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lüll Targeting cytotoxic T-lymphocyte antigen-4 (CTLA-4): a novel strategy for the treatment of melanoma and other malignancies O'Day SJ; Hamid O; Urba WJCancer 2007[Dec]; 110 (12): 2614-27Cancer 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.|Algorithms[MESH]|Animals[MESH]|Antibodies, Monoclonal, Humanized[MESH]|Antibodies, Monoclonal/*therapeutic use[MESH]|Antigens, CD/*immunology[MESH]|Antigens, Differentiation/*immunology[MESH]|CTLA-4 Antigen[MESH]|Clinical Trials as Topic[MESH]|Drug Delivery Systems[MESH]|Humans[MESH]|Immune Tolerance[MESH]|Ipilimumab[MESH]|Melanoma/immunology/*therapy[MESH]|Mice[MESH]|Skin Neoplasms/immunology/*therapy[MESH] |