Targeting cytotoxic T‐lymphocyte antigen‐4 (CTLA‐4)

Cancer immunotherapy centers on modulating the host's tumor‐directed immune response. One promising approach involves augmentation of cell‐mediated immunity by interrupting T‐cell pathways responsible for immune down‐regulation or tolerance. The discovery of cytotoxic T‐lymphocyte antigen‐4 (CTLA‐4) and its role as a key negative regulator for T cells has prompted efforts to target this signaling molecule to improve cancer therapy. Activation, or ‘priming’, of naive T cells in response to tumor‐cell invasion comprises a dual‐signaling mechanism. Signal 1 requires tumor‐associated antigen recognition by the T‐cell receptor, while signal 2 occurs through binding of CD80 or CD86 (B7.1 of 2) on the antigen presenting cell (APC) with CD28 on the T cell. Importantly, there is a final step responsible for naturally occurring immune regulation; this occurs in response to competitive binding of CD80/CD86 on the APC by CTLA‐4 on the T cell. This ‘immune checkpoint’ interrupts signal 2 and inhibits the activated T cell. Targeting CTLA‐4 as an anticancer strategy: Following proof‐of‐concept studies in animals, fully human anti‐CTLA‐4 antibodies were developed and 2 are undergoing clinical evaluation. Ipilimumab and tremelimumab have shown promising antitumor activity, initially in patients with advanced melanoma. Class‐specific immune‐related adverse events (irAEs) were common and mostly transient and/or manageable. These events are thought to be mechanism‐of‐action‐related, indicating immune tolerance is broken; this relation may also explain the association between irAEs and response seen in several trials. Interruption of immune inhibitory pathways via CTLA‐4 blockade appears to be a promising strategy for cancer immunotherapy. Cancer 2007. © 2007 American Cancer Society.