<Oncology Frontier>: Ipilimumab is a human monoclonal antibody against CTLA-4， which was recently approved by US FDA for the treatment of metastatic melanoma. Could you please give us a brief introduction to its activity and related mechanisms with reference to clinical trials?
Dr Lipson: Ipilimumab is a first-in-class medication that targets the CTLA-4 regulatory protein which helps determine whether an immune cell is activated against a potential target. One of the larger trials that was reported a few years ago here at ASCO was a trial involving 676 patients that were randomized to either vaccine， vaccine plus ipilimumab or ipilimumab alone.  What was shown was an increase in overall survival in that phase III trial. For a large part， it was that which prompted the FDA to approve the agent in 2011. It has now become one standard of care for patients with metastatic melanoma.

　　《肿瘤瞭望》：伊匹单抗是抗CTLA-4的人单克隆抗体，最近美国FDA批准其用于转移性黑色素瘤的治疗。您能结合相关临床试验为大家简单介绍一下伊匹单抗的作用及其相关机制吗？
Dr. Lipson：伊匹单抗是针对CTLA-4调节蛋白的一类新药，它通过针对一个潜在靶点决定是否激活免疫细胞。一项关于伊匹单抗较大的临床试验是几年前在ASCO年会上公布的。这项试验共纳入676例受试者，随机将其分为疫苗治疗组、疫苗联合伊匹单抗治疗组和伊匹单抗单药治疗组。Ⅲ期临床试验结果显示其可以延长总生存期。更重要的是，这项研究促使FDA在2011年批准伊匹单抗用于临床。伊匹单抗现已成为转移性黑色素瘤的标准治疗方案之一。

<Oncology Frontier>:  Is it possible to predict the side effects that can potentially develop during the course of immunotherapy? Is there any genetic signature predictive of toxicity?
Dr Lipson: It is difficult to predict the side effects prior to starting therapy. We do know the more common side effects based on the drug we are using. For example， ipilimumab’s most common toxicities involve the skin (rash and dermatitis) and enterocolitis. It is difficult to predict on an individual patient basis who might experience toxicities before starting therapy. Having said that though， we choose our patients very carefully. Patients with underlying autoimmune conditions such as rheumatoid arthritis may not be given an immune checkpoint agent up front for fear of exacerbating an ongoing autoimmune issue.

　　《肿瘤瞭望》：在免疫治疗过程中能够预测可能发生的副反应吗？是否存在可以预测毒性的遗传学标志呢？
Dr. Lipson：在开始治疗之前是很难预测副反应的。我们只了解目前正在使用的药物的常见副作用。例如，伊匹单抗最常见的毒副反应包括皮疹、皮炎和结肠炎。开始治疗之前，在患者个体基础上预测谁将出现毒性反应是很难的。话虽如此，我们还是该仔细挑选患者。患者自身免疫系统的基础很重要，例如伴有类风湿性关节炎的患者就不能使用免疫检验点抑制剂，以免加重其自身免疫疾病。

<Oncology Frontier>: According to the mechanisms related to toxicity， can we combine immune checkpoint blockade therapy with immunosuppressors to reduce any potential toxicity?
Dr Lipson: We often do that. The patients who were seen to be responding to ipilimumab in several of the trials in the last five or six years， often required corticosteroids as an immune suppressor to mitigate adverse events. Those patients’ response to therapy in terms of tumor regression did not seem to be affected by the administration of corticosteroids. So often we apply the checkpoint agent; if necessary we apply an immunosuppressor to relieve some of the adverse events; and at least in the case of ipilimumab， we don’t think the antitumor effects of the drug are being decreased. I should say that in a phase II trial several years ago， prophylactic steroids for the prevention of colitis was attempted and it was shown that even with the addition of budesonide (the steroid they used)， the investigators were not able to show a decrease in the level of grade 2 or greater diarrhea with prophylactic steroid use. So there isn’t a role up front for the administration of immunosuppression but when adverse events do show up， then we administer steroids.

　　《肿瘤瞭望》：根据相关毒性的发生机制，我们是否可以将免疫检验点抑制剂与免疫抑制剂联合使用，以降低其潜在毒性呢？
　Dr. Lipson：我们经常这样处理。在过去五六年间的几项临床试验中，凡是对伊匹单抗有效的患者，通常都需要将糖皮质激素作为免疫抑制剂来联合使用，以减轻治疗带来的不良反应。糖皮质激素的使用似乎并不影响伊匹单抗在患者中发挥其抗肿瘤作用。因此，我们可以大胆使用检验点抑制剂；如果需要，我们可以使用免疫抑制剂来减轻不良反应；至少在伊匹单抗的使用中，其抗肿瘤作用并未被削弱。
我必须提及数年前的一项Ⅱ期临床试验。为了预防结肠炎，研究人员尝试给患者预防性使用类固醇激素，然而结果显示，即便预防性使用布地奈德治疗，仍然不能降低2级及更严重腹泻的发生。因此提前使用免疫抑制剂并无作用，但是当不良反应明确出现时，我们则可以使用类固醇治疗。

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