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Targeting cytotoxic T-lymphocyte antigen-4 (CTLA-4)†
A novel strategy for the treatment of melanoma and other malignancies
Article first published online: 14 NOV 2007
Copyright © 2007 American Cancer Society
Volume 110, Issue 12, pages 2614–2627, 15 December 2007
How to Cite
O'Day, S. J., Hamid, O. and Urba, W. J. (2007), Targeting cytotoxic T-lymphocyte antigen-4 (CTLA-4). Cancer, 110: 2614–2627. doi: 10.1002/cncr.23086
Editorial and writing assistance for this article was provided by Rebecca Turner.
- Issue published online: 3 DEC 2007
- Article first published online: 14 NOV 2007
- Manuscript Accepted: 20 JUL 2007
- Manuscript Revised: 17 JUL 2007
- Manuscript Received: 21 MAY 2007
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.