In the third and final instalment of our blog series on immunotherapies, we explore the emerging field of chimeric antigen receptor (CAR) T cell therapy.
So just what is a CAR T cell?
The previous blogs in this series have shown that a type of immune cell known as T cells are shaping up to be the main players in the development of immunotherapies; CAR T cell therapy takes this one step further – genetically altering T cells so that they specifically recognise and attack proteins found on cancer cells.
CAR T cell therapy involves producing large quantities of these highly specialised T cells, which can only be generated on an individual basis for each patient. Patients provide a blood sample, which their T cells are extracted from and ‘reprogrammed’ to recognise a specific target protein found on the patient’s tumour. To achieve this, the T cells are injected with a harmless virus, which inserts a gene into the T cell’s DNA which causes the T cell to produce a ‘receptor’ on its surface, which specifically recognises the tumour protein. Large quantities of the T cells, all of which are now primed to recognise the tumour, will then be grown in the lab before being injected back into the patient where they will seek out the target protein on cancer cells and attack.
As is often the case with immunotherapies, CAR T cell therapy has already shown success in treating blood cancers. A new CAR T cell therapy, Kymriah, has recently been approved in the United States to treat acute lymphoblastic leukaemia (ALL), a common childhood cancer. Clinical trials were set up to investigate the impact of Kymriah in ALL patients whose condition had relapsed or become resistant to treatment; remarkably, the trial showed that 83% of patients were in remission within three months of this CAR T cell therapy. Although we now need to understand the long term benefits of Kymriah and shouldn’t underestimate its potentially severe side-effects, the approval of Kymriah marks a huge step forwards in the use of CAR T cell therapies to treat a group of patients with limited treatment options.
CAR T cell therapy Kymriah; the first approved cancer treatment to use a patient’s own immune cells (Photo - Novartis)
What about breast cancer?
Although research into treating breast cancer with CAR T cells is at an earlier stage, it’s been found that triple negative breast cancers may be more likely to respond to immunotherapies than other types of breast cancer and so scientists are now focusing on identifying protein targets on the surface of triple negative cancer cells. This is potentially good news for women with triple negative breast cancer, which is typically aggressive and unfortunately there are no current treatments available which specifically target these cancer cells.
One of the protein targets currently under investigation is mesothelin; early stage clinical trials, based in the US, are looking at whether CAR T cells that target this protein can be safely given to patients with triple negative breast cancer. Researchers are also using mouse models of breast cancer to find out whether another protein, known as the folate receptor α (FRα), is also a potential target for CAR T cell therapy, again to treat triple negative breast cancer.
What's the hold up?
As we have discussed previously, the natural ability of a tumour to suppress the immune system can greatly reduce the impact of immunotherapies, including CAR T cells, however researchers also face the major challenge of ensuring that CAR T cells are safe for patients. One of the main risks associated with immunotherapies is the potential to trigger an uncontrolled immune response; known as cytokine release syndrome. This over-activation of the immune cells can cause fever-like symptoms and in more severe cases (a cytokine storm) may even be fatal. Although researchers are investigating different ways to combat this, such as drugs that reverse an excessive immune response or ‘suicide genes’ that are switched on to eliminate the T cells if necessary, further work is clearly needed to ensure patient safety.
Another issue is the ‘on target, off tumour’ effect, where the T cell’s target protein is also found on cells other than the tumour. Breast Cancer Now-funded scientist and self-proclaimed ‘CAR mechanic’, Dr John Maher, is currently working on a way to minimise these side effects in CAR T cells which target the HER2 protein, high levels of which are found on some tumour cells. Small amounts of HER2 are also found in the heart and lungs, meaning that these tissues can also be targeted, leading to damage. Dr Maher is aiming to introduce a ‘brake system’ which would prevent the CAR T cells from attacking tissues where low levels of HER2 are present.
Immunotherapy; the good, the bad and the frustrating
Over recent years there has been an explosion in research into immunotherapies, with great progress being made. Although immunotherapies for breast cancers are currently lagging behind other conditions, such as blood and skin cancers, they still hold great promise for the future. Breast cancer patients urgently need highly targeted, effective treatments that both minimise side effects and reduce the risk of recurrence, and immunotherapies may be able to meet this need.
As research into checkpoint inhibitors, vaccines and CAR T cell therapy progresses to clinical trials and scientists find ways to improve these treatments, we are hopeful that, in time, immunotherapies could become used to treat breast cancer. There are, however, still many hurdles to clear to ensure that immunotherapies are safe to use in patients and to overcome the tumour’s natural ability to hide from the immune system.
As we reach the end of our blog series on immunotherapies for breast cancer, it’s clear that we can expect to hear a lot more from this field in the coming years and we look forward to seeing results from our own scientists and work being carried out worldwide.