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 [20].