Introduction

What is metastatic cancer?

Metastasis is a hallmark of cancer, and the largest cause of cancer-associated deaths. It refers to when cancer cells break off from a primary tumour and are carried through the blood vessels to a new location where they grow and form a secondary tumour.¹

What is immunotherapy?

Immunotherapy is a type of cancer treatment that helps your immune system fight cancer, rather than directly treating the cancer itself. Some different types of immunotherapy treatment include: 

• Monoclonal antibodies 
• Vaccines 
• Checkpoint inhibitors 
• Cytokines 
• CAR T-cell therapy 

Immunotherapy can be used alone or in combination with other treatment types, such as radiotherapy or chemotherapy, to treat many types of cancer, such as kidney, cervical, and liver cancer.²

Examples of immunotherapy for metastatic cancer

Checkpoint inhibitors

The immune system is made up of many types of immune cells, including T cells, or T lymphocytes. T cells play a central role in the destruction of cancer cells. They have receptors on their surface which can detect cancer cells, bind to antigens on the cell surface, and release chemicals to kill them.

However, T cells also have a type of receptor on their surface called ‘checkpoints’. When checkpoints are activated, the T cell can no longer destroy cancer cells. Some cancer cells can activate checkpoints, meaning that they can continue to multiply freely.³

Immune checkpoint inhibitors (ICIs) target checkpoints on the surface of T-cells so that they can’t be activated, allowing T cells to destroy cancer cells. The most commonly targeted checkpoints are cytotoxic T-lymphocyte associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1), and programmed death-ligand (PD-L). Some examples of checkpoint inhibitors include: pembrolizumab, ipilimumab, nivolumab, and atezolizumab.

Different cancer checkpoint inhibitors are effective against:

CTLA-4 inhibitors

• Melanoma
• Advanced renal cell carcinoma (RCC)
• Metastatic colorectal cancer
• Malignant pleural mesothelioma (MPM)
• Non-small-cell lung cancer (NSCLC)

PD-1 Inhibitors:

• Merkel cell carcinoma (MCC)
• Melanoma
• Head and neck squamous cell carcinoma (HNSCC)
• Non-small-cell lung cancer

PD-L1 Inhibitors:

• Metastatic breast cancer
• Metastatic non-small-cell lung cancer
• Merkel cell carcinoma
• Renal cell carcinoma
• Metastatic or locally advanced urothelial carcinoma

Many checkpoint inhibitors are used in combination with each other, or with different types of therapy such as chemotherapy and radiotherapy, to improve the outcome of treatment.⁴

In recent years, more checkpoint inhibitors that may be effective in treating metastatic cancer have emerged and are in the early stages of development, including those that target TIM-3 and LAG-3. TIM-3 checkpoint inhibitors have been used in combination with PD-1 checkpoint inhibitors and found to be effective against lung, colorectal, and melanoma cancer cells in mice. LAG-3 checkpoint inhibitors have also been used in combination with PD-1 inhibitors to treat fibrosarcoma, colorectal, and metastatic ovarian cancer cells in mice.⁵

Chimeric antigen receptor (CAR) T-cell therapy

In CAR-T cell therapy, T cells are collected from the patient and are genetically modified to produce a type of receptor called a chimeric antigen receptor (CAR), which can bind to antigens on the surface of cancer cells. The CAR-T cells are then introduced to the patient’s bloodstream so that they can fight the cancer cells. Currently, in the UK, CAR-T cell therapy is only available to some child and adult leukaemia patients, and some adults with lymphoma.⁶

Cancer vaccines

Vaccines are usually used as a preventative measure that train the immune system to recognise antigens on certain viruses before you become infected. Cancer vaccines are a relatively new emergence in immunotherapy to treat cancer. As such, they are mainly offered to patients taking part in clinical trials. 

Initially, cancer vaccines involved taking an antigen commonly found in a certain type of cancer and injecting it into the patient to activate the patient’s T cells to fight the cancer. However, these vaccines were usually unsuccessful in trials as each patient’s cancer has different variations of antigens. Subsequently, researchers looked at taking a more targeted, personalised approach.

Another type of cancer vaccine targets differentiation antigens - the antigens that are only expressed by healthy tissues during certain stages of growth. This means that target antigens are only found on the tumour and tissue of origin, making the vaccine more targeted and less likely to affect healthy tissue. Two clinical trials for this type of vaccine against advanced metastatic melanoma were carried out, but they had only limited success. However, the Provenge vaccine was approved in 2010 in the USA as a treatment for patients with asymptomatic/mildly symptomatic metastatic prostate cancer.⁷

Talimogene Laherparepvec (T-Vec)

T-Vec is the first approved vaccine in the UK for treating metastatic advanced melanoma. It uses a modified version of herpes simplex virus type 1 (HSV-1) which is injected directly into tumours, where it invades and replicates inside cancer cells, causing them to burst. When the cancer cells burst, they release more virus particles which can infect more cancer cells. They also leave behind ‘debris’ which activates T-cells to respond and destroy them.⁸

Benefits of immunotherapy for metastatic cancer

• Immunotherapy has a high success rate and has been found to significantly improve long-term survival rates
• It is very targeted, meaning it is less likely to affect healthy cells and other body parts unaffected by cancer
• It can restore and strengthen the immune system, preventing metastasis and re-emergence of cancer⁹

Risks and side effects

Side effects can vary between each patient, and are dependent on many factors such as the type of cancer, how advanced it is, and the type and dose of immunotherapy the patient receives.

Some common side effects include:

• Skin reactions at injection sites e.g. pain, swelling, redness, itchiness
• Flu-like symptoms e.g. fever, chills, dizziness, nausea, fatigue
• Weight gain
• Heart palpitations
• Sinus congestion
• Diarrhoea

Dermatological adverse effects

Dermatologic effects are very common with immunotherapy, such as skin rashes or itching. However, other effects such as lichen dermatitis or psoriasis have also been reported. In rare cases, patients have experienced life-threatening conditions such as erythema multiforme or Stevens-Johnson syndrome.

Adverse cardiovascular effects

Cardiovascular effects are most commonly associated with checkpoint inhibitors and CAR T-cell therapy. These effects include structural effects such as: myocardial necrosis (death of heart muscle cells), myocarditis (inflammation of heart muscle), pericarditis (inflammation of the lining of the heart), or arrhythmias such as atrial fibrillation. 

Adverse endocrine effects

Most endocrine adverse effects are associated with checkpoint inhibitor therapy. The most common complications are acute hypophysitis and thyroid dysfunction. Some patients have also reported adrenal insufficiency and pancreatic dysfunction, which can lead to poor blood sugar control and diabetes.

Adverse pulmonary effects

Pneumonitis is a common side effect of the checkpoint inhibitor ipilimumab, with it being observed in 3-5% of patients, with cases being more common in current or ex-smokers.¹⁰

Summary

Immunotherapy is a form of cancer treatment that helps your immune system to fight cancer. There are many different types of immunotherapy, such as checkpoint inhibitors, CAR-T cell therapy, and cancer vaccines. In the UK, CAR-T cell therapy has been approved for the treatment of some leukaemia and lymphoma patients, and the cancer vaccine T-Vec is used to treat some cases of malignant melanoma.

Immunotherapy comes with many benefits, as it has a high success rate whilst being a very targeted form of cancer treatment. However, some patients may experience common side effects such as skin reactions at injection sites and flu-like symptoms. Very few patients experience more severe adverse effects that affect different body systems, but it is still important to be aware of such risks.