Upgrading the immune system

Scientists re-engineer body’s immune system for safer and more effective cancer treatment

Scientists have demonstrated a new way of re-engineering the body’s immune system to target cancer, paving the way for a new generation of drugs, unprecedented in safety and effectiveness.

Researchers from Cardiff used powerful X-ray technology to engineer an enhanced kind of white blood cell – known as a T-Cell– capable of targeting cancerous tissue while minimising contact with healthy tissue, which can be fatal to patients receiving this kind of experimental therapy.

Targeting cancer using T-cells is a growing therapeutic area. They are however limited in their cancer-fighting potential, owing to their inability to attack the body’s own tissue. This is a major obstacle for researchers trying to target cancer cells which often derive from healthy cells.

To overcome this, scientists use an enhanced, modified T-cell receptor (TCR); a molecule on the surface of T-cells that acts like highly-sensitive fingertips that probe the body for signs of disease. This approach is currently being trialed for a wide range of cancer targets, but remains potentially dangerous to trial participants.

In 2013, a New York-based cancer immunotherapy phase 1 clinical trial had to suspend patient recruitment owing to the deaths of two patients who received modified TCRs, which caused lethal damage to their heart tissue.

For the first time, scientists based within the University’s School of Medicine have been able to explain why the experimental therapy caused these deaths. Their findings are published today in the journal Scientific Reports.

Using Diamond Light Source, the UK’s synchrotron science facility, the group was able to use intense light, 10 billion times brighter than the sun, to uncover how these tragedies took place.

Exploiting a technique known as X-ray crystallography – the same technique used to solve the structure of DNA – they demonstrate how a modified TCR, which was intended to target a cancerous antigen, mistakenly began attacking healthy heart tissue.

The synchrotron enabled the team to visualize this interaction between the engineered TCR and the cancer and heart tissue markers, to reveal that at an atomic level they were both similar in shape, making it extremely difficult for the T-cells to differentiate between the two.

Dr David Cole, from the University’s School of Medicine, senior author on the study, said: “This discovery is significant in a number of ways. Firstly, the images gleaned by the X-ray crystallography enabled us to directly reengineer the modified TCRs to significantly reduce its contact with healthy tissue, which is proof of concept for a safer, more effective design for a next generation of cancer drugs.

“Secondly, it shows how T-cells might cause unwanted damage to healthy tissue in other diseases such as type 1 diabetes, multiple sclerosis and rheumatoid arthritis. Moreover, the data explains, at the molecular level, why two patients suffered from cardiovasculardamage after receiving a novel cancer treatment – and how to avoid this from happening in future.”

Dr Pierre Rizkallah, lead author, also from the University’s School of Medicine, said: “The key to the new findings is the ability to visualise, at the atomic level, how the TCR ‘sees’ different markers, whether expressed on cancer cells or healthy cells. This is drug design on the scale of a protein, and X-ray diffraction is truly an incomparable tool in our hands for achieving these results.”

Professor Brian Baker, from the University of Notre Dame, said: “Modified T-cells are currently generating a huge amount of interest as a new breakthrough therapy to fight cancer. However, there is still much to learn about the potential side effects that these modified cells may have.

“The striking new study by Dr Cole and colleagues represents a very significant step in demonstrating why unanticipated side effects can occur, and how they might be avoided in future work, improving both safety and efficacy in cancer immunotherapy.”

The research was funded by The Wellcome Trust, with support from the facilities and staff at Diamond Light Source.