Blood test uses human stem cells to predict severe drug reactions
Scientists have developed a blood test using human stem cells that predicts whether new drugs will cause severe side effects. The test, which only requires blood from a single donor, could help prevent catastrophic inflammatory reactions known as a cytokine storm in people participating in drug trials.
"As biological therapies become more mainstream, it’s more likely that drugs being tested on humans for the first time will have unexpected and potentially catastrophic effects," says Professor Jane Mitchell from the National Heart and Lung Institute at Imperial College London, who led the study. "We’ve used adult stem cell technology to develop a laboratory test that could prevent another disaster like the TGN1412 trial."
In 2006 six healthy young men were hospitalized with multiple organ failure after experiencing a cytokine storm as a result of taking part in the first tests in humans of the drug TGN1412.
Tests on human cells are essential because biological therapies, or "biologics" (such as the cancer drugs Herceptin and Avastin), use antibodies which are specific to humans. They can cause severe reactions, such as a cytokine storm, that don’t occur in animal studies.
Cytokine storm reactions are difficult to predict using tests where just one cell type is used because they require interactions between blood cells and endothelial cells (the cells which form the lining of blood vessels).
However, because endothelial cells are located deep within the body and are difficult to access, they are normally only grown from tissue removed in surgery, during post-mortem, or from umbilical vessels after birth. Current testing is therefore performed on endothelial cells from one donor and white blood cells from a different donor.
This in itself can present issues; when cells from two different donors are used, one may have an immune reaction to the other, meaning the body is already primed for inflammation before the drug is added, potentially leading to false test results.
The Imperial College London team has developed a new method of testing which requires blood from only one donor, making it far more reliable.
By taking stem cells from the blood of a volunteer and using them to grow endothelial cells in a dish, a process which takes seven to 20 days, then adding them to the donor's white blood cells, they have recreated the unique conditions found in the donor's blood vessels. When the researchers added TGN1412 to the test tube, the cells released a cytokine storm, just as would happen inside the body.
The scientists are now developing an off-the-shelf kit to enable drug companies to use the test on a large scale.
"Our assay so far has used freshly cultured endothelial cells and freshly isolated immune cells," says Mitchell. "The off-the-shelf kit will use endothelial cells and immune cells grown from frozen stocks. This way we can send out to companies a 'kit' with two vials of frozen cells from the same donor and the company can then just add them to their own culture dish and the assay will be ready within days."
"A further benefit of this new technology is that personalized therapies can be tested to see how safe and effective they will be for an individual," adds Dr Daniel Reed, the first author on the study.
The research is published in the FASEB Journal.
Source: Imperial College London