Second Department of Internal Medicine, University of Tuebingen Center for Medical Research (ZMF), Tuebingen, Germany.
Division of Cancer Studies, King's College London, London, UK.
Immunology. 2018 Apr;153(4):415-422. doi: 10.1111/imm.12870. Epub 2017 Dec 20.
Melanoma has long been recognized as a potentially immunogenic tumour, but only recently has it become clear that the reason for this resides in its many ultraviolet (UV)-induced mutations and expression of multiple autoantigens which can be targeted by the immune system. The first successful applications of immune-based treatments included passive immunotherapy using high-dose interleukin (IL)-2 and/or adoptive transfer of natural killer (NK)-cells, as well as active immunotherapy using whole cell-derived or peptide vaccines. In the intervening decades, it has become clear that these approaches can lead to durable responses in stage III/IV melanoma, and even to functional cures - but only in a vanishingly small fraction of patients. With the advent of immune checkpoint blockade first with anti-cytotoxic T-lymphocyte 4 (CTLA-4), then with anti-programmed cell death 1 (PD-1) antibodies, and combinations thereof, the small percentage of responding patients may be increased to half, a major accomplishment in this refractory disease. Improved techniques for identifying mutation-derived neoantigens and thus more sophisticated active immunotherapies, probably combined with checkpoint blockade, currently hold great promise for further increasing the fraction of responding patients. As additional immunomodulatory antibodies and therapies become available, it will be increasingly important to develop diagnostic tools to determine which particular therapy is likely to elicit the best response for the individual patient. Practically speaking, therapy selection and efficacy monitoring on the basis of the results of a blood test would be most desirable. The purpose of this review is to consider the feasibility of identifying 'immune signatures' for predicting responses and determining mechanisms responsible for success or failure of these immunotherapies.
黑色素瘤一直被认为是一种具有潜在免疫原性的肿瘤，但直到最近才清楚，其原因在于它有许多紫外线（UV）诱导的突变和表达的多种自身抗原，这些抗原可以被免疫系统靶向。免疫治疗的首次成功应用包括使用大剂量白细胞介素（IL）-2 和/或自然杀伤（NK）细胞的被动免疫疗法，以及使用全细胞衍生或肽疫苗的主动免疫疗法。在这几十年中，已经清楚这些方法可以在 III/IV 期黑色素瘤中导致持久的反应，甚至可以实现功能性治愈 - 但仅在极少数患者中。随着免疫检查点阻断的出现，首先是抗细胞毒性 T 淋巴细胞 4（CTLA-4），然后是抗程序性细胞死亡 1（PD-1）抗体，以及它们的组合，反应患者的比例可能会从一小部分增加到一半，这在这种难治性疾病中是一个重大成就。用于识别突变衍生的新抗原的改进技术，从而更复杂的主动免疫疗法，可能与检查点阻断相结合，目前为进一步增加反应患者的比例提供了巨大的希望。随着更多的免疫调节抗体和疗法的出现，开发用于确定哪种特定疗法可能为个体患者产生最佳反应的诊断工具将变得越来越重要。实际上，基于血液测试结果进行治疗选择和疗效监测将是最理想的。本综述的目的是考虑确定“免疫特征”以预测反应并确定这些免疫疗法成败的机制的可行性。
