A new study from scientists at the Centre for Cancer Immunology has revealed further insight into the mechanisms of immune checkpoint blocking antibodies.
Immune checkpoints are important molecules on immune cells that need to be released to permit an immune response. This checkpoint system gives our bodies a means to stop incorrect immune responses happening in the first place or, alternatively, turning off immune responses when they need to stop. Unfortunately, in cancer, where we want an immune response, often the checkpoint system is active sending an “off” signal to immune cells preventing them from destroying the cancer.
Immunotherapy drugs called immune checkpoint blocking antibodies work by stopping checkpoint proteins from binding with their partner proteins thereby ‘releasing’ an anti-cancer response. These drugs have transformed cancer treatment and produced positive outcomes for some patients, but unfortunately the majority of patients do not respond or benefit from their use. Understanding better how these drugs work should allow them to be used to treat more patients.
In a new study published in Journal for ImmunoTherapy of Cancer, a team led by Professor Stephen Beers and Dr Juliet Gray, analysed the ‘handle’ portion on a PD-1 immune checkpoint blocking antibody to understand the impact this had on how well it works. Naturally occurring antibodies form an important part of our immune defences to infections by tagging pathogens for clearance. The handle of an antibody is the part that the immune system normally recognises (or ‘grabs hold of’) when the antibody is one that binds to an invading organism. This tagging by the antibody marks out the pathogen to the immune system to kill the invader.
The team showed that for PD-1 immune checkpoint blocking antibodies if the ‘handle’ of the antibody was not functional, a better response was observed. This was because when the handle was active (like a natural antibody) this made the immune system recognise the ‘released’ immune cell and kill them stopping them from acting.
The team used two models of analyses and found that the importance of the handle varied according to whether it was a cancer setting or not and whether there was inflammation or not. In a vaccination model, the team showed that if the handle was able to be bound by the immune system at all there was no immune response. In tumours however the inflammatory environment of the tumour (how many immune cells were there) played a role in how well the immune system responded and the handle became less important, although a non-functioning handle was still best.
Professor Stephen Beers explained: “This tells us that for the best and most consistent results we need an antibody that doesn’t have an active handle. Importantly it also tells us that in less inflamed cancers, we would need to give a combination with a booster drug to wake up an immune response to kill the cancer.”
The team are now working on which combination of drugs would enhance the response in a cold tumour setting.