Cytokines in the Treatment of Cancer
Cytokines in the Treatment of Cancer
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DOI：
10.1089/jir.2018.0019
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发表时间：
2019-01-01
影响因子：
2.3
通讯作者：
Waldmann, Thomas A.
中科院分区：
文献类型：
--
作者：
Conlon, Kevin C.;Miljkovic, Milos D.;Waldmann, Thomas A.
细胞因子是先天免疫和适应性免疫的主要调节因子，使免疫系统的细胞能够短距离通信。激活癌症患者免疫系统的细胞因子治疗一直是一种重要的治疗方式，并且仍然是当前临床癌症研究的关键贡献者。干扰素α（IFN）被批准用于完全切除的高危黑色素瘤患者和几种难治性恶性肿瘤的辅助治疗。高剂量白细胞介素-2（HDIL-2）被批准用于治疗转移性肾细胞癌和黑色素瘤，但随着新药物的开发，这两种药物目前都不太常用。粒细胞-巨噬细胞集落刺激因子（GM-CSF）、IFN γ（IFN）、IL-7、IL-12和IL-21在临床试验中进行了评价，并仍是某些研究性试验的一部分。期待已久的IL-15的初始单药临床试验已经完成，与抗肿瘤抗体或检查点抑制剂（CPI）的联合试验已经启动。然而，单一疗法中的细胞因子尚未实现在临床前实验中看到的功效的承诺。它们通常与重度剂量限制性毒性相关，这些毒性可通过适当给药进行管理，现在更好地理解为诱导免疫抑制性体液因子、抑制性细胞和细胞检查点，而不会持续诱导肿瘤特异性应答。为了规避这些障碍，细胞因子正在临床上用新的工程化细胞因子突变体（超级因子）、嵌合抗体-细胞因子融合蛋白（免疫因子）、抗癌疫苗、CPI和癌症定向单克隆抗体进行研究，以增加其抗体依赖性细胞毒性或维持细胞应答和抗癌功效。本文综述了细胞因子单药治疗或与其他生物制剂联合治疗的现状及临床应用。我们强调对这些细胞因子的研究的未来方向的讨论，使它们成为转移性恶性肿瘤治疗的主要贡献者。
Cytokines are major regulators of innate and adaptive immunity that enable cells of the immune system to communicate over short distances. Cytokine therapy to activate the immune system of cancer patients has been an important treatment modality and continues to be a key contributor to current clinical cancer research. Interferon alpha (IFN) is approved for adjuvant treatment of completely resected high-risk melanoma patients and several refractory malignancies. High-dose interleukin-2 (HDIL-2) is approved for treatment of metastatic renal cell cancer and melanoma, but both agents are currently less commonly used with the development of newer agents. Granulocyte-macrophage colony-stimulating factor (GM-CSF), IFN gamma (IFN), IL-7, IL-12, and IL-21 were evaluated in clinical trials and remain part of certain investigational trials. The initial single-agent clinical trials with the long-awaited IL-15 have been completed and combination trials with antitumor antibodies or checkpoint inhibitors (CPIs) have been initiated. However, cytokines in monotherapy have not fulfilled the promise of efficacy seen in preclinical experiments. They are often associated with severe dose-limiting toxicities that are manageable with appropriate dosing and are now better understood to induce immune-suppressive humoral factors, suppressive cells, and cellular checkpoints, without consistently inducing a tumor-specific response. To circumvent these impediments, cytokines are being investigated clinically with new engineered cytokine mutants (superkines), chimeric antibody-cytokine fusion proteins (immunokines), anticancer vaccines, CPIs, and cancer-directed monoclonal antibodies to increase their antibody-dependent cellular cytotoxicity or sustain cellular responses and anticancer efficacy. In this review, we summarize current knowledge and clinical application of cytokines either as monotherapy or in combination with other biological agents. We emphasize a discussion of future directions for research on these cytokines, to bring them to fruition as major contributors for the treatment of metastatic malignancy.