Key Clinical Questions
When should immune-related adverse events (irAEs) be suspected in acutely ill hospitalized oncology patients?
How do you evaluate an oncology patient who may have an irAE related to immunotherapy treatment?
How do you manage patients with irAEs?
What should you consider when discharging a patient that has been treated for an irAE?
The function of the immune system is to protect the host tissues, recognized as “self,” against foreign organisms, recognized as “nonself.” Upon recognition as “nonself” an antigen, shown in red in Figure 183-1, is captured and presented on an antigen presenting cell (APC), which then displays that antigen to the immune effector T-cell. T-cells predominantly recognize peptide antigens derived from “nonself” proteins displayed on major histocompatibility complex (MHC) class I/II. The T-cell is activated to generate a response against the specific antigen. Activation requires two signals directed by the APC: (a) the presentation of the antigenic peptide to stimulate the T-cell receptor (TCR), and (b) the binding of CD28 on T-cells to B7.1 (CD80) or B7.2 (CD86) on the APC. This process of T-cell activation of the host plays a critical role in mediating immune surveillance.
T-cell regulation by CTLA-4 and PD-1 pathways. (From Kasper DL, et al, eds. Harrison’s Principles of Internal Medicine, 19th edition. New York, NY: McGraw-Hill Education Medical; 2015.)
To counter the possibility of unregulated activation of T-cells, two molecules, CTLA-4 (cytotoxic T-lymphoctye-associated-protein-4) and PD-1 (programmed death receptor-1) play a critical role. Once the T-cell is activated, CTLA-4, a molecule present on the activated T-cell that can bind with greater avidity to B7 than CD28, is upregulated to shut down the system and mute the immune response, avoiding an uncontrolled inflammatory cascade of events. Besides CTLA-4 inhibition, there are other mechanisms to inhibit the inflammatory signaling that occurs in the periphery. One pathway, of particular importance in tumors, that down regulates the T-cell response is the programmed death 1 (PD-1) receptor: PD-Ligand (PD-L) pathway. The PD-1 receptor on the surface of the activated T-cell binds to one of two ligands expressed on the surface of antigen presenting cells, PD-L1 or PD-L2, to limit the activity of the already activated T-cells. When PD-1 binds to the ligand, an “off” signal is sent to the T-cell to suppress expansion and stop the attack. These inhibitory checkpoints are essential in a delicate system of checks and balances to ensure there is not overactivation of the immune system and protect the body from a chronic inflammatory state.
A number of tumors develop complex mechanisms that allow them to specifically evade the immune system and ensure their survival within a host. Despite having tumor antigens that may be recognized as “nonself,” they develop an ability to dampen this normal antitumor response by taking full advantage of the inhibitory checkpoint pathways, creating an ...