Baksh Kathryn, Weber Jeffrey
Donald A. Adam Comprehensive Melanoma Research Center and Department of Cutaneous Oncology, Moffitt Cancer Center, Tampa, FL; University of South Florida School of Medicine, Tampa, FL.
Donald A. Adam Comprehensive Melanoma Research Center and Department of Cutaneous Oncology, Moffitt Cancer Center, Tampa, FL.
Semin Oncol. 2015 Jun;42(3):363-77. doi: 10.1053/j.seminoncol.2015.02.015. Epub 2015 Feb 16.
Over the last two decades, our understanding of the molecular basis of immunity has revealed the complexity of regulatory pathways involved in immune responses to cancer. A significant body of data support the critical importance of immune checkpoints in the control of the adaptive immune response to malignancy, and suggest that inhibitors of those checkpoints might have significant utility in treating cancer. This has been borne out by the recent US Food and Drug Administration (FDA) approvals of two different antibodies, one against cytotoxic T-lymphocyte antigen-4 (CTLA-4) and one against programmed death-1 (PD-1). Here, we provide a comprehensive review of the literature regarding the preclinical justification for the use of CTLA-4 and PD-1 blockade as monotherapy, and as combination therapy in the treatment of cancer. The animal data strongly supported the use of these drugs in patients, and in many cases suggested strategies that directly led to successful registration trials. In contrast, many of the toxicities, and some of the unusual response patterns seen in patients with these drugs, were not predicted by the preclinical work that we cite, highlighting the importance of early-phase trials with patients to inform future drug development. In addition, we review herein the preclinical data surrounding emerging immune checkpoint proteins, including BTLA, VISTA, CD160, LAG3, TIM3, and CD244 as potential targets for inhibition. The current comprehensive review of the literature regarding CTLA-4 and PD-1, as well as a number of novel checkpoint proteins demonstrates a strong preclinical basis for the use of these antibodies singly and in combination to overcome checkpoint inhibition in the treatment of cancer. We also suggest that the use of these antibodies may augment the efficacy of other activating immune antibodies, cytokines, radiation, and adoptive cell therapy in human cancer.
在过去二十年中，我们对免疫分子基础的理解揭示了癌症免疫反应中涉及的调控途径的复杂性。大量数据支持免疫检查点在控制对恶性肿瘤的适应性免疫反应中的关键重要性，并表明这些检查点的抑制剂在治疗癌症方面可能具有显著效用。美国食品药品监督管理局（FDA）最近批准了两种不同的抗体，一种针对细胞毒性T淋巴细胞抗原4（CTLA-4），另一种针对程序性死亡1（PD-1），这证实了上述观点。在此，我们对有关将CTLA-4和PD-1阻断作为单一疗法以及联合疗法治疗癌症的临床前依据的文献进行了全面综述。动物数据有力地支持了这些药物在患者中的应用，并且在许多情况下提出了直接促成成功注册试验的策略。相比之下，我们引用的临床前研究并未预测到使用这些药物的患者中出现的许多毒性反应以及一些不寻常的反应模式，这凸显了患者早期试验对指导未来药物开发的重要性。此外，我们在此回顾了围绕新兴免疫检查点蛋白的临床前数据，包括BTLA、VISTA、CD160、LAG3、TIM3和CD244作为潜在抑制靶点。目前对有关CTLA-4和PD-1以及一些新型检查点蛋白的文献的全面综述表明，单独或联合使用这些抗体以克服检查点抑制在癌症治疗中的应用具有坚实的临床前基础。我们还建议，使用这些抗体可能会增强其他激活免疫抗体、细胞因子、放射疗法和过继性细胞疗法在人类癌症治疗中的疗效。
