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Review
. 2010 Dec;25(6):601-13.
doi: 10.1089/cbr.2010.0865.

Releasing the brake on the immune system: ipilimumab in melanoma and other tumors

Ahmad Tarhini  1 , Ernest Lo, David R Minor
Affiliations
Review

Releasing the brake on the immune system: ipilimumab in melanoma and other tumors

Ahmad Tarhini et al. Cancer Biother Radiopharm. 2010 Dec.

Abstract

Advanced melanoma has proven difficult to treat for many years, and no previous agent has shown improved survival in a phase 3 trial. The deepening understanding of tumor immunobiology and the complexity of the interactions between host T cells and cancer have led to novel treatment approaches. Among these, ipilimumab is a first-in-class T-cell potentiator that works by blocking cytotoxic T-lymphocyte antigen-4, a critical negative regulator of the antitumor T-cell response. From phase 1 studies, ipilimumab has shown encouraging activity in melanoma and other cancers, with unusual response patterns and mechanism-related, predictable toxicities that are medically manageable and mostly reversible but can sometimes be life threatening unless recognized and treated early. Early indications of a survival benefit in phase 2 studies have been confirmed recently in the first randomized phase 3 trial; the primary endpoint of the trial, overall survival (OS), was met with ipilimumab significantly prolonging median OS both as a single agent (10.1 months; p = 0.003) and combined with gp100 vaccine (10.0 months; p < 0.001) compared with vaccine control (6.4 months). Even more noteworthy was the improvement in long-term survival at 24 months from 13.7% (gp100 alone) to 21.6% and 23.5% for the combination and single ipilimumab, respectively. The addition of gp100 vaccine did not appear to impact OS since data for ipilimumab alone were similar to those for the combination with vaccine. Re-induction with ipilimumab in selected patients who progressed gave further clinical benefits. Ipilimumab has also shown promising activity in melanoma patients with brain metastases, and patients with non-small cell lung cancer, renal cell cancer, and castrate-resistant prostate cancer. Ipilimumab not only has a novel mechanism of action but demonstrates unique immune-related toxicities that require particular care in their recognition and treatment.

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Figures

FIG. 1.
FIG. 1.
T-cell activation and mechanism of action of ipilimumab (adapted with permission from Weber51). APC, antigen presenting cell; CTLA-4, cytotoxic T lymphocyte antigen-4; TCR, T-cell receptor; MHC, major histocompatibility complex.
FIG. 2.
FIG. 2.
Four response patterns to ipilimumab have been seen: (1) response from the outset; (2) durable SD with or without subsequent response; (3) response after PD, and (4) response in some lesions accompanied by the appearance of new ones.
See this image and copyright information in PMC

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