials, we design custom-made panels to understand the mechanism of action and develop different assays. This helps us measure target engagement or the pharmacodynamics of the drug. In certain cases, we also perform phospho-flow assays.

What are the challenges of using flow cytometry in drug discovery trials?

The biggest challenge is that we are looking at the periphery. When working in the clinical flow cytometry space, the material available is peripheral blood which doesn’t actually demonstrate exactly what is occurring at the tumour site.

An additional limitation is stability. Due to operational issues with large clinical trials, they are usually global multisite trials where the samples need to be shipped to the testing facility. There often needs to be expanded optimisation and validation to discern the stability of the markers being followed, as they may not be stable over extended periods of time.

In addition, we have to come up with customisable approaches to figure out what type of blood collection tubes need to be used in order to perform biomarker testing and demonstrate that it is relevant and precise.

Can flow cytometry be used effectively with other diagnostic tools?

In drug discovery, flow cytometry certainly needs to be used in conjunction with other diagnostic tools. As the flow cytometry is primarily testing peripheral blood samples, the data needs to be combined with results from the tumour. In immuno-oncology, this means combining it with tumour specific assays. In this case, the majority of the work is done either through immunohistochemistry following different markers or looking at gene expression in single cell RNA from the tumour. By combining all this data we can understand the full picture.

Also, it very important to be careful at which timepoints to do the assay testing because this helps significantly in understanding the kinetics of drug response. You cannot do stricter testing because you want to see the pharmacodynamics of the drug and how it is engaging the receptors. Understanding the whole picture is vital for proper clinical trial design.

How would you like to see you use of flow cytometry develop?

We definitely need to be able to work with multiparameter flow cytometry, which will be significantly more convenient to use. Current systems have been providing limited numbers of fluorochromes that can be used to track the biomarker. Setting up the optimisation of instruments can, therefore, be very time consuming and complicated. Developing technology in this area to allow us to track a larger number of markers is very important.

The other area to develop is being able to look at flow cytometry assays from the tumour itself. These clinical trials are being done in academic centres but right now they are not really used in our company.  We want to be able to look at the tumour cells, and therefore one of our next key frontiers is understanding better the tumour sites during therapy.

The ongoing improvement in technology is crucial for improving our scientific understanding of drug discovery and immuno-oncology. As it increases, it will enable us to better understand the mechanisms of action of the disease, identify responders to the therapy, and stratify patients in order to be more successful in the future.

 

Vilma Decman is Associate Director of Flow Cytometry at Bristol-Myers Squibb.

 

The Flow Cytometry Congress will focus on advances in flow cell and sheath fluid design, the development of new fluorophores, and next-generation detection systems. Visit the event page to download the agenda and register today.

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