Immunotherapy and its side effects

Checkpoint inhibitors are a group of monoclonal antibodies that have become the standard of care for several 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 (lymphocyte activation gene-3) on T cells (and NK cells) has been shown to benefit advanced cancer in combination with anti-PD-1 agents.

Checkpoint inhibitors are also used more before surgery (neo-adjuvant) to improve tumour control, surgical outcomes and boost immune response.

Checkpoint inhibitors are used after surgery (adjuvant therapy) to reduce the risk of recurrence and in treating advanced or metastatic cancers for disease control and survival benefits. 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 the ability to significantly improve survival compared to standard treatment. They can produce a durable long-term response in a proportion of patients compared to other traditional treatments, such as chemotherapy in some cancers.

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

Checkpoint inhibitors have very different side effects from chemotherapy. Importantly, because they stimulate 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 list below. Fatigue is the most common side effect. It is usually mild but can be severe in rare cases. It is important to rule out thyroid, pituitary, diabetes and other endocrine disorders, such as adrenal insufficiency.

Examples of immune-related adverse events (irAEs) and some possible symptoms

Eye (eg uveitis, iritis, episcleritis, conjunctivitis, orbital inflammation, optic neuritis)

• Blurred vision

• Change in colour vision

• Distortion

• Eyelid swelling

• Bulging eyes

• Decreased visual acuity

• Dry eyes

• Redness

• Pain

• Photophobia

Endocrine

Endocrine (eg diabetes, hyper or hypo thyroidism, hypophysitis, adrenal insufficiency)

• Headaches

• Nausea or vomiting

• Cold or heat intolerance

• Dry skin

• Constipation or frequent bowel movements

• Weight gain or loss

• Palpitations

• Insomnia

• Abdominal pain

• Visual field defects

• Fatigue or weakness

• Dehydration

• Hypotension, orthostasis or syncope

• Hyperglycaemia, polyuria or polydipsia

• Electrolyte abnormalities

Liver

Liver (hepatitis)

• Raised LFTs

• Jaundice

• Fever

• Fatigue

• Nausea and vomiting

• Anorexia

• Pain on right side of abdomen

• Dark urine

• Bleeding or bruising more easily than normal

Skin

• Pruritus with or without a rash

• Inflammatory dermatoses (maculopapular, psoriasiform, eczematous and lichenoid)

• Immunobullous diseases (bullous pemphigoid, vitiligo depigmentation -melanoma only, connective tissue diseases)

• Mucosal toxicities (ulcers, periodontal disease, stomatitis, dry mouth related to CPI Sjögren’s Syndrome, vaginal dryness, oral and genital lichen planus)

• Hair and nail toxicities

• Palmoplantar erythrodysesthesia or hand-foot syndrome

• Stevens-Johnson syndrome

Blood

• Haemolytic anaemia

• Thrombocytopenia or thrombocythaemia

• Neutropenia

• Haemophilia

Musculoskeletal

• Myositis

• Arthritis

• Myopathies

• Polymyalgia-like syndrome

Gastrointestinal (eg colitis, enterocolitis, gastritis, pancreatitis)

• Diarrhoea (may include blood or mucus)

• Fever

• Cramping abdominal pain

• Urgency

• Nausea and vomiting

• Upper abdominal pain

• Difficulty swallowing

Renal (nephritis, acute kidney injury)

• Urinary frequency

• Dark or cloudy urine

• Fluid retention in face, abdomen and extremities

• Sudden weight gain

• Abdominal or pelvic pain

• Nausea or vomiting

• High blood pressure

• Change in mental status

• Raised creatinine

• Oliguria

Cardiovascular (eg myocarditis, arrhythmias, impaired ventricular function, pericarditis, vasculitis, thromboembolism)

• Fatigue, myalgia or weakness

• Presyncope or syncope

• Shortness of breath

• Arrhythmias

• Chest pain

• Peripheral oedema

• Extremity pain or swelling

• Increased skin vein visibility or purpuric rash or erythema

• Reduced exercise tolerance

Respiratory (eg pneumonitis, pleuritis)

• Breathlessness

• New or worsening cough

• Reduced saturations

• Chest pain

• Wheezing

• Fever

Neurological

• Peripheral neuropathy

• Guillain-Barré syndrome

• Myasthenia gravis with myositis overlap

• Aseptic meningitis

• Encephalitis

• Demyelinating disorders

These irAEs can happen at any time but most often occur within days to a delayed onset of up to 26 weeks after starting treatment. There are reports of some irAEs starting after treatment has finished. Therefore, although rare, patients are monitored for 1-2 years after treatment completion for delayed IRAE onset. The incidence and severity of irAEs depend on the drug. Anti-CTLA4 drugs usually have more adverse effects (up to 80%) compared to anti-PD1 (27%) and anti-PDL1 (17%) drugs. Combinations increase the incidence and severity of irAEs, with more than 50% experiencing moderate-severe irAEs with Ipilimumab and Nivolumab, for example. Many irAEs cause little discomfort to patients if detected early and may be asymptomatic. However, irAEs can affect any organ and be potentially life-threatening. Most irAEs are reversible when detected early. Therefore, patients with suspected irAEs must be assessed promptly so that they can receive potentially life-saving treatment. Management of irAEs is based on the severity of toxicity (grade 1 to 4), as graded by the Common Terminology Criteria for Adverse Events (CTCAE). Treatment with checkpoint inhibitors may be withheld for a time, depending on the severity of the side effects. Most patients with higher grade toxicities (grades 2 to 4) will require prompt initiation of steroids and holding of drugs for reversibility, as guided by their oncology team. Depending on the severity of toxicity, immunotherapy may be restarted once the toxicity has resolved to grade 1 or below and the steroid dose weaned. Most 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. 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.