In the first part of our 'Breast Cancer Now Explains...' blog series, we take a close look at immunotherapy and, in particular, immune checkpoint inhibitors – what are they and why are they important?

Monday 20 March 2017      Research blog
A healthy human T cell

A scanning electron micrograph of a healthy human T cell

Immune checkpoint inhibitors

The development of treatments that use the immune system to target and kill cancer cells, known as immunotherapy, is a rapidly growing and exciting area of research. We take a look at the science behind immunotherapies and the different ways researchers around the world are harnessing the immune system to attack breast cancer.

The immune system – what’s it ever done for us?

Our immune system is made up of specialised cells, tissues and organs which work together to patrol our bodies on the lookout for pathogens such as bacteria and viruses, which may harm our health.

The cells of our immune system are in fact white blood cells; there are many different types of white blood cell, each with a unique role in protecting the body from infection. One type, known as antigen-presenting cells, ‘eat’ the pathogens that they encounter and then display the digested proteins from these pathogens on their surface. These proteins are called ‘antigens’ and act as a flag to alert other white blood cells known as T cells to an infection.

T cells have the important role of assessing whether cells are healthy or potentially harmful; if a harmful antigen is detected, T cells spring into action and trigger an immune response, activating other immune cells to immediately target and kill the pathogens. This also leads to the development of antibodies, which recognise pathogens with the same antigens if they are encountered again in the future, meaning they can be rapidly targeted.

Antigen detection by immune cells: Diagram showing antigen-presenting cell (APC) and Pathogen and the immune response triggered when a T-cell detects a harmful antigen.

Antigen detection by immune cells: An immune response is triggered when T-cells detect harmful antigens on the surface of immune cells known as antigen-presenting cells.

Why use immunotherapy to treat cancer?

To give breast cancer patients the best possible chance of surviving the disease, they often undergo an extensive course of treatment, including surgery, radiotherapy, chemotherapy and targeted drugs such as tamoxifen. While these common treatments have dramatically improved breast cancer survival rates in recent decades, they unfortunately come with side effects and don’t always stop breast cancer from coming back.

In addition to developing more effective ways to treat breast cancer, it’s crucial that these new treatments allow patients to live their lives to the full.

Many researchers believe that immunotherapies could be the answer; these highly targeted treatments are designed to harness the power of a patient’s own immune system to detect and kill cancer cells, and cancer cells alone – reducing the risk of harmful side-effects. It’s also hoped that the immune system’s ability to ‘remember’ potentially damaging antigen ‘flags’ means that immunotherapies may offer long lasting protection against cancer.

What’s the hold up?

Some immunotherapies are now routinely used to treat cancers such as melanoma and advanced kidney cancer. Outcomes for melanoma patients have dramatically improved with the use of immunotherapies. A follow-up study of advanced melanoma patients who received the immunotherapy drug nivolumab (Opdivo) found that over a third of patients who received the drug in early-stage clinical trials were still alive five years later, and on average patients in the trial lived for 17.3 months. Before the introduction of immunotherapies, the average survival time for advanced melanoma patients was around 11 months.

However, immunotherapies for breast cancer have not seen the same headline-grabbing success. For many years it was believed that this is because breast cancer cells do not provoke a strong immune response, however recent research has suggested that breast cancer and the immune system are more closely linked than previously thought. Studies have shown that triple negative breast cancers are likely to be more sensitive to the immune system than other types of breast cancer, and it is possible to predict how triple negative patients will respond to treatment based on the number of immune cells found within their tumour. Much of the current immunotherapy research is therefore being carried out into triple negative breast cancer, so progress in this field could have a real impact for these patients, who currently have limited treatment options available to them.

There are many different ways in which researchers are investigating the use of immunotherapies in breast cancer. In this blog series, we'll explain the main methods currently being investigated: immune checkpoint inhibitors, vaccines and adoptive T cell transfer.

So what are immune checkpoint inhibitors?

An important function of the immune system is its ability to recognise our own cells and tissues as ‘self’, which stops them from being attacked. Although cancer cells are produced by our bodies, their many genetic mutations alert the immune system that they are abnormal and therefore need to be destroyed. Unfortunately, cancer cells are master manipulators and quickly develop ways to evade the immune system and suppress its response.

One of the ways that cancer cells can avoid detection is via their ability to ‘hide’ from the immune system by manipulating molecules called immune checkpoints. These molecules have a crucial role in regulating the immune system and normally ‘switch off’ an immune response when it’s no longer needed, preventing healthy cells and tissues from damage.

Checkpoint molecules, such as PD-1 and CTLA-4, are found on the surface of T cells. They interact with proteins on the surface of other cells to decide whether an immune response is required, or if it should be suppressed. Cancer cells are able to hijack this process by producing proteins which instruct T cells not to activate an immune response.

One such checkpoint interaction - between the PD-1 receptor on T cells and the PD-L1 protein on the cancer cell, is currently being investigated as a potential target for immunotherapy drugs to treat breast cancer. Drugs are being developed that will block either PD-1 on the T cell or PD-L1 on the cancer cell and prevent the interaction between these two molecules. This will ‘unmask’ the cancer cells, meaning that an immune response can be activated.

Stage one: Immune response suppressed: diagram of a T-cell, breast cancer cell and antigens. Stage two: Immune response activated: diagram of a T-cell and breast cancer cell, which shows drugs blocking PD-L1 and PD-1 receptor

Stage one - Immune response suppressed: An immune response is suppressed when the PD-L1 protein on a cancer cell interacts with the PD-1 receptor on a T-cell.

Stage two - Immune response activated: An immune response against the cancer cell is activated when drugs prevent PD-L1 and the PD-1 receptor from activating.

Stage one: Immune response suppressed: diagram of a T-cell, breast cancer cell and antigens.

Stage one - Immune response suppressed: An immune response is suppressed when the PD-L1 protein on a cancer cell interacts with the PD-1 receptor on a T-cell.

Stage two: Immune response activated: diagram of a T-cell and breast cancer cell, which shows drugs blocking PD-L1 and PD-1 receptor

Stage two - Immune response activated: An immune response against the cancer cell is activated when drugs prevent PD-L1 and the PD-1 receptor from activating.

Stage one: Immune response suppressed: diagram of a T-cell, breast cancer cell and antigens.

Stage one - Immune response suppressed: An immune response is suppressed when the PD-L1 protein on a cancer cell interacts with the PD-1 receptor on a T-cell.

Stage two: Immune response activated: diagram of a T-cell and breast cancer cell, which shows drugs blocking PD-L1 and PD-1 receptor.

Stage two - Immune response activated: An immune response against the cancer cell is activated when drugs prevent PD-L1 and the PD-1 receptor from activating.

Does it work though?

Patients in England and Wales with advanced melanoma recently became the first in Europe to be given a combination of two drugs that block immune checkpoints. Clinical trials showed that over 60% of patients responded well to the drugs, nivolumab (Opdivo) and ipilimumab (Yervoy), which block the immune checkpoints PD-1 and CTLA-4 respectively. In comparison, only 11% of patients given ipilimumab alone responded well. Although this combination of drugs shows great promise for many melanoma patients, around a third of the trial participants had to stop taking the treatment due to the side effects they experienced.

Research is still being carried out to confirm whether checkpoint inhibitor drugs could be safe and effective in the treatment of breast cancer. Much of this research is still in the early stages, but so far, we have seen some promising results, especially in patients receiving the checkpoint inhibitor atezolizumab (Tecentriq) alongside chemotherapy drugs, and pembrilozumab (Keytruda).

Early stage clinical trials are being carried out worldwide, including in the UK, where patients with advanced triple negative breast cancer are being given a drug called durvalumab (previously known as MEDI4736) that blocks PD-L1 in combination with another drug, the PARP-inhibitor olaparib. We’re expecting to hear early results from some of these trials in the coming years, so stay tuned for more checkpoint inhibitor news as we learn about the potential benefits and side-effects of these innovative drugs for breast cancer patients.

More information

Read more about the research projects into immunotherapy we are funding:


Next up in our 'Breast Cancer Now explains. . . Immunotherapy' series, we’ll be discussing breast cancer vaccines.


 

About the author

Rachel Leahy is a Research Communications Officer at Breast Cancer Now.

She has a Masters in Regenerative Medicine and gets excited talking about tissue engineering.

The Research Communications team keeps our supporters and the public up to date with the exciting progress our scientists are making against breast cancer, as well as research news from around the world.