Immunotherapy side effects: clinical aspects

Question 1

Can immune-related adverse events occur in all tissue types?

Answer 1

Immune-related adverse events can occur in any tissue type, in any organ, but some toxicities are seen more often than others.

Question 2

Why do immune-related adverse events occur?

Answer 2

They occur due to impaired self-tolerance from loss of T-cell function.

• Self-tolerance in humans is partly maintained by the inhibition of autoreactive T-cells through CTLA-4 and PD-1/PD-L1 axes.
• Polymorphisms of PD-1 and CTLA-4 are associated with autoimmune conditions but have no predictive value.

Question 3

Which targeted pathways are associated with what types of immune-related adverse events?

Answer 3

Anti-CTLA-4: hypophysitis, because of ectopic expression of CTLA-4 in pituitary gland: headaches, hypothyroidism, adrenal insufficiency, etc

Anti-PD-1: hypothyroidism (in itself), because of anti-thyroid antibodies.

Question 4

What is the pathophysiology of adverse events in immunotherapy?

Answer 4

• Targeting of antigens shared by normal and tumor tissue.
• Epitope spreading; recruitment of additional T-cells and development of an immune response to epitopes distinct from the primary epitope.

Question 5

What is the general management of immune-related adverse events?

Answer 5

1. Close monitoring.
2. Often treatment interruption or delay.
3. Usually treatment suspension, initiation of high-dose corticosteroids (prednisone 1-2mg/kg per day).
4. Permanent discontinuation, unless endocrinopathy controlled with hormone replacement.

Question 6

Do steroids interfere with treatment?

Answer 6

Steroids usually don’t interfere with the efficacy of treatment.

Question 7

What is the management of immune-related adverse events with CAR T-cell treatment?

Answer 7

Supportive care, steroids, tocilizumab (anti-IL6).