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Published online: 2024-04-08

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LAG-3 as a therapeutic target in melanoma

Anna M Terlecka12, Piotr Rutkowski1, Paweł Sobczuk1


The advent of immune checkpoint inhibitors (ICIs) marked a paradigm shift in melanoma therapy, particularly in advanced settings. Although anti-PD-1 and anti-CTLA-4 antibodies have already established their efficacy and safety profiles through extensive trials, the recognition of lymphocyte activation gene 3 (LAG-3, CD223) around three decades ago, introduced a promising alternative in improving the antitumor immune response. As a potent reactive checkpoint expressed in various populations of immune cells, including CD4+, CD8+, and regulatory T-cells, LAG-3 has attracted attention acrossmultiple tumor types, including melanoma. Preliminary findings and emerging phase III evidence already highlight the advantage of combining anti-PD-1 with anti-LAG-3 agents over anti-PD-1 monotherapy. This review investigates the current landscape of anti-LAG-3 therapies, encapsulating recent breakthroughs and pivotal trials, including the landmark RELATIVITY-047 study on the combination of nivolumab and relatlimab. In addition to comprehensively evaluating the latest findings, this analysis describes the ongoing phase I–III trials exploring novel agents, shedding light on the most promising data and perspectives. By synthesizing the latest advances in anti-LAG-3 treatment modalities, this article could serve as a timely and insightful resource for clinicians and researchers, navigating the evolving landscape of melanoma immunotherapy. 

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