Overcoming resistance to targeted therapy with immunotherapy and combination therapy for metastatic melanoma.
Overcoming resistance to targeted therapy with immunotherapy and combination therapy for metastatic melanoma.
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DOI：
10.18632/oncotarget.18523
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发表时间：
2017-09-26
期刊：
影响因子：
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通讯作者：
Wells JW
中科院分区：
文献类型：
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作者：
Keller HR;Zhang X;Li L;Schaider H;Wells JW
对靶向治疗的抗性是成功治疗IV期转移性黑色素瘤的持续问题。对于许多患者来说，使用靶向治疗，如BRAF激酶抑制剂，最初是有希望的，但耐药性不可避免地发生。即使在将BRAF激酶抑制剂与MEK途径抑制剂组合以抵消MAP激酶途径的再活化之后，仍记录到抗性。同样，免疫检查点抑制剂作为单药治疗的结果对于一些没有复发或进展的患者来说是乐观的，但大多数接受单药治疗的患者都有疾病进展。免疫疗法和联合疗法试验能否克服转移性黑色素瘤的耐药性？为了治疗耐药疾病，目前正在进行新的临床试验，评估免疫疗法与其他疗法的组合，如激酶抑制剂，过继细胞疗法，嵌合CD40配体以增强共刺激，或肿瘤特异性溶瘤病毒增强粒细胞巨噬细胞集落刺激因子（GM-CSF）表达。关于抵抗机制、免疫逃逸和重振免疫细胞的选择的最新研究支持不断发现新的和改进的治疗形式。
Resistance to targeted therapy is an ongoing problem for the successful treatment of Stage IV metastatic melanoma. For many patients, the use of targeted therapies, such as BRAF kinase inhibitors, were initially promising yet resistance inevitably occurred. Even after combining BRAF kinase inhibitors with MEK pathway inhibitors to offset re-activation of the MAP kinase pathway, resistance is still documented. Similarly, outcomes with immune checkpoint inhibitors as monotherapy were optimistic for some patients without relapse or progression, yet the majority of patients undergoing monotherapy have progressive disease. Will immunotherapy and combination therapy trials overcome resistance in metastatic melanoma? In an effort to treat resistant disease, new clinical trials evaluating the combination of immunotherapy with other therapies, such as kinase inhibitors, adoptive cell therapy, chimeric CD40 ligand to boost costimulation, or a tumor-specific oncolytic virus enhancing granulocyte macrophage colony-stimulating factor (GM-CSF) expression, are currently underway. Updated studies on the mechanisms of resistance, immune escape and options to reinvigorate immune cells support the continued discovery of new and improved forms of therapy.