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6.1 CTLA-4 Inhibitors (Cytotoxic T-Lymphocyte-Associated Protein-4)
CTLA-4 blockade with ipilimumab: biology, safety, efficacy, and future considerations.
CTLA-4 knockout mice demonstrate an early fatal autoimmune syndrome characterized by lymphoproliferation, (3) while some strains of PD-1 knockout animals develop autoimmunity later in life.
CD28 and CTLA-4 share similar ligands called CD80 (B7.1) and CD86 (B7.2).
The protective effector function of T cells may be compromised by inhibitory receptors such as CTLA-4 and PD-L1 (3, 5).
After the initial studies showing the effects of CTLA-4 and PD-1 blockade, the clinical development has been dramatic.
Hypophysitis after treatment with a CTLA-4 inhibitor, such as ipilimumab, can approach 12%, though it is much less common with the checkpoint inhibitors that target PD-1 and PD-L1.
Furthermore, a decrease in the expression of CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4) was described in these cells, both in the surface membrane and intracellularly (8).
In recent years, cytotoxic T lymphocyte protein-4 (CTLA-4) and programmed cell death protein-1 (PD-1) have shown promise as novel therapeutic targets in some cancers [7-10].
Malignant cells may also express ligands for the immune checkpoint CTLA-4 (cytotoxic T lymphocyte antigen 4) and PD-1 (programmed cell death 1), present on the surface of activated T lymphocytes, inhibiting their functions [14-19].
In addition, several studies have identified phenotypic markers within the [CD25.sup.high] [CD127.sup.low] [Foxp3.sup.+] population that are differentially expressed by discrete Treg subsets, according to activation and memory status (CD45RA naive and CD45RO memory), chemotactic profile (chemokine receptors like CCR4 and CCR9), suppressive functions (CTLA-4, CD39, and CD73), and more .
Cytotoxic T lymphocyte antigen-4 (CTLA-4) is an important immunoregulatory molecule that plays a role in the maintenance of T cell homeostasis.
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