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Review
. 2011 Dec;84(4):381-9.

Ipilimumab and Cancer Immunotherapy: A New Hope for Advanced Stage Melanoma

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Free PMC article
Review

Ipilimumab and Cancer Immunotherapy: A New Hope for Advanced Stage Melanoma

Matthew Mansh. Yale J Biol Med. .
Free PMC article

Abstract

Metastatic melanoma remains one of the most lethal and poorly treated forms of human cancer. Its incidence is on the rise, but no therapies offering improved survival rates have been developed over the last 40 years. This has changed with the recent Food and Drug Administration (FDA) approval of the CTLA-4 function blocking antibody Ipilimumab (Yervoy), proven to extend life in patients with previously treated or untreated metastatic melanoma [39,40]. CTLA-4 is a receptor that normally functions to inhibit inappropriate or prolonged activation of T-cells. This review presents the history of initial research into the function of the CTLA-4 receptor, the pre-clinical evidence for CTLA-4 blockade's utility in cancer treatment, and the recent human clinical trials that have proven its efficacy in advanced stage melanoma. Ipilimumab represents one of a growing class of cancer immunotherapies currently under development and highlights both the promise and relative infancy of these agents in the clinical setting.

Keywords: CTLA-4; T-cells; cancer; dermatology; immunology; immunotherapy; ipilimumab; melanoma; skin.

Figures

Figure 1
Figure 1
T-cell regulation, CTLA-4, and Ipilimumab. A) Normal T-cell activation occurs via presentation of MHC-bound antigens on APCs that signal through the TCR. This process is amplified by the co-stimulatory signal produced by interaction of the CD80/86 (B7) receptor on APCs with CD28 molecules on the T-cell. Prolonged T-cell activation initiates the upregulation of CTLA-4, a membrane receptor that competes with CD28 for binding to CD80/86 (B7). CTLA-4 has a higher affinity for CD80/86 (B7) than CD28 and its binding oppositely produces inhibitory signals through decreased proliferation and IL-2 production. This relationship allows normal T-cells to prevent over-activation through feedback upregulation of CTLA-4. B) Ipilimumab binds to CTLA-4 and prevents interaction with CD80/CD86 (B7) molecules on APCs. This removes CTLA-4 induced inhibitory signals allowing for unregulated and prolonged activation of T-cells in a non-specific manner.

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