Scientists at UCL have engineered a rare type of immune cell to kill slow-growing bowel cancer cells that are resistant to current therapies, a breakthrough that could lead to new treatments in the future.
Bowel cancer is one of the deadliest cancers in the world, causing over 900,000 deaths every year. While chemotherapy can help, it mostly works by killing fast-growing cancer cells. Unfortunately, many bowel cancer cells grow slowly, which means they can evade treatment and come back later, often more dangerous than before.
An alternative way to kill cancer cells is to use engineered immune cells (the body’s natural defence against infection), which have been shown to be successful in treating blood cancers, such as leukaemia.
For this research, published in Cancer Research, scientists at UCL Cancer Institute and UCL Great Ormond Street Institute of Child Health studied a special and far rarer immune cell type known as ’ T cells’ (pronounced "gamma-delta T cells").
They were building on previous UCL work, which found T cells can be engineered to kill bone cancer cells; however, they were unsure if similar results could be achieved for tumours found outside the bones.
To do this, researchers took T cells from seven healthy people and used a lentivirus to insert a gene into the T cells. This enables the T cells to produce a special protein called stIL-15 which boosts them, helping the cells survive longer and grow faster. A subset of these engineered T cells were also given a B7-H3 antibody, which ’supercharges’ them, helping the cells recognise and bind to bowel cancer cells that express the B7-H3 protein.
They then combined all these engineered cells with mini tumours, called organoids, from ten bowel cancer patients. Organoids mimic cancers’ harsh environment and how the disease behaves, so scientists can see how treatments might work across a range of patients. They did the same for regular (non-engineered) T cells, to see the difference the supercharging made. In total the researchers studied over 1,000 different experimental conditions to understand how T cells interact with bowel cancer cells.
The results were exciting. First, researchers found that while regular T cells died or became weak when exposed to cancer, the engineered T cells could survive for a long time. Second, when the engineered T cells used only one method of attack (known as Antibody-Independent Cytotoxicity (AIC)), the cancer cells were able to defend themselves by "re-wiring" the T cells - basically tricking the immune cells into being less effective.
However, when the supercharged T cells (with the B7-H3 antibody) used two methods of attack (AIC and Antibody-Dependent Cellular Cytotoxicity (ADCC)), the engineered cells were able to restore their wiring and go on to kill the cancer cells - even the slow-growing ones that do not respond to chemotherapy. They also lived far longer and multiplied more.
Corresponding author, Professor Chris Tape (UCL Cancer Institute) said: "This is an exciting step forward. We’ve shown supercharged engineered immune cells can kill bowel cancer cells that are resistant to current clinical therapies. Moreover, by giving T-cells more than one way to attack, we can stop cancer from turning the tables and weakening our immune response."
He added: "This discovery could lead to new treatments for people with bowel cancer, especially those whose cancer has come back or doesn’t respond to chemotherapy."
To observe how the T cells and cancer cells reacted, scientists used a powerful ’phenoscaping’ (single-cell analysis) tool developed at UCL, which creates a detailed map of how cells behave and change.
Corresponding author, Dr Jonathan Fisher (UCL Great Ormond Street Institute of Child Health), who developed the engineered T cell technology, said: "These results highlight the power of engineered T cells in the fight against cancer. We’ve very excited to build on these findings to develop new immunotherapies for solid cancers."
How T cells differ from more common T cells
T cells are far less abundant than regular T cells (alpha-beta) and work in a slightly different way: unlike T cells, which respond to antigens (infection) via warning signals - known as MHC receptors - T cells simply sense when cells are ’stressed’ or behaving oddly and act.
Importantly, unlike T cell therapies that must come from the cancer patient themselves, T cells can be transferred from one person to another so anti-cancer T cells could be supplied by healthy donors.
Engineered T cells explained
Regular T cells’ natural mode of attack is called Antibody-Independent Cytotoxicity (AIC), however the regular cells are naturally weak and die off. Engineering the T cells, expressed with stIL-15, means they can survive longer and use AIC. Further supercharging the engineered T cells with the B7-H3 antibody, allows them to use two methods of attack AIC and Antibody-Dependent Cellular Cytotoxicity (ADCC).
What’s Next?
The scientists hope to continue developing these engineered immune cells and eventually test them in clinical trials. If successful, researchers say, this could become a new kind of therapy for bowel cancer and possibly other solid tumours.
Links
- University College London, Gower Street, London, WC1E 6BT (0) 20 7679 2000
Henry Killworth
E: h.killworth@ucl.ac.uk
