Immune-checkpoint blockade: the springboard for immuno-combination therapy.
Immune-checkpoint blockade: the springboard for immuno-combination therapy.
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免疫检查点阻断：免疫组合治疗的跳板。
DOI：
10.1038/gt.2015.98
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发表时间：
2015
期刊：
影响因子：
5.1
通讯作者：
Ibrahim AM
中科院分区：
文献类型：
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作者：
Ibrahim AM
今天，人们普遍认为免疫系统在肿瘤破坏和肿瘤促进中发挥作用。临床上明显的肿瘤是即使在免疫系统的压力下，也逃脱了免疫识别的肿瘤。随着最近发现肿瘤从免疫系统逃逸的机制，免疫治疗已经在靶向和个性化癌症治疗中占据了主导地位。与传统的化疗、放疗甚至靶向治疗相比，癌症免疫治疗已经成为一种更有吸引力的治疗选择，这主要是由于后者缺乏对癌细胞的特异性和/或耐药倾向高。此外，免疫疗法具有最大的潜力来破坏肿瘤，对正常组织的副作用最小，并通过长期记忆的发展来防止复发。此外，过多的体细胞突变及其在癌症中的持续演变为靶向治疗带来了挑战，而新抗原则暴露于免疫识别。然而，转化的细胞通过限制其展示新抗原和麻痹浸润的免疫效应子功能来抑制宿主免疫应答。2也就是说，通过各种疫苗策略，细胞因子方案和过继性T细胞治疗来增强免疫系统的努力已经使免疫系统的癌症负调节中的一个潜在问题变得模糊不清。当免疫增强或“踩油门”的努力转向重新编程效应器功能和缓解免疫抑制时，癌症免疫治疗领域出现了转机，通常被称为“松开刹车”。这导致了临床上成功的药物易普利姆玛（ipilimumab）（Yerelum; Bristol-Myers Squibb，纽约市，NY，USA）的开发，其是一种抗细胞毒性T淋巴细胞相关蛋白（CTLA）-4人源化抗体，其在2011年被美国食品和药物管理局（FDA）批准用于治疗转移性黑素瘤。3免疫检查点通常用于控制过度的免疫激活，也可能是肿瘤控制的一种手段。免疫检查点阻断剂如伊匹单抗靶分子参与T细胞的调节，而不是直接靶向恶性细胞，如用靶向药物。因此，他们惊人的临床成功是没有预见到的。此外，免疫检查点阻断的最终结果不是攻击肿瘤细胞上的靶标，而是消除阻碍有效抗肿瘤反应的天然抑制反应。4临床前研究表明，CTLA-4的完全丧失导致小鼠中的大量淋巴细胞增殖、自身免疫和死亡5，并且单克隆抗体的部分抑制表明可以实现治疗窗。6在抗CTLA-4药物的临床试验后，发现抑制检查点蛋白程序性死亡受体（PD）-1导致外周T淋巴细胞的更特异性活化。此外，在肿瘤组织上发现其配体PD-L1和PD-L2是开发抗PD-1单克隆抗体（如纳武单抗）以及抗PD-L1药物（如MPDL 3280 A）的先驱。正如预期的那样，由于PD-1受体在活化的T细胞上的表达和PD-L1在恶性细胞上的表达，这些药物实现了更高的响应率，并且伴随着更低的毒性。大规模的临床试验已经证明，免疫检查点阻断治疗可以在晚期恶性肿瘤患者中产生强大，持久的临床反应，这些患者具有一些危及生命的，但大多数是可控的。
Today, it is well accepted that the immune system plays a role in both tumour destruction and tumour promotion. A clinically apparent tumour is one that, even under the pressure of the immune system, has escaped from immune recognition. With the more recent discovery of the mechanisms of tumour escape from the immune system, immunotherapy has taken over the driver’s seat in targeted and personalized cancer therapy. Cancer immunotherapy has become a more attractive therapeutic option compared to traditional chemotherapy, radiation and even targeted therapy, mostly due to the latter’s lack of specificity for cancer cells and/or high propensity for resistance. Furthermore, immunotherapy holds the greatest potential to destroy tumours with minimal side effects to normal tissues, and to prevent recurrence through the development of long-term memory. 1 In addition, the plethora of somatic mutations and their continuous evolution in cancer create challenges for targeted therapies, whereas new antigens are exposed to immune recognition. However, transformed cells dampen the host immune response by limiting their display of neo-antigens and paralysing infiltrating immune effector functions. 2 That said, efforts to boost the immune system with various vaccine strategies, cytokine regimes and adoptive T-cell therapy have clouded an underlying issue in cancer—negative regulation of the immune system. The field of cancer immunotherapy took a turn for the better when immuneenhancing or ‘stepping on the gas pedal’efforts moved towards reprogramming effector functions and relieving immune suppression, often referred as ‘taking off the brakes’. This led to the development of the clinically successful agent ipilimumab (Yervoy; Bristol-Myers Squibb, New York City, NY, USA), an anti-cytotoxic T-lymphocyte-associate protein (CTLA)-4 humanized antibody that was approved by the US Food and Drug Administration (FDA) in 2011 for the treatment of metastatic melanoma. 3 Immune checkpoints normally function to control excessive immune activation and may also be a means of control by tumours. Immune checkpoint blockade agents such as ipilimumab target molecules are involved in the regulation of T-cells rather than targeting malignant cells directly, such as with targeted drugs. For that reason, their astonishing clinical success was not foreseen. Moreover, the end result of immune checkpoint blockade is not to attack a target on a tumour cell, but rather to remove natural inhibitory responses that are impeding an effective antitumour response. 4 Preclinical studies demonstrated that the complete loss of CTLA-4 led to massive lymphoproliferation, autoimmunity and death in mice 5 and partial inhibition with a monoclonal antibody demonstrated that a therapeutic window could be achieved. 6 Following clinical trials with anti-CTLA-4 agents, the discovery of inhibiting the checkpoint protein programmed death receptor (PD)-1 led to a more specific activation of T-lymphocytes in the periphery. Furthermore, the discovery of its ligands, PD-L1 and PD-L2, on tumour tissues was the precursor to the development of anti-PD-1 monoclonal antibodies such as nivolumab, but also anti-PD-L1 agents such as MPDL3280A. As was expected because of the expression of the PD-1 receptor on activated T-cells, and the expression of PD-L1 on malignant cells, these agents achieve higher response rates and are accompanied by less toxicities. Large-scale clinical trials have demonstrated that immune checkpoint blockade treatment leads to robust, durable clinical responses in patients with advanced malignancies with some lifethreatening, but mostly manageable …