Immunotherapy and its side effects

Checkpoint inhibitors are a group of monoclonal antibodies that have become standard of care for a number of cancers in recent years (see table below). These drugs stop the tumour from evading white blood cells. They target specific checkpoint proteins on white blood cells called CTLA-4 (cytotoxic T lymphocyte-associated antigen 4) or PD-1 (programmed death-1 receptor), or its ligand PD-L1. PD-L1 is also found on the surface of some cancer cells.

How Checkpoint Inhibitors work

Checkpoint inhibitors are usually used to treat advanced (metastatic) cancers. They are either given as a single agent or two different agents and can be combined with other treatments such as chemotherapy or targeted therapy. More recently, checkpoint inhibitors have also started to be used in the adjuvant setting for stage 3 melanoma.

Checkpoint inhibitors can have a significant benefit on survival compared to standard treatment, and in a proportion of patients can produce long term response and even “cure” metastatic disease. 

With increasing numbers of cancer patients likely to be treated with checkpoint inhibitors, it’s important to be aware of the side effects and when they might happen.

Checkpoint inhibitors currently in use on the NHS (excluding those used in trials)

The side effects of checkpoint inhibitors are very different to chemotherapy. Importantly they can cause inflammatory and autoimmune complications, which can affect any part of the body. They most frequently affect the skin, colon, endocrine organs, liver and lungs.

Fatigue is the most common side effect. It is usually mild, but in rare cases can be severe. It is important to rule out thyroid, pituitary and other endocrine disorders such as adrenal insufficiency.

Examples of immune-related adverse events and some possible symptoms

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These immune-related adverse events (irAEs) can happen at any time but most often occur within the first few weeks or months after starting treatment. There are reports of some irAEs starting even a year or more after treatment has finished.

IrAEs are usually mild and generally well tolerated by patients. However they can be severe, even life threatening, in up to 27% of patients having anti CTLA-4 drugs and 20% of those having anti PD-1/PD-L1 drugs. The number of patients who have severe toxicity with combination therapy is much higher – about 55%.

It’s essential that patients with suspected irAEs are assessed promptly so that they can receive potentially life-saving treatment.

Most side effects are reversible with prompt initiation of corticosteroids. Patients who develop endocrinopathies, such as hypothyroidism and hypopituitarism, usually do not regain function and need long term hormone replacement therapy.

Treatment with checkpoint inhibitors may be withheld for a time, depending on the severity of the side effects. But can generally be restarted once the toxicity has resolved and the steroid dose weaned.

Currently it is not possible to predict who will develop irAEs, but patients with pre-existing autoimmune disorders may be at higher risk. Those with a history of lung conditions, such as asthma or COPD, are at increased risk of developing pneumonitis.

icon_laptop_darkblue_rgb.png	Flag all patients having immunotherapy on patient system to highlight risk of side effects during treatment and for at least 12 months after finishing treatment.
icon_test_tube2_magenta_rgb.png	Patients can present with non-specific symptoms so consider blood tests to rule out biochemical-only changes, such as hepatitis, adrenal insufficiency and thyroid dysfunction.
icon_time_arrow_darkblue_rgb.png	Initially mild symptoms such as diarrhoea, breathlessness or headaches can rapidly progress into colitis, pneumonitis or encephalitis.
icon_phone_cyan_rgb.png	Contact hospital advice line/oncologist straightaway if concerned your patient may have immunotherapy side effects –they may carry an immunotherapy alert card with details.
icon_arrow_magenta_rgb.jpg	Refer to UKONS Oncology/Haematology Treatment Toxicity Risk Assessment Tool regarding side effects (includes immunotherapy).

Remember - Think possible ‘itis’ for any patient that is on or has had immunotherapy.