**2. Immune checkpoint inhibitors (ICIs)**

T-cell-mediated immunity has multiple steps for selecting specific antigens, trafficking them to different sites, and executing their functions. These steps are regulated by counterbalancing stimulatory and inhibitory signals to maintain balance. Under normal physiologic conditions, the immune system has a series of modulating responses to control the duration and amplitude of response to minimize organ damage. These modulations are regulated by special stop signals called immune checkpoints. On tumor cells, there is an overexpression of inhibitory ligands and receptors. With this overexpression, cancer cells can evade T-cell detection of the host immune system.

The soluble and membrane-bound receptor–ligand immune checkpoints are the most targeted for cancer therapy. Antibodies that block immune checkpoints do not target tumor cells directly. Instead, they target lymphocyte receptors or their ligands in order to enhance endogenous antitumor activity [6]. The two immune checkpoints that have been most actively studied in the context of clinical cancer immunotherapy are cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4, also known as CD152) and programmed cell death protein 1 (PD1, also known as CD279) [6]. Checkpoint inhibitors work by blocking the interaction of tumor cells with these ligands leading to increased antitumor response. Inhibition of the immune checkpoint pathways has led to the United States Food and Drug Administration's (FDA) approval of seven drugs in the United States [7]. **Table 1** shows a list of all seven drugs. There are key similarities and differences in these pathways.

## **2.1 Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) inhibitors**

CTLA-4 was the first immune checkpoint receptor to be clinically targeted [6]. It is exclusively expressed on T-cells, where it primarily downregulates cellular activation [6, 8, 9]. CTLA-4 is a membrane-bound receptor expressed in the plasma membrane of activated T-cells. During an active immune state, antigen-presenting cells (APCs) bind to CTLA-4 to attenuate T-cell activity, diminishing host organ damage.

## *2.1.1 Ipilimumab*

Currently, only one FDA-approved ICI targets CTLA-4. The generic name is Ipilimumab and the trade name is Yervoy (Bristol-Meyers Squib). It is an intravenous


## **Table 1.**

*FDA-approved immune checkpoint inhibitors.*

infusion currently approved to treat metastatic or unresectable melanoma and melanoma recurrence. It is also approved for renal cell carcinoma, non-small cell lung cancer, malignant pleural mesothelioma, and esophageal cancer, but only if used as a combination therapy with nivolumab, PD-1 receptor antibody. In a study by Dow ER et al., they found that in patients with immunotherapy-associated uveitis, 96% of all cases with Ipilimumab were associated with metastatic melanoma [10]. This could be due to the restrictive indications the FDA has approved this medication use as monotherapy.
