Immunotherapy

Question 1

brief explanation about mechanism of action of immunotherapy drugs

Answer 1

• Modern cancer immunotherapy drugs, sometimes referred to as “immune checkpoint inhibitors”, are designed to target and block key components of the immune regulatory pathways that tend to be dominant in the cancer and/or peripheral immune system of cancer patients.
• Essentially, these strategies “take the brakes off” the immune system to allow it to mount an effective response to unique antigens expressed by tumours (so called “tumour associated antigens”).
• Without treatment, tumours are known to have a wide range of mechanisms by which they evade the immune system

Question 2

immunotherapy targets

Answer 2

Current targets include:
* Cytotoxic T Lymphocyte Antigen 4 (CTLA4) expressed on T lymphocytes
* Programmed cell death protein 1 (PD1) more broadly expressed across a range of immune cells including B cells and antigen-presenting cells, and its ligand
* Programmed death Ligand 1 (PDL1) expressed on a broad range of both immune and cancer cells.
However, many new treatment strategies are still under investigation

Question 3

established, licenced immunotherapy drugs mechanism of action

Answer 3

Established, licensed drugs are all long-acting monoclonal antibodies which act via immune checkpoint blockade to release anti-tumour immunity.
Some may also act against cancer cells through complement pathways and antibody-dependent cytotoxicity.

All are delivered intravenously and dosing is either calculated by weight or flat dosing based on idealised body weight.

Current examples include ipilimumab, nivolumab, pembrolizumab and atezolizumab.

Question 4

immunotherapy drugs current uses and which cancers specifically

Answer 4

These drugs are now used in a wide range of cancers - including melanoma, lung, bladder, head and neck, and kidney cancer.

Most treatment is palliative, for patients with advanced disease, although even in these groups long term remission (>10 years) can occasionally be seen (most notably with combination immunotherapy treatment in metastatic melanoma).

Adjuvant treatment is of proven benefit in some melanoma patients and is under investigation across a broad range of cancers.

Question 5

summary list of side effects for immunotherapy

Answer 5

• general features
• rash and/or itch: maculopapular, “eczema type” rash on the trunk but a wide variety of other patterns have been described, including psoriatic plaques, angioedema and vitiligo, steven johnson syndrome
• pneumonitis
• diarrhea/colitis
• hepatitis
• nephritis
• myalgia/arthralgia
• endocrinopathies
• Safety issues for long-term steroid immunosuppression

Question 6

• Peak incidence of new immune mediated side effects is

Answer 6

6-8 weeks after first treatment but the range is very wide.

Question 7

• First side effects can occur when?

Answer 7

• First side effects can occur any time from the start of first infusion until many months after the drug(s) have been withdrawn.
• Many side effects do not wax and wane with the cycle of treatment (in contrast to chemotherapy).

Question 8

Side effects of most interest and concern appear to be…

Answer 8

Side effects of most interest and concern appear to be immune-mediated. Although there are parallels with established immune pathologies (e.g. ulcerative colitis, thyroiditis, type 1 diabetes), the natural history and sometimes the best treatment to use can vary.

Onset can be rapid and the clinical situation can change quickly.

Question 9

describe features of rash you get as a side effect of immunotherapy and treatment

Answer 9

Question 10

penumonitis symtoms as a SE of immunotherapy:
Median time to onset after single agent nivolumab is :

Answer 10

• (dry) cough, shortness of breath, reduced exercise tolerance and fatigue.
• Symptoms may develop rapidly over a few days or more slowly over several weeks.
• Median time to onset after single agent nivolumab is 3-4 months and symptoms usually take 4-6 weeks to improve .

Question 11

investigations and treatment for pneumonitis

Answer 11

Initial assessment should include observations, FBC, CRP and CXR. Full biochemistry screen may pick up other side effects and sputum and screening for viral, opportunistic and bacterial chest infections is of benefit. Most patients will benefit from oral steroids though some (e.g. with pyrexia, high neutrophil & CRP) will require treatment for infection first.

Question 12

interpret CXR

Answer 12

Figure 11 1 Pneumonitis can look like infection. The CXR shows apparent consolidation in the right lower lobe and hazy shadowing in the left lower lobe.

Symptoms and signs settled with high dose steroids, which were started after initial treatment with antibiotics.

Question 13

SE of immunotherapy: diarrhoea time of onset and features of concern

Answer 13

Diarrhoea is a common side effect and often starts within the first two months of treatment. A careful history allows an assessment of severity. Features of concern include:
* frequency >6 times a day
* associated abdominal pain
* bloody diarrhoea
* nausea
* nocturnal diarrhoea.

Question 14

diarrhea investigations

Answer 14

Initial assessments include
* observations,
* fluid balance,
* FBC,
* CRP,
* stool sample (for MCS & C.difficile toxin)
* and AXR.
* Flexible sigmoidoscopy is useful in guiding later treatment.

Question 15

diarrhoea treatment

Answer 15

Patients with mild symptoms can be managed in the community with symptomatic measures and regular clinical review.

Serious cases often require admission, hydration, high dose steroids once infection has been excluded and specialist referral.

Complications such as perforation are occasionally seen.

Question 16

SE of immunotherapy: hepatitis presentation

Answer 16

Hepatitis is often picked up on safety blood tests before planned treatment and may be asymptomatic at first or present with jaundice, right sided abdominal pain and/or fatigue

Question 17

hepatatitis investigations

Answer 17

Initial assessment considers the wide differential diagnosis and should include a
* medication review (consider recent statins, antibiotics),
* alcohol history,
* hepatitis blood screen (including viral hepatitis & iron studies)
* and imaging (usually USS) to investigate thrombosis and possible metastases.

Question 18

hepatitis treatment

Answer 18

Mild cases can be managed by withholding cancer immunotherapy treatment and frequent biochemical re-assessment. Serious cases will require immunosuppression with high dose steroids and specialist referral.

Question 19

SE of immunotherapy: nephritis presentation

Answer 19

Nephritis is less common, occurring in 1-4% of patients treated with cancer immunotherapy but needs to be considered in the broad differential if these patients present with acute kidney injury.

Nephritis may be asymptomatic at first or present with the symptoms of uraemia: weakness, fatigue, anorexia, malaise, thirst and reduced urine output.

Question 20

nephritis assessment

Answer 20

Initial assessment includes a careful history, with particular focus on medication and infective and / or lower urinary tract symptoms. Next, evaluate fluid balance, and perform biochemistry, urine dipstick (send for MCS to microbiology if appropriate) and urine protein / creatinine ratio.

Question 21

treatment for nephritis including differentials

Answer 21

Consider the wide differential including: dehydration, recent iv contrast, infection, medications, hypotension, obstructive uropathy.

Serious cases will require immunosuppression with high dose steroids and specialist referral

Question 22

commonest pattern of nephritis as a SE of immunotherapy

Answer 22

Acute tubulo-interstitial nephritis, with lymphocytic infiltration, is the commonest pattern and can be confirmed with renal biopsy.

Question 23

SE of immunotherapy: myalgia/arthralgia presentation and assessment

Answer 23

• Myalgia (muscle pain) is common, arthralgia (joint pain without swelling) less frequent.
• More serious rheumatological complications such as acute myositis, polymyalgia rheumatica and arthritis can be seen.
• Initial assessment includes rheumatological history, examination of skin and joints and use of plain x-rays to exclude bone metastases.

Question 24

myalgia/arthralgia treatment

Answer 24

Mild cases can be managed symptomatically (e.g. with paracetamol and/or ibuprofen).

Moderate or severe cases (i.e. patients with significant pain or swelling affecting function esp. activities of daily living) benefit from specialist referral and oral or intra-articular steroids

Question 25

SE of immunotherapy: endocrinopathies presentation

Answer 25

Cancer immunotherapy can cause a wide range of endocrine disturbance. Patients with these problems often present with non-specific symptoms such as fatigue, mild headache, mood change, malaise, thirst, weight change or feeling generally unwell

Onset of endocrine disturbance can be acute or more gradual but it is common for assessment to be delayed due to a non-specific presentation.

Question 26

assessment of endocrinopathies

Answer 26

Standard safety bloods for patients on cancer immunotherapy should include regular assessment of thyroid function (T4, TSH) and cortisol (unless on systemic steroids).

Acute assessment of toxicity may require a wider panel of hormone bloods along with simple observations (BP critical) and biochemistry (look for low sodium in adrenal insufficiency)

Question 27

SE of immunotherapy: thyroiditis onset, progression, assessment and treatment

Answer 27

Thyroid disorders are common. A wide range of patterns are seen (and sometimes depends on the timing of blood tests) but in many cases acute thyroiditis causes hyperthyroidism (high T4, low TSH) followed, after a delay of some weeks, by hypothyroidism (low T4, high TSH).
Steroids are of no proven benefit.

Some patients require symptomatic management of hyperthyroidism with carbimazole and/or propranolol.

Always check for and treat any abnormality of adrenal function before starting thyroid replacement.

Most patients with hypothyroidism require lifelong thyroid replacement but can continue treatment with cancer immunotherapy.

Question 28

SE of immunotherapy: endocrinopathies: Acute pituitary inflammation presentation

Answer 28

Acute pituitary inflammation (hypophysitis) can cause headache, visual disturbance and a wide range of hormone abnormalities including adrenal insufficiency and secondary hypothyroidism (low T4, low TSH)

Question 29

Acute pituitary inflammation (hypophysitis) investigations

Answer 29

Blood cortisol levels vary across the day (9am sample is most useful) and formal assessment of adrenal function with a short Synacthen test is ideal, but only if the patient is clinically stable.
A short Synacthen test is based on measurement of serum cortisol before and after an injection of synthetic ACTH

Question 30

Patients with proven adrenal insufficiency or high clinical index of suspicion management

Answer 30

Patients with proven adrenal insufficiency or high clinical index of suspicion should start hydrocortisone replacement with advice about sick day rules (double dose), back up intramuscular injection if vomiting and specialist referral. Adrenal crisis is a life-threatening medical emergency so, if in doubt, consider hydrocortisone and ask for help.

Question 31

Safety issues for long-term steroid immunosuppression

Answer 31