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Checkpoint Modulators in Cancer Immunotherapy

Volumen 5, Edición 1-2, 2014, pp. 69-82
DOI: 10.1615/ForumImmunDisTher.2015013940
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SINOPSIS

Enhancing the T-cell-mediated immune response against cancers is currently an attractive therapeutic approach, particularly for cancers that are intractable to conventional chemotherapy. Immune checkpoints are molecules that control the degree of T-cell activation and effector functions. These checkpoint molecules are comprised of costimulatory receptors (e.g., 4-1BB, glucocorticoid-induced T-cell-receptor [GITR]-related [protein], and OX40), co-inhibitory receptors (e.g., programmed cell death-1 [PD-1], cytotoxic T-lymphocyte-associated protein-4 [CTLA-4,] and T-cell immunoglobulin mucin-3 [TIM-3]), and enzymes (e.g., indoleamine 2,3-dioxygenase [IDO] and CD73). There has been a surge in the development of antibody- (and small-molecule)-based therapy aimed at enhancing the antitumor T-cell response by targeting immune checkpoints. The clinical experience with modulators of CTLA-4 and PD-1 has been highly positive and has stimulated the development of modulators of other immune checkpoints. This review describes the role of some key checkpoint molecules in governing the antitumor immune response and assesses the evidence for the therapeutic utility of checkpoint modulation. The rationale for combining a checkpoint modulator with other approaches (such as chemotherapy or radiation) or indeed with other checkpoint modulators is discussed. The safety concerns that arise with checkpoint modulation and the strategies used to mitigate safety risk are also considered. Finally, the challenges in the development and clinical deployment of safe, new checkpoint modulators are outlined.

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