Despite major advances with immunotherapy and targeted therapy in the past decade, metastatic melanoma continues to be a deadly disease for close to half of all patients. Over the past decade, advancement in immune profiling and a deeper understanding of the immune tumor microenvironment (TME) have enabled the development of novel approaches targeting and a multitude of targets being investigated for the immunotherapy of melanoma. However, to date, immune checkpoint blockade has remained the most successful with programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) and cytotoxic T-lymphocyte antigen-4 (CTLA-4) inhibitors, alone or in combination, yielding the most robust and durable clinical outcome in patients with metastatic melanoma. The highest rate of durable responses is achieved with the combination with PD-1 and CTLA-4 inhibition, and is effective in a variety of settings including brain metastases; however, it comes at the expense of a multitude of life-threatening toxicities occurring in up to 60% of patients. This has also established melanoma as the forefront of immuno-oncology (IO) drug development, and the search for novel checkpoints has been ongoing with multiple relevant targets including T-cell immunoglobulin and mucinodomain containing-3 (TIM-3), LAG-3, V-domain immunoglobulin suppressor T-cell activation (VISTA), T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif (ITIM) domain (TIGIT), among others. Lymphocyte activation gene-3 (LAG-3), which is a co-inhibitory receptor on T cells that suppress their activation, has revolutionized immunomodulation in melanoma. The 'game changing' results from the RELATIVITY-047 trial validated LAG-3 blockade as a relevant biological target and established it as the third clinically relevant immune checkpoint. Importantly, LAG-3 inhibition in combination with PD-1 inhibition offered impressive efficacy with modest increases in toxicity over single agent PD-1 inhibitor and has been U.S. Food and Drug Administration approved for the first-line therapy of patients with metastatic melanoma. The efficacy of this combination in patients with untreated brain or leptomeningeal metastases or with rare melanoma types, such as uveal melanoma, remains to be established. The challenge remains to elucidate specific mechanisms of response and resistance to LAG-3 blockade and to extend its benefits to other malignancies. Ongoing trials are studying the combination of LAG-3 antibodies with PD-1 inhibitors in multiple cancers and settings. The low toxicity of the combination may also allow for further layering of additional therapeutic approaches such as chemotherapy, oncolytic viruses, cellular therapies, and possibly novel cytokines, among others.

中文翻译：

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LAG-3 检查点阻断在黑色素瘤中的引入：PD-1 和 CTLA-4 抑制之外的免疫治疗前景。

尽管过去十年免疫疗法和靶向治疗取得了重大进展，但转移性黑色素瘤仍然是近一半患者的致命疾病。在过去的十年中，免疫分析的进步和对免疫肿瘤微环境（TME）的更深入了解使得黑色素瘤免疫治疗的新靶向方法和多种正在研究的靶点的开发成为可能。然而，迄今为止，免疫检查点阻断仍然是最成功的，即程序性细胞死亡 1 (PD-1)/程序性细胞死亡配体 1 (PD-L1) 和细胞毒性 T 淋巴细胞抗原 4 (CTLA-4) 抑制剂单独或联合使用，可为转移性黑色素瘤患者带来最稳健和持久的临床结果。与 PD-1 和 CTLA-4 抑制相结合可实现最高的持久反应率，并且在包括脑转移在内的多种情况下均有效；然而，它的代价是高达 60% 的患者会出现多种危及生命的毒性反应。这也确立了黑色素瘤作为免疫肿瘤学 (IO) 药物开发的前沿，并且一直在针对多个相关靶点寻找新的检查点，包括 T 细胞免疫球蛋白和 mucinodomain contains-3 (TIM-3)、LAG-3 、V 域免疫球蛋白抑制 T 细胞激活 (VISTA)、T 细胞免疫球蛋白和基于免疫受体酪氨酸的抑制基序 (ITIM) 域 (TIGIT) 等。淋巴细胞激活基因 3 (LAG-3) 是 T 细胞上的一种共抑制受体，可抑制 T 细胞的激活，彻底改变了黑色素瘤的免疫调节。RELATIVITY-047 试验的“改变游戏规则”的结果验证了 LAG-3 阻断作为相关的生物靶标，并将其确立为第三个临床相关的免疫检查点。重要的是，与单药 PD-1 抑制剂相比，LAG-3 抑制与 PD-1 抑制相结合提供了令人印象深刻的疗效，但毒性略有增加，并已被美国食品和药物管理局批准用于转移性黑色素瘤患者的一线治疗。这种组合对于未经治疗的脑部或软脑膜转移瘤或罕见黑色素瘤类型（例如葡萄膜黑色素瘤）的患者的疗效仍有待确定。挑战仍然是阐明 LAG-3 封锁的具体反应和抵抗机制，并将其益处扩展到其他恶性肿瘤。正在进行的试验正在研究 LAG-3 抗体与 PD-1 抑制剂在多种癌症和环境中的组合。该组合的低毒性还可能允许进一步分层其他治疗方法，例如化疗、溶瘤病毒、细胞疗法和可能的新型细胞因子等。