Immune checkpoint inhibitors increase T-cell activity against tumour cells, but they also increase T-cell activity
against healthy cells
Cancer immunotherapies aim to improve the ability of the body to generate an immune response to tumour cells.1 Two
key receptor systems involved in influencing T-cells and their ability to recognise and target tumours are the cytotoxic
T-lymphocyte antigen-4 (CTLA-4) receptor, and the programmed death-1 (PD-1) receptor and its ligand PD-L1. These two
receptor systems act as self-recognition signals to distinguish between cells of the body and foreign pathogens; they
are also known as immune checkpoints. Immune checkpoints can be co-opted by tumour cells to reduce T-cell activity
and reduce immune responses to cancer.2 Immune checkpoint inhibitors are antibodies which target these receptor
systems and increase T-cell activity in order to improve the immune response to tumour cells. However, this also results
in increased T-cell activity against healthy cells and an increased risk of immune-related adverse effects.
There are currently four immune checkpoint inhibitors approved for use in New Zealand
Immune checkpoint inhibitors approved in New Zealand are currently indicated for use in patients with melanoma, non-small
cell lung cancer, renal cancer, bladder cancer and Hodgkin’s lymphoma.3 However, further clinical trials
are ongoing and their scope of use in clinical practice is likely to expand to other types of cancer in the future.
Some patients in New Zealand may be administered these medicines in clinical trials.
Immune checkpoint inhibitors currently approved for use in New Zealand are:3, 4
- Pembrolizumab (Keytruda) and nivolumab (Opdivo), which target the PD-1 receptor; these are subsidised with Special
Authority approval for the treatment of inoperable or metastatic melanoma
- Ipilimumab (Yervoy), which targets CTLA-4; it is not subsidised.
- Atezolizumab (Tecentriq), which targets PD-L1, the ligand for the PD-1 receptor; it is not subsidised
Patients are treated with immune checkpoint inhibitors for varying lengths of time; they could be treated until their
cancer has progressed and they are discharged to home or palliative care, they may have their cancer successfully treated
and go into remission with increasing intervals between follow-up appointments, or they may have treatment with an
immune checkpoint inhibitor stopped prematurely due to adverse effects.
There are a large range of immune-related adverse effects associated with the use of immune checkpoint inhibitors.
Most cases occur within weeks to months of a patient starting treatment, but adverse effects are still possible a year
or more later.5, 6
Immune-related adverse effects are very common
Many patients administered an immune checkpoint inhibitor will experience some degree of immune-related adverse effect.
The most common adverse effects include skin rash, diarrhoea and colitis, thyroiditis and hepatitis. Adverse effects
can range from mild to serious in severity, and some rare adverse effects can be potentially fatal. Rare adverse effects
are wide ranging and include primary adrenal insufficiency (Addison’s disease), colon perforation associated with enterocolitis,
type 1 diabetes, renal, cardiac or ocular toxicity and drug rash with eosinophilia and systemic symptoms (DRESS).7 Table
1 lists the main adverse effects of immune checkpoint inhibitors, and their approximate incidence rate.
Medicines which target CTLA-4, such as ipilimumab, are associated with a greater incidence and severity of adverse
effects than medicines which target PD-1 or PD-L1, such as nivolumab, pembrolizumab and atezolizumab.8
Meta-analyses of clinical trials show that:9, 10
- 27% of patients treated with PD-1/PD-L1 inhibitors develop some degree of immune-related adverse effects, with
6% being severe
- 72% of patients treated with CTLA-4 inhibitors develop some degree of immune-related adverse effects, with 24%
being severe
The risk of immune-related adverse effects is higher if combination treatment with both CTLA-4 and PD-1/PD-L1 inhibitors
is used than either medicine alone.7 There are less data available on the incidence of immune-related adverse
effects when these medicines are used sequentially. Anecdotal reports suggest a longer duration of treatment with an
immune checkpoint inhibitor may be associated with a greater incidence of immune-related adverse effects.
Table 1. Immune-related adverse effects associated with the use of immune checkpoint inhibitors.7, 9, 10, 12
| Organ and adverse effect |
Approximate incidence rate |
Characteristics |
Typical timing after treatment starts* |
|
Patients treated with
PD-1/PD-L1 inhibitors
(e.g. nivolumab, pembrolizumab, atezolizumab) |
Patients treated with
CTLA-4 inhibitors
(e.g. ipilimumab) |
|
|
Skin |
>30% |
>30% |
Most commonly rash or pruritus. Can include lichenoid drug eruption and vitiligo.
Severe cases are rare but can include:
- Acute febrile neutrophilic dermatosis (Sweet syndrome)
- Stevens-Johnson syndrome
- Toxic epidermal necrolysis
|
Within the first few weeks |
Gastrointestinal adverse effects |
Between 5–15% |
>30% |
Can include:
- Diarrhoea
- Abdominal pain
- Weight loss
- Fever
- Vomiting
- Mouth ulcers
- Anal lesions
- Colon perforation can occur in severe cases
|
Can occur at any time during treatment. May occur up to several months after the last dose. |
Thyroid dysfunction |
Between 5–15% |
Between 5–15% |
Usually hypothyroidism but can present as temporary hyperthyroidism which progresses to hypothyroidism |
Two to three months |
Immune-related hepatitis |
Between 5–15% |
Between 5–15% |
Hepatitis is usually asymptomatic and detected only on laboratory investigations; monitoring occurs during
treatment |
One to four months |
Hypophysitis (inflammation of the pituitary) |
Rare |
Between 5–15% |
- Mostly affects males
- Symptoms include headache, visual disturbances, nausea or symptoms related to hypogonadism and hypothyroidism,
e.g. fatigue, weakness, temperature intolerance, insomnia, loss of libido
- Laboratory investigations may show simultaneously low levels of:
- Thyroid stimulating hormone (TSH)
- Adrenocorticotropic hormone (ACTH)
- Follicle-stimulating hormone (FSH)
- Luteinizing hormone (LH)
- Cortisol
- Testosterone
- In severe cases may cause life-threatening adrenal insufficiency
|
Four to five months |
Neurological adverse effects |
< 5% |
< 5% |
Can include:
- Polyneuropathy
- Facial nerve palsy
- Myasthenia gravis
- Guillain-Barré syndrome
|
One to three months |
Pneumonitis |
< 5% |
< 5% |
N.B. Less severe lung adverse effects such as cough and dyspnoea occur in 20-40% of patients administered
PD-1/PD-L1 inhibitor treatment (nivolumab, pembrolizumab and atezolizumab) |
Four to eight months |
Drug rash with eosinophilia and systemic symptoms (DRESS) |
Rare |
Rare |
Assess vital signs, skin surfaces and mucus membranes; lymphadenopathy, facial or distal extremity swelling
may indicate DRESS |
Rare; no typical timing |
* Note that patients may develop late adverse effects occurring a year or more after the start of treatment.6
Communication between the primary care team and the patient’s oncologist is necessary to ensure that potential immune-related
adverse effects are detected early and appropriately treated.
If adverse effects occur while the patient is still undergoing treatment, it is likely they will be detected and
managed by the oncology team. Management may involve delaying the next dose or withdrawing the immune checkpoint inhibitor.7 High
dose oral corticosteroids are often used to treat the adverse effects, and other medicines may also be necessary (see
below).
Consider immune-related adverse effects in patients with unexplained symptoms and signs discovered in primary care
If a patient has received treatment with an immune checkpoint inhibitor, or they are still actively undergoing treatment,
clinicians in primary care should be alert for symptoms and signs that may indicate an immune-related adverse effect.
If there is suspicion of this, the patient’s oncologist should be contacted to discuss an appropriate management strategy.
The symptoms and signs of immune-related adverse effects can be diverse and are often non-specific. As these adverse
effects are induced by a medicine, rather than by an autoimmune condition, the speed of onset and severity of symptoms
and signs may differ from a general practitioner’s previous experience. Consider if there are any alternative explanations
for the signs and symptoms, such as infection, an adverse effect of another medicine or an unrelated condition. Laboratory
investigations, such as a full blood count, liver and renal function tests may assist in diagnosis.7
Corticosteroids are the cornerstone of treatment
High dose oral corticosteroids, e.g. prednisone 1–2 mg/kg/day, are used to provide immunosuppression while a patient
is undergoing treatment with an immune checkpoint inhibitor.11 Lower doses may be used in patients with
less severe symptoms.7 The aim of corticosteroid treatment is to minimise adverse effects while still allowing
sufficient immune response to the cancer being treated. Corticosteroids are also used as a treatment for specific immune
adverse effects that may develop, such as low levels of cortisol caused by hypophysitis or primary adrenal insufficiency.7
Depending on the organs affected and severity of symptoms, patients may be initiated on a variety of additional treatments
in secondary care, such as thyroxine for hypothyroidism, and less commonly infliximab for gastrointestinal adverse
effects or mycophenolate mofetil or tacrolimus for severe symptoms or where stronger immunosuppression is required.7 If
patients develop hormone deficiencies due to immune-related adverse effects, they may require hormone substitution
for the remainder of their life to replace thyroid, adrenal, pancreatic or sex hormones.
If patients have been initiated on high dose oral corticosteroids, check the intended duration and purpose of treatment
Some patients who have received treatment with an immune checkpoint inhibitor may still be required to take high
dose oral corticosteroids after their treatment has concluded. Clinicians in primary care will need to check the patient’s
notes or instructions from their oncologist regarding the purpose for prescribing oral corticosteroids and the expected
length of treatment; the appropriate course of action if patients develop symptoms or signs of adrenal insufficiency
will differ depending on the reason for initiation.
If oral corticosteroids were initiated for primary adrenal insufficiency, patients will need to continue them indefinitely
and dose increases may be required if symptoms of adrenal insufficiency develop. In other cases, patients may be able
to withdraw from oral corticosteroids, with tapering, after an immune-related adverse effect has subsided; this should
be done in consultation with the treating oncologist.
Treatment with immune checkpoint inhibitors can affect other aspects of healthcare
Immune-related adverse effects or the treatments initiated to control them, such as high dose corticosteroids, may
complicate the management of a patient’s general medical conditions. Be alert for the potential for medicine interactions
and treatment contraindications or restrictions, such as administering live vaccinations.
Patient information on immune checkpoint inhibitors and their adverse effects is available from: www.cancerresearchuk.org/about-cancer/cancer-in-general/treatment/immunotherapy/types/checkpoint-inhibitors
