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Review
. 2013:13:5.
Epub 2013 Jan 22.

CTLA-4 blockade in tumor models: an overview of preclinical and translational research

Joseph F Grosso  1 , Maria N Jure-Kunkel
Affiliations
Review

CTLA-4 blockade in tumor models: an overview of preclinical and translational research

Joseph F Grosso et al. Cancer Immun. 2013.

Abstract

Cytotoxic T lymphocyte antigen-4 (CTLA-4) is a key negative regulator of T cell activation. A complex integration of positive and negative co-stimulatory signals in the well-defined B7:CD28/CTLA-4 pathway modulates the generation and maintenance of immune responses. Inhibiting negative regulation through binding of CTLA-4 has been shown to promote stimulation of adaptive immunity and potentiation of T cell activation. CTLA-4-blocking antibodies have demonstrated efficacy in various murine malignancy models when administered as monotherapy; additionally, they have shown synergistic anti-tumor activity when utilized with other agents, such as vaccines, chemotherapy, and radiation. Preclinical studies have supported the rationale for current clinical development of anti-CTLA-4 antibodies, including ipilimumab and tremelimumab, as novel therapeutic strategies to augment anti-tumor immunity in cancer. Both ipilimumab and tremelimumab have been evaluated extensively in melanoma; notably, ipilimumab was recently approved as monotherapy for the treatment of advanced melanoma. Tremelimumab is currently undergoing evaluation in phase II trials as monotherapy in melanoma and malignant mesothelioma, while ipilimumab is under clinical investigation in phase II and III trials in various tumor types, including in melanoma, prostate, and lung cancers as monotherapy and with other therapeutic modalities, such as chemotherapy and radiation. In this review, we will provide a detailed overview of preclinical advances that have delineated many features of CTLA-4 and have helped define its role in T cell response. We will also highlight clinical application of anti-CTLA-4 therapy in cancer and describe knowledge gaps that future studies may address.

Keywords: CTLA-4; T cell; antibody; co-stimulation; preclinical.

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Figures

Figure 1
Figure 1
Complementary approaches to overcome tumor-induced tolerance. Blockade of CTLA-4 on potential effector cells in secondary lymphoid organs is combined with different strategies, such as chemotherapy, radiation, surgery, cryoablation, vaccination, adoptive T cell therapy, cytokine therapy, and antibody blockade of additional negative (i.e., PD-1, LAG-3, Tim-3) or positive (i.e., CD137) regulatory receptors to achieve synergistic anti-tumor effects. [Adapted from Bartlett JB et al. (93)].
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