Emerging Strategies in Systemic Therapy for the Treatment of Melanoma.
Emerging Strategies in Systemic Therapy for the Treatment of Melanoma.
复制标题
DOI：
10.1200/edbk_199047
复制
发表时间：
2018-05-23
期刊：
影响因子：
--
通讯作者：
Goff, Stephanie
中科院分区：
文献类型：
--
作者：
Ascierto, Paolo A;Flaherty, Keith;Goff, Stephanie
近年来，随着各种新型全身免疫治疗和靶向治疗的出现，晚期黑色素瘤患者的生存率得到了重大改善。随着我们对这些药物及其各种作用机制的理解的提高，通过使用各种组合策略，包括将不同的免疫疗法相互结合以及与其他方式结合，正在取得更令人印象深刻的结果。然而，尽管在晚期黑色素瘤中取得了改善的结局，但对治疗的反应是异质的，可能并不总是持久的。需要在治疗方面取得更多进展，一些新兴的策略是关注的焦点。这些包括研究几种新的免疫疗法和/或靶向疗法组合，例如检查点抑制剂（抗PD-1/抗CTLA-4）与其他免疫疗法（例如，吲哚胺2，3双加氧酶[IDO]抑制剂、抗淋巴细胞活化3 [抗LAG-3]、组蛋白脱乙酰酶[HDAC]抑制剂、Toll样受体9 [TLR-9]激动剂、抗糖皮质激素诱导的肿瘤坏死因子受体[抗GITR]、聚乙二醇化白介素-2 [IL-2]）、联合靶向治疗（例如，MEK和CDK 4/6共抑制），以及联合免疫疗法和靶向疗法（例如，BRAF/MEK抑制与抗PD-1的三联体组合）。MAP激酶途径中新治疗靶标的鉴定也提供了通过克服对BRAF/MEK抑制的从头和获得性抗性（例如，ERK抑制剂的开发）。此外，过继性细胞转移，即输注大量活化的自体淋巴细胞，可能在免疫治疗后疾病进展的患者中发挥潜在作用。总之，这些新方法为增加晚期黑色素瘤患者的全身治疗选择和改善长期结局提供了进一步的潜力。
Recent years have seen major improvements in survival of patients with advanced melanoma with the advent of various novel systemic immunotherapies and targeted therapies. As our understanding of these agents and their various mechanisms of action improves, even more impressive outcomes are being achieved through use of various combination strategies, including the combining of different immunotherapies with one another as well as with other modalities. However, despite the improved outcomes that have been achieved in advanced melanoma, responses to treatment are heterogeneous and may not always be durable. Additional advances in therapy are required, and several emerging strategies are a focus of interest. These include the investigation of several new immunotherapy and/or targeted therapy combinations, such as checkpoint inhibitors (anti-PD-1/anti-CTLA-4) with other immunotherapies (e.g., indoleamine 2,3 dioxygenase [IDO] inhibitors, antilymphocyte activation 3 [anti-LAG-3], histone deacetylase [HDAC] inhibitors, Toll-like receptor 9 [TLR-9] agonists, antiglucocorticoid-induced tumor necrosis factor receptor [anti-GITR], pegylated interleukin-2 [IL-2]), combined targeted therapies (e.g., MEK and CDK4/6 coinhibition), and combined immunotherapy and targeted therapy (e.g., the triplet combination of BRAF/MEK inhibition with anti-PD-1s). The identification of novel therapeutic targets in the MAP kinase pathway also offers opportunities to improve outcomes by overcoming de novo and acquired resistance to BRAF/MEK inhibition (e.g., the development of ERK inhibitors). In addition, adoptive cell transfer, the infusion of large numbers of activated autologous lymphocytes, may have a potential role in patients whose disease has progressed after immunotherapy. Taken together, these new approaches offer further potential to increase systemic treatment options and improve long-term outcomes for patients with advanced melanoma.