From the Guest Editors: Recent Advances and Evolving Challenges in Treating Unresectable Melanoma.
From the Guest Editors: Recent Advances and Evolving Challenges in Treating Unresectable Melanoma.
复制标题
来自客座编辑：治疗不可切除黑色素瘤的最新进展和不断变化的挑战。
DOI：
10.1097/ppo.0000000000000244
复制
发表时间：
2017
期刊：
影响因子：
--
通讯作者：
Kluger,HarrietM
中科院分区：
文献类型：
--
作者：
Weiss,SarahA;Kluger,HarrietM
最近在治疗转移性黑色素瘤方面取得的巨大进展在10年前似乎是无法实现的。直到2011年，转移性黑色素瘤几乎没有有效的治疗方法，总生存期大约为几个月。达卡巴嗪于1975年被美国食品和药物管理局（FDA）批准，并且仍然是唯一被批准用于黑色素瘤的化疗药物，反应率高达15%，但耐久性有限。1998年，高剂量白细胞介素2获得批准，在少数患者（高达15%）中具有长期持久反应的潜力，但以显著毒性为代价。经过几十年的干旱，基因组分析的出现加上对免疫逃逸机制的理解的突破，导致了基于免疫操纵和识别可靶向致癌驱动因素的更有效疗法的批准。自2011年FDA批准CTLA-4抑制剂ipilimumab和BRAF抑制剂vemurafenib以来，该领域的乐观情绪飙升，这两种药物都为疾病控制提供了无与伦比的选择。从那时起，CTLA-4和PD-1抑制剂的双重免疫检查点阻断以及BRAF和MEK抑制剂的垂直丝裂原活化蛋白激酶途径抑制现在是护理标准。黑色素瘤治疗中的挑战已经从寻找有效药物转变为理解首先使用哪种药物、如何联合收割机药物以诱导协同抗肿瘤作用、如何克服原发性或获得性耐药性以及如何减轻治疗相关毒性。这个综合性的特刊由领先的黑色素瘤专家的深思熟虑的观点组成。从关注免疫治疗开始，Loo等人回顾了单剂和双剂免疫检查点阻断在晚期黑色素瘤中的应用，以及正在进行的个性化这些方法的研究工作。Hu-Lieskovan等人在本章的基础上探索了使用CTLA-4和/或PD-1抑制剂作为骨架的联合治疗策略，而Giuroiu等人则讨论了靶向新免疫分子的早期临床开发中的新药。随后对辅助疗法进行了探索，包括Escorcia等人的放射在增强抗肿瘤免疫反应中的作用，以及Bommareddy等人的瘤内方法的使用和原理。Merhavi-Shoham等人回顾了过继细胞疗法的经验，包括使用肿瘤浸润淋巴细胞、T细胞受体基因操作和具有遗传修饰的嵌合抗原受体的T细胞。该版本的重点然后转移到更新的分子靶向治疗的Iams等。和Gibney等。和过渡到目前的调查管理黑色素瘤脑转移的奥利瓦等。尽管突破性的进展，已经在系统治疗晚期黑色素瘤在过去的十年中，仍然存在多种障碍，正如Izar及其同事对临床试验设计的评论和Sznol对黑色素瘤临床研究挑战的反思所强调的那样。我们已经在晚期黑色素瘤中达到了前所未有的时代，其中一线CTLA-4和PD-1免疫治疗的客观缓解率达到57.7%，而PD-1抑制剂单药治疗的缓解率达到43.7%。这一成功刺激了这些药物在其他免疫原性恶性肿瘤中的快速研究和/或FDA批准。然而，目前还没有可靠的预测性生物标志物来帮助患者选择，3-4级毒性的发生率仍然很高，可能使患者无法接受后续的免疫治疗。甚至...
The dramatic progress recently made in the treatment of metastatic melanoma seemed unachievable only 10 years ago. Until 2011, few effective therapies existed for metastatic melanoma, and overall survival was on the order of months. Dacarbazine was US Food and Drug Administration (FDA) approved in 1975 and remains the only chemotherapy ever approved for melanoma, with response rates of up to 15%, but with limited durability. 1 Approval of high-dose interleukin 2 followed in 1998, with the potential for long-term durable responses in a minority of patients (up to 15%), but at the expense of significant toxicity. 2 After decades of drought, the advent of genomic profiling combined with breakthroughs in understanding immune escape mechanisms has led to approval of more effective therapies based on immunologic manipulation and identification of targetable oncogenic drivers. 3 Optimism in the field has soared since the 2011 FDA approval of the CTLA-4 inhibitor ipilimumab and the BRAF inhibitor vemurafenib, both of which provided unmatched options for disease control. Since then, dual immune checkpoint blockade with CTLA-4 and PD-1 inhibitors and vertical mitogen-activated protein kinase pathway inhibition with BRAF and MEK inhibitors are now standards of care. The challenges in melanoma therapeutics have shifted from finding an effective drug to understanding which drug to use first, how to combine drugs to induce a synergistic anti-tumor effect, how to overcome primary or acquired drug resistance, and how to mitigate treatment-related toxicity. This comprehensive special issue is composed of thoughtful perspectives from leading melanoma experts. Beginning with a focus on immunotherapy, Loo et al. review the use of single and dual-agent immune checkpoint blockade in advanced melanoma and the ongoing research efforts to personalize these approaches. Hu-Lieskovan et al. build off this chapter to explore combination therapy strategies using CTLA-4 and/or PD-1 inhibitors as a backbone, whereas Giuroiu et al. segue into a discussion of novel drugs in early clinical development that target new immune molecules. An exploration of adjunctive therapies follows, including radiation’s role in amplifying the antitumor immune response by Escorcia et al. and the use of and rationale for intratumoral approaches by Bommareddy et al. Merhavi-Shoham et al. review the experience with adoptive cell therapy including use of tumor infiltrating lymphocytes, T-cell receptor gene manipulation, and T cells with genetically modified chimeric antigen receptors. The edition’s focus then shifts to an update on molecularly targeted therapies by Iams et al. and Gibney et al. and transitions to current investigations for the management of melanoma brain metastases by Oliva et al.Despite the groundbreaking progress that has transpired in systemic therapies for advanced melanoma over the past decade, multiple barriers remain, as highlighted in Izar and colleagues’ commentary on clinical trial design and Sznol’s reflection on the challenges of clinical research in melanoma. We have reached an unprecedented era in advanced melanoma in which objective response rates to frontline combination CTLA-4 and PD-1 immunotherapy reach 57.7%, whereas response rates to monotherapy PD-1 inhibitors reach 43.7%. 4 This success has stimulated the rapid investigation and/or FDA approval of these drugs in other immunogenic malignancies. However, no reliable predictive biomarkers currently exist to aid in patient selection, and the rate of grade 3-4 toxicity remains high, potentially precluding patients from receiving subsequent immunotherapies. Even …