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首页> 外文期刊>Clinics in dermatology >Adjuvant immunotherapy of melanoma and development of new approaches using the neoadjuvant approach
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Adjuvant immunotherapy of melanoma and development of new approaches using the neoadjuvant approach

机译：黑色素瘤的辅助免疫疗法和使用新辅助方法的新方法的开发

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Melanoma is the third most common skin cancer but the leading cause of death from cutaneous malignancies. Although early-stage disease is frequently cured by surgical resection with excellent long-term survival, patients with deeper primary lesions (AJCC stage IIB-C) and those with microscopic (IIIA) or clinically evident regional lymph node or in-transit metastases (IIIB-C) have an increased risk of relapse and death, the latter approaching 70% or more at 5 years.In patients at high risk of recurrence/metastases, adjuvant therapy with high-dose interferon alpha-2b (HDI) following definitive surgical resection has been shown to improve relapse-free and overall survival. Neoadjuvant chemotherapy and/or radiotherapy have offered the prospect to improve regional recurrence risk and overall survival in several solid tumors. The advent of effective new molecularly targeted therapies for metastatic disease and new immunotherapies that overcome checkpoints of immune response have augmented the range of new options that are in current trial evaluation to determine their role as potential adjuvant therapies, alone and in combination with one another, and the established modality of IFN-α. The differential characteristics of the host immune response between early and advanced melanoma provide a strong mechanistic rationale for the use of neoadjuvant immunotherapeutic approaches in melanoma, and the opportunity to evaluate the mechanism of action suggest neoadjuvant trial evaluation for each of the new candidate agents and combinations of interest. Several neoadjuvant trials have been conducted in the phase II setting, which have illuminated the mechanism of IFN-α, as well as providing insight to the effects of anti-CTLA4 blocking antibodies. These agents (anti-CTLA4 blocking antibody ipilimumab, and BRAF inhibitor vemurafenib) are likely to be followed by other immunotherapies that may overcome the PD-1 checkpoint (anti-PD1 and anti-PDL-1) as well as other molecularly targeted agents such as the BRAF inhibitor dabrafenib and the MEK inhibitors trametinib, selumetinib, and MEK162 in the near future. Evaluation of the clinical role of these agents as adjuvant therapy will take years to accomplish to ascertain the relapse-free survival benefits and overall survival benefits of these agents, but neoadjuvant exploration may provide early critical evidence of the therapeutic benefits, as well as clarifying the mechanisms of these agents alone and in combination.
机译：黑色素瘤是第三大最常见的皮肤癌，但是皮肤恶性肿瘤致死的主要原因。尽管早期疾病通常可以通过手术切除治愈，并具有长期良好的生存期，但原发灶较深的患者（AJCC IIB-C期）和镜下病变（IIIA）或临床上明显的局部淋巴结转移或转移中的患者（IIIB） -C）复发和死亡的风险增加，后者在5年时接近70％或更高。对于复发/转移的高风险患者，在明确的手术切除后使用大剂量干扰素α-2b（HDI）进行辅助治疗已显示可改善无复发和总体生存率。新辅助化疗和/或放疗为改善局部实体瘤的局部复发风险和总体生存率提供了前景。有效的针对转移性疾病的分子靶向新疗法的出现以及克服免疫应答检查点的新免疫疗法的出现，扩大了新的选择范围，这些新选择目前正在试验评估中，以确定它们作为单独或相互结合的潜在佐剂的作用，并建立了IFN-α的模式。早期和晚期黑色素瘤之间宿主免疫反应的差异性特征为在黑色素瘤中使用新辅助免疫治疗方法提供了强有力的机制基础，并且有机会评估作用机理提示对每种新的候选药物和组合进行新辅助试验评估出于兴趣。在II期试验中进行了几项新辅助试验，这些试验阐明了IFN-α的机制，并为抗CTLA4阻断抗体的作用提供了见识。这些药物（抗CTLA4阻断抗体ipilimumab和BRAF抑制剂vemurafenib）很可能会跟随其他可能克服PD-1检查点的免疫疗法（抗PD1和抗PDL-1）以及其他分子靶向药物，例如作为BRAF抑制剂dabrafenib和MEK抑制剂曲美替尼，selumetinib和MEK162在不久的将来。要确定这些药物的无复发生存获益和总体生存获益，评估这些药物作为辅助疗法的临床作用将花费数年的时间，但是新辅助研究可能会提供治疗益处的早期关键证据，并阐明这些试剂单独或组合的作用机理。

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