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 and stimulate an immune response against the tumour 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. More recently, a third class of checkpoint inhibitors targeting LAG3 on T cells (and NK cells) has been shown to have benefit in advanced cancer, in combination with anti PD-1 agents.

Checkpoint inhibitors are used after surgery (adjuvant therapy) to reduce the risk of recurrence, and in treating advanced cancers for disease control and survival benefit. 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. Checkpoint inhibitors have also started to be used more recently in the neo-adjuvant setting.

Checkpoint inhibitors can have a significant benefit on survival compared to standard treatment, and in a proportion of patients can produce a long-term response.

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.

Examples of checkpoint inhibitors currently in use on the NHS (excluding those used in trials)

*not currently accepted for use in Scotland

The side effects of checkpoint inhibitors are very different to chemotherapy. Importantly, due to stimulation of the immune system, 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, joints and lungs. The serious toxicities can also include cardiac, neurological and renal impairment as detailed in the figure below.

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

examples-of-immune-related-adverse-events-and-some-possible-symptoms.png

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 single agent anti CTLA-4 drugs and 20% of those having anti PD-1 or PD-L1 drugs. The number of patients who have severe toxicity with combination therapy is much higher – about 55%.

When detected early, most iRAEs are reversible. Therefore, it’s essential that patients with suspected irAEs are assessed promptly so that they can receive potentially life-saving treatment.

Management of iRAEs is based on the severity of toxicity, as graded by the CTCAE (Common Terminology Criteria for Adverse Events). Treatment with checkpoint inhibitors may be withheld for a time, depending on the severity of the side effects. Most patients with higher grade toxicities will require prompt initiation of steroids for reversibility, as guided by their oncology team. For milder toxicities, immunotherapy may be restarted once the toxicity has resolved and the steroid dose weaned. Patients who develop endocrinopathies, such as hypothyroidism and hypopituitarism, usually do not regain function and may need long term hormone replacement therapy.

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 COPD, may have a predisposition to more severe pneumonitis.

Primary care providers play an extremely important role in early identification of potential toxicities and communication with the oncology teams, in addition to optimising patients’ comorbidities, mental wellbeing and preventative care.

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.