Adverse events in immunotherapy Flashcards
Why is it important to think about the adverse events of immunotherapy?
Patients also have a chance of getting cured without immunotherapy
When is (which) immunotherapy used in melanoma?
Immunotherapy (with nivolumab with or without ipilimumab) leads to long-term survival in metastatic melanoma. Immunotherapy is also approved in the adjuvant setting (so in combination with e.g. surgery) (stage 3).
Why has the occurence of (once rare) adverse events increased in the last 10 years?
In the last 10 years, immunotherapy has become more common.
The occurrence of (once rare) adverse events has increased in the wake of the number of available treatments. This is because:
o More indications
o More combinations
o Patients live longer
o Aplied in earlier disease stages
Can immune related adverse events occur in all tissue types?
Immune related adverse events can occur in any tissue type, in any organ, but some toxicities are seen more often than others. E.g. skin toxicities very often, thyroid very common.
When does diarrhea and colitis occur in immunotherapy treatment and what does it look like?
- Occurs in 10-30% of patients
- Very common in Ipilimumab treatment
- Onset after ~6-20 weeks
- Diarrhea: increased defaecation frequency, also during the night
- Colitis: abdominal cramps, bloody stools
- Endoscopy: mucosal erythema (red), ulcerations
- Microscopy of biopsy: features of IBD, lymphocytic infiltration
Why do immune related adverse events occur?
Immune related adverse events occur due to impaired self-tolerance from loss of T-cell function
o Self-tolerance in humans partly maintained by the inhibition of autoreactive T-cells through CTLA-4 and PD-1/PD-L1 axes
o Polymorphisms of PD-1 and CTLA-4 associated with autoimmune conditions, but have no predictive value
Which targeted pathways are associated with what types of immune related adverse events?
Anti-CTLA-4: hypophysitis, because of ectopic expression of CTLA-4 in pituitary gland: headaches, hypothyroidism, adrenal insufficiancy, etc
Anti-PD-1: hypothyroidism (in itself), because of anti-thyroid antibodies
What is the pathofysiology of adverse events in immunotherapy?
The pathofysiology is not completely understood, but these are possible causes:
•Targeting of antigens shared by normal and tumour tissue:
o Research: patients developing dermatitis: 9 T-cell antigens shared
o Research:2 patients with myocarditis: muscle specific antigens in tumours
• Epitope spreading:
o Recruitment of additional T-cells and development of an immune response to epitopes distinct from the primary epitope (self-antigens from the death of bystander cells, can give a second wave of activated T-cells that can reenter the tissue and cause damage and off-target effects) recognized by the original effector T-cells
What are the different grades of adverse events and their treatments?
Grade. description, treatment:
- Mild, intervention not indicated
- Moderate, minimal intervention indicated
- Severe or medically significant but not life-threatening, hospitalization or prolongation of hospitalization indicated.
- Life-threatening, urgent intervention indicated
- Death related to adverse event.
However, there are no specific criteria for immune-related adverse events.
What is the general management of immune related adverse events?
Grade of adverse event. treatment
- Close monitoring
- Often treatment interruption or delay
- Usually treatment suspension, initiation of high-dose corticosteroids (prednisone 1-2mg/kg per day)
- Permanent discontinuation, unless endocrinopathy controlled with hormone replacement
What % of patients experience an immune related adverse event when treated with Nivolumab and Ipilimumab?
Nivolumab & Ipilimab:
Any treatment-related adverse event: 96%
Grade 3-4: 59%
Treatment-related adverse event leading to discontinuation: 39%
What is the pragmatic subdivision of immune-related adverse events?
Common: o Fatigue o Skin rash o Fever, chills o Malaise o Thyroid disorders o Diarrhea o Hepatitis
Less frequent, rare, often challenging and potentially life threatening: o Grade 3-4 colitis or hepatitis o Pneumonitis o Type 1 diabetes o Adrenal insufficiency
Rare, scary toxicity:
o Neurological toxicity: encephalitis, meningitis, Guillain-Barre
o Cardiac toxicity: myocarditis
What is the median time to toxicity of ipilimumab?
Median time to toxicity of ipilimumab:
It is given 4 times in 3 week cycles
• After 1st cycle: rash (pruritis)
• After 2nd cycle: some of the liver enzymes increase, but not above grade 1 or 2
• After 3rd cycle: diarrhea, colitis, hypophysitis
What is management of immune-related adverse events based on?
There are no randomized studies to base it on, so it is based on:
o Expert opinion: e.g. ESMO guideline, reviews
o Case series
o Experience from autoimmune diseases (e.g. ulcerative colitis, hepatitis)
Hepatitis: treatment with mycophenolate, tacrolimus
Colitis: treatment with infliximab (anti-TNFa), vedolizumab (integrin α4β7 mAb, more locally active)
o Common sense: interuptions, permanent discontinuation
o Consultation with “organ specialist”: endocrinologist, gastro-enterologist, etc
Do steroids interfere with treatment?
Steroids usually don’t interfere with efficacy of treatment
