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The monoclonal antibody to cytotoxic T lymphocyte antigen 4, ipilimumab, in the treatment of melanoma.

Verschraegen C - Cancer Manag Res (2012)

Bottom Line: The toxicities are autoimmune events and guidelines for treatment of these effects are discussed.The first two Phase III randomized studies showed an improvement of survival at 1, 2, and 3 years.Other studies are currently underway to better understand the optimal treatment administration of ipilimumab in melanoma.

View Article: PubMed Central - PubMed

Affiliation: Professor of Medicine, Division of Hematology Oncology, University of Vermont, Vermont Cancer Center, VT, USA.

ABSTRACT

Background: Cytotoxic T lymphocyte antigen 4 (CTLA-4) is an inhibitory regulator of the T-cell immune response against tumor cells. Ipilimumab is a monoclonal antibody directed against CTLA-4.

Objective: This review describes the basic mechanism of ipilimumab and discusses data available to date with regards to its safety and efficacy profile.

Methods: Data from clinical trials including abstracts was reviewed using the PubMed Database, as well as the American Society of Clinical Oncology Abstract Database.

Conclusion: CTLA-4 inhibition with a monoclonal antibody is usually well tolerated and has efficacy as a therapeutic agent in a variety of cancers. The classical response interpretation has changed because of the delayed mechanism of action. The toxicities are autoimmune events and guidelines for treatment of these effects are discussed. Therapy with ipilimumab leads to durable responses. The first two Phase III randomized studies showed an improvement of survival at 1, 2, and 3 years. Other studies are currently underway to better understand the optimal treatment administration of ipilimumab in melanoma.

No MeSH data available.


Related in: MedlinePlus

When an antigen (Ag) is presented in the context of the major histocompatibility complex (MHC) to the T cell receptor (TCR), binding of B7 with CD28 occurs which activates the T cell. Slightly later, the activated T cell stimulates CTLA4 which also binds to B7 to down-regulate the T cell. Ipilimumab inactivates the binding of CTLA4 with B7, allowing the T cell to remain activated.Abbreviations: Ag, antigen; MHC, major histocompatibility complex; TCR, T cell receptor.
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f1-cmar-4-001: When an antigen (Ag) is presented in the context of the major histocompatibility complex (MHC) to the T cell receptor (TCR), binding of B7 with CD28 occurs which activates the T cell. Slightly later, the activated T cell stimulates CTLA4 which also binds to B7 to down-regulate the T cell. Ipilimumab inactivates the binding of CTLA4 with B7, allowing the T cell to remain activated.Abbreviations: Ag, antigen; MHC, major histocompatibility complex; TCR, T cell receptor.

Mentions: CTLA-4 is important in immune homeostasis and in the induction of tolerance to self-antigens.5,6 T-cell activation requires at least two signals: the presentation of an antigen to the T-cell receptor by a major histocompatibility complex molecule on an antigen presenting cell, and interaction of the T-cell with other receptors that either enhance or inhibit the T-cell response.7 CD28 and CTLA-4 competitively interact with the B7-1 and B7-2 ligands located on the antigen presenting cell, with antagonistic effects.8,9 CD28 enhances T-cell activation and IL-2 production and CTLA-4 antagonizes T-cell activation by interfering with IL-2 secretion and IL-2 receptor expression.10 IL-2 stimulates T-cell growth, but has also been implicated in the expansion of regulatory T-cells that express CTLA-4. CTLA-4 binds to B7-1 and B7-2 ligands with greater affinity than CD28.11 Although CD28 is constitutively expressed on naive T-cells, CTLA-4 becomes functional only after T-cell activation.12 This temporal delay in CTLA-4 upregulation allows for initial T-cell activation by CD28, followed by a regulatory feedback loop mediated by CTLA-4. Ipilimumab binds to CTLA-4 and allows the T-cell immune response to persist (Figure 1).


The monoclonal antibody to cytotoxic T lymphocyte antigen 4, ipilimumab, in the treatment of melanoma.

Verschraegen C - Cancer Manag Res (2012)

When an antigen (Ag) is presented in the context of the major histocompatibility complex (MHC) to the T cell receptor (TCR), binding of B7 with CD28 occurs which activates the T cell. Slightly later, the activated T cell stimulates CTLA4 which also binds to B7 to down-regulate the T cell. Ipilimumab inactivates the binding of CTLA4 with B7, allowing the T cell to remain activated.Abbreviations: Ag, antigen; MHC, major histocompatibility complex; TCR, T cell receptor.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3278204&req=5

f1-cmar-4-001: When an antigen (Ag) is presented in the context of the major histocompatibility complex (MHC) to the T cell receptor (TCR), binding of B7 with CD28 occurs which activates the T cell. Slightly later, the activated T cell stimulates CTLA4 which also binds to B7 to down-regulate the T cell. Ipilimumab inactivates the binding of CTLA4 with B7, allowing the T cell to remain activated.Abbreviations: Ag, antigen; MHC, major histocompatibility complex; TCR, T cell receptor.
Mentions: CTLA-4 is important in immune homeostasis and in the induction of tolerance to self-antigens.5,6 T-cell activation requires at least two signals: the presentation of an antigen to the T-cell receptor by a major histocompatibility complex molecule on an antigen presenting cell, and interaction of the T-cell with other receptors that either enhance or inhibit the T-cell response.7 CD28 and CTLA-4 competitively interact with the B7-1 and B7-2 ligands located on the antigen presenting cell, with antagonistic effects.8,9 CD28 enhances T-cell activation and IL-2 production and CTLA-4 antagonizes T-cell activation by interfering with IL-2 secretion and IL-2 receptor expression.10 IL-2 stimulates T-cell growth, but has also been implicated in the expansion of regulatory T-cells that express CTLA-4. CTLA-4 binds to B7-1 and B7-2 ligands with greater affinity than CD28.11 Although CD28 is constitutively expressed on naive T-cells, CTLA-4 becomes functional only after T-cell activation.12 This temporal delay in CTLA-4 upregulation allows for initial T-cell activation by CD28, followed by a regulatory feedback loop mediated by CTLA-4. Ipilimumab binds to CTLA-4 and allows the T-cell immune response to persist (Figure 1).

Bottom Line: The toxicities are autoimmune events and guidelines for treatment of these effects are discussed.The first two Phase III randomized studies showed an improvement of survival at 1, 2, and 3 years.Other studies are currently underway to better understand the optimal treatment administration of ipilimumab in melanoma.

View Article: PubMed Central - PubMed

Affiliation: Professor of Medicine, Division of Hematology Oncology, University of Vermont, Vermont Cancer Center, VT, USA.

ABSTRACT

Background: Cytotoxic T lymphocyte antigen 4 (CTLA-4) is an inhibitory regulator of the T-cell immune response against tumor cells. Ipilimumab is a monoclonal antibody directed against CTLA-4.

Objective: This review describes the basic mechanism of ipilimumab and discusses data available to date with regards to its safety and efficacy profile.

Methods: Data from clinical trials including abstracts was reviewed using the PubMed Database, as well as the American Society of Clinical Oncology Abstract Database.

Conclusion: CTLA-4 inhibition with a monoclonal antibody is usually well tolerated and has efficacy as a therapeutic agent in a variety of cancers. The classical response interpretation has changed because of the delayed mechanism of action. The toxicities are autoimmune events and guidelines for treatment of these effects are discussed. Therapy with ipilimumab leads to durable responses. The first two Phase III randomized studies showed an improvement of survival at 1, 2, and 3 years. Other studies are currently underway to better understand the optimal treatment administration of ipilimumab in melanoma.

No MeSH data available.


Related in: MedlinePlus