Immune Checkpoint Inhibitors

Question 1

Explain the role of CTLA-4 and PD-1/PD-L1 pathways in immune regulation. How do ICIs target these pathways?

Answer 1

Inhibitory signals are mounted to prevent overwhelming activation of the T cell. The PD-1 receptor expressed on the surface of the T cell binds to the PD-L1 ligand on the APCs or tumor cells, which then “deactivates” the cytotoxic effect resulting in inhibition of killing on the tumor cell. ICIs target these pathway by blocking the PD-1 receptor to enhance killing ability of the T cells.

Question 2

Nivolumab mechanism of action?

Answer 2

Antibody that inhibits PD-1 receptor on the T cell

Question 3

What are the adverse effects that melanoma patients have that received ICIs?

Answer 3

Worse digestive tract side effects, vitiligo in melanoma patients

Question 4

How can you combine ICIs?

Answer 4

OX40 + PD-L1 or alpha 4-1BB + PD-1

Question 5

How is the concept of “tumor mutational burden” related to the efficacy of immune checkpoint inhibitors?

Answer 5

Studies have shown that the higher mutational burden the tumor has, the efficacy of ICIs is better. This is due to the high amount of immune checkpoint expressions, such as PD-1 receptor, in highly mutated cells, resulting in better efficacy of the immune checkpoint inhibitors. On the other hand, the expression of immune checkpoints in low mutational burden tumors is lower, making it harder to target by the ICIs.