Introduction 

Immunotherapy refers to a range of treatments that utilises the person’s immune system to fight cancer. Immunotherapy is currently used to treat a range of cancers, including breast cancer either on its own or in combination with other treatments. Fortunately, there are good immunotherapy treatments for triple-negative breast cancer, which has historically had less treatments and had a poorer prognosis compared to other breast cancer types.¹

Understanding the immune system 

The immune system functions to protect the host against microorganisms through distinguishing between self (own cells) and non-self cells. The immune system also has an antitumor response, where it recognises cancer antigens (markers) that are only expressed on cancer cells. Cells such as NK and T cells recognise these markers and initiate the killing of the cancer cell).

However, cancer cells and tumours can evade the immune system by: 

• Not expressing cancer antigens 
• Interfering with immune cell development 
• Suppression of T cells 
• Inhibition of T cell migration to the tumour
• Upregulate immune checkpoints³

When this immune response fails and cancer cells successfully evade detection by the immune system, cancer cells are allowed to uncontrollably divide and form tumours. Immunotherapy aids our immune system to recognise and eliminate cancer. 

Immunotherapy for breast cancer 

Breast cancer is the most diagnosed cancer in the world, with 2.3 million new cases in 2020 alone. Therefore, new therapeutic treatments such as immunotherapy are required to treat breast cancer and reduce the chances of metastasis.⁴ Breast cancer cells over-express specific molecular markers such as: 

• Human epidermal growth factor response-2 (HER2) 
• Estrogen receptor (ER) 
• Progesterone receptor (PR)⁵

These markers such as HER2 are expressed on normal cells, so the immune system has built tolerance to them, therefore are not recognised as “non-self’.⁴ These markers can be utilised by immunotherapy to target breast cancer cells.⁵

Immunotherapies can be administered before or after breast cancer surgery. Immunotherapy use before surgery is carried out to shrink the size of the tumour to allow for a less invasive surgery such as a lumpectomy (only removing the tumour) as opposed to a mastectomy (removing the entire breast), or double mastectomy (removing all breast tissue). The use of immunotherapy after surgery is to lower the risk of relapse. 

Types of immunotherapy 

There are a range of different cancer immunotherapies that function in different ways to treat breast cancer. These include: 

• Immune checkpoint inhibitors 
• CAR T cells 
• Monoclonal antibodies 
• Cancer vaccines 
• Cytokines 

Immune checkpoint inhibitors 

Immune checkpoint inhibitors are commonly antibodies that function by interacting with and blocking immune checkpoints (molecules that are overexpressed in cancer cells to evade the immune system). By blocking these molecules, cancer cells cannot evade the immune system and are targeted and killed by immune cells. 

Immune checkpoint inhibitors are a standard treatment for solid tumours such as breast cancer as well as liquid tumours.⁶ The Food and Drug Administration (FDA) has approved three classes of immune checkpoint inhibitors for their treatment of a range of cancers. These include:

• PD-1 inhibitors - Nivolumab, Pembrolizumab, and Cemiplimab
• PDL-1 inhibitors- Atezolimumab, Durvalumab and Avelumab
• CTLA-4 inhibitors - Ipilimumab

PD-1 and PDL-1 inhibitors 

Cancer cells hijack the PD-1/PDL-1 pathway to evade the immune system. Cancer cells express PDL-1, which interacts with PD-1 on immune cells (T cells) and prevents the T cell from killing the cancer cell. PD-1 and PDL-1 inhibitors prevent this by blocking PD-1 on cancer cells and PDL-1 on T cells respectively, allowing T cells to kill cancer cells.⁷

The PD-1 inhibitor pembrolizumab has shown to be effective in treating non-metastatic (KEYNOTE-522) and metastatic (KEYNOTE-355) triple negative cancers. The FDA recently approved a treatment regime consisting of pembrolizumab and chemotherapy.^8–10

CTLA-4 inhibitors 

The expression of CTLA-4 on cancer cells prevents the activation of T cells, preventing T cells from killing cancer cells. CTLA-4 inhibitors block this molecule and allow T cells to kill cancer cells.⁷

Immune checkpoint inhibitors can also be administered in combination. The PDL-1 inhibitor durvalumab and the CTLA-4 inhibitor tremelimumab were used as a treatment for metastatic triple negative breast cancer and there was a clinical benefit for these.¹¹

Other immune checkpoint inhibitors targeting other immune checkpoint molecules are in development.⁷

Monoclonal antibodies 

Monoclonal antibodies interact with and block proteins on the surfaces of cancer cells. These antibodies are highly specific, which means only cancer cells are targeted and not healthy cells. They are called ‘monoclonal’ since they are only produced by one cell type, ensuring that these antibodies are all identical. 

Several monoclonal antibodies have been approved by the FDA for breast cancer therapy. These include: 

• Trastuzumab emtansine- HER2 inhibitor 
• Pertuzumab- HER2 inhibitor 
• Denosumab- RANKL inhibitor 
• Bevacizumab- VEGF inhibito⁵

Cancer vaccines 

Cancer vaccines would function to elicit an antitumor immune response through activating immune cells. The vaccines would use tumour antigens, allowing immune cells to recognise them when present on cancer cells. Despite a range of clinical trials being conducted using cancer vaccines, none have shown significant clinical benefits at phase 3. There are currently no breast cancer vaccines that have been approved by the FDA. 

However, research is still ongoing to provide a breast cancer vaccine. Evidence has shown that the combination of HER2-derived vaccines with the anti-HER2 monoclonal antibody trastuzumab is a promising breast cancer treatment.¹²

Patient considerations and side effects 

Despite the common use of immunotherapies to treat breast cancer, your treatment depends on the type of breast cancer. Fortunately, immunotherapies treating triple-negative breast cancer have been approved recently.¹³ Your doctor will speak to you about any new treatments that you are eligible for to make an informed decision on your treatment. 

Due to their specificity, immunotherapies have fewer side effects compared to other treatments such as chemotherapy. However, side effects such as fatigue and diarrhoea have been reported with the PD-1 inhibitor cemiplimab. Despite this, the drug has a reasonable safety profile.⁷ Your oncologist will explain any common side effects.

Due to the treatment’s interaction with the immune system, there is a risk of autoimmune reactions. This means the immune system may attack healthy cells as well as cancer cells. This can lead to serious problems with different organs. Please speak to your doctor about any unexpected side effects you may experience taking immunotherapies. Your doctor may cease your immunotherapy treatment and prescribe you with medication that suppresses your immune system. 

Future prospects 

There have been recent advancements in the treatment of breast cancer using immunotherapies. There are several other immune checkpoint molecules that could be targeted for treatment. Currently, immune checkpoint inhibitors that target lymphocyte activation gene 3 (LAG-3) are undergoing investigation. Immunotherapies that have been successful and approved to treat other cancers are also being investigated as possible breast cancer treatments. There have been promising studies treating early-stage triple-negative breast cancer with immune checkpoint inhibitors. However, further research is required to determine optimal timing and duration of treatment with immune checkpoint inhibitors.

Oncolytic viruses have been approved by the FDA to treat metastatic melanoma. This treatment is being investigated for the treatment of triple-negative breast cancer.¹

FAQs

How do I know if I’m eligible for cancer immunotherapy treatment? 

Your oncologist will consider your breast cancer type, its stage and whether the cancer cells express cancer markers such as PDL-1 or HER2 to decide on your type of treatment. 

Is immunotherapy a cure for cancer? 

Despite producing good results in many cancer cases, this treatment is not guaranteed to be a cure for all breast cancer types or prevent any chance of the cancer returning. 

What is the most common immunotherapy for breast cancer? 

A common immunotherapy for breast cancer is pembrolizumab. 

What do I do if I experience adverse effects from immunotherapy? 

Please speak to your doctor about any adverse effects you experience. With this information, your doctor can decide to either change your treatment plan or continue it. It is common to experience symptoms with cancer treatments. Please don’t cease cancer treatment without consulting your doctor.

Summary

Immunotherapy is a common cancer treatment where the body’s own immune system is utilised to treat and eliminate cancer. It can be used as a sole treatment, or alongside other cancer treatments such as chemotherapy or radiotherapy. There are a range of different cancer immunotherapies that all function in different ways to prevent cancer cells from evading the immune system.