编者按：2017年9月14~17日，第十一届国际肝癌协会（ILCA）年会在韩国首尔隆重召开。大会正式开幕的第一天，享有国际声誉的肿瘤免疫学大师、法国巴黎-笛卡尔大学科德利埃研究中心主任兼欧洲乔治-蓬皮杜医院免疫系主任Wolf-Hervé Fridman教授受邀作了关于肿瘤免疫治疗的大会主旨报告。本刊特邀Fridman教授针对肝癌的免疫治疗基础与应用等问题进行了深度访谈。

 

《国际肝病》：随着免疫治疗的兴起，它已成为近年来肿瘤领域的主要进展。请简要介绍一下免疫治疗的机制和主要代表药物？

 

Fridman教授：免疫治疗的机制是基于患者的免疫系统能够识别其自身的肿瘤。在这种情况下，使用直接靶向检查点分子的抗体来激活免疫应答，否则免疫应当仍将被抑制。患者的免疫系统无法识别自身肿瘤的情况下，使用如抗体或抗肿瘤T细胞的免疫制剂来对治疗肿瘤是无效的。因此，在明确重要识别靶点的情况下，才能够使用针对肿瘤相关抗原的疫苗。

 

《国际肝病》：肝脏作为人体的重要器官，其中包括多种非实质细胞，其中包括人体内最大的巨噬细胞群体（也称 Kupffer 细胞），其他还有肝树突状细胞亚群，肝窦内皮细胞和肝星状细胞等，这些细胞可通过不同机制来诱导耐受。那么肝癌在免疫治疗上是否有一定的难度？

 

Fridman教授：正如你所说，因为肝脏是能够控制免疫耐受的器官，所以HCC难以进行靶向治疗。肝脏的作用是处理体内的大量信号调控机制。因此，我们需要深入了解肿瘤细胞所处的微环境特点，从而确定适宜的免疫治疗方法。考虑到肝脏免疫环境的特殊性，其使用的免疫治疗方法也应有别于其他癌症。

 

《国际肝病》：从目前的前期研究来看，肝癌的消融治疗和TACE与免疫治疗的联合治疗获得了较好的疗效，您如何分析这一结果？

 

Fridman教授：需要了解免疫系统控制肿瘤是通过肿瘤实体与免疫应答之间的平衡来实现。缩小肿瘤实体的消融治疗能够有助于优化相互作用的平衡。消融治疗也是其中一种可能有助于改变先前平衡状态（倾向于促进肿瘤发展并抑制免疫应答）的方法。其他调节这种相互作用的方法包括使用细胞因子、干扰素等。

 

《国际肝病》：您如何看肿瘤免疫治疗的不良反应？ 

 

Fridman教授：肿瘤免疫治疗可诱导特殊的毒性效应，我将之定义为医源性免疫治疗导致的自身免疫性综合征，其可能破坏肠道、肝脏的细胞，诱发甲状腺炎、皮疹等。应对措施也应该是多层面的。首先，对患者治疗后的随访应更为密切。其次，当出现症状时应当进行治疗，其中使用糖皮质激素也是较好的治疗选择。第三，尽可能减少并发症造成的影响。最后，如果甲状腺遭到破坏，需要采取甲状腺激素替代治疗。一方面，需要积极治疗癌症这种致死性疾病；另一方面，也必须处理好治疗相关毒性效应，在考虑患者的耐受的情况下，选择对患者而言最优的治疗策略。

 

《国际肝病》：您如何看未来肿瘤免疫治疗的前景？

 

Fridman教授：我认为免疫治疗的未来发展将基于对肿瘤与个体免疫系统之间相互作用的更深入认识。其并非仅局限于肝脏、直肠或皮肤，而是取决于肿瘤与器官之间复杂的相互作用关系。一旦对此得到深入的了解，更为精确的个体化靶向免疫治疗将得到应用，从而取代目前十分昂贵及副作用较大的非特异性治疗。

 

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Dr Fridman: The mechanisms of immunotherapy are based on the fact that the patient’s immune system is capable of recognizing their own tumor in some cases. When this is the case, the tools aim to unlock the immune reaction by antibodies directed towards checkpoint molecules that otherwise would keep it locked. In the case where the immune system of the patient does not recognize their own tumor, immunotherapy can be more passive in the sense that the therapies bring the immune reagents against the tumor, such as antibodies or anti-tumor T-cells. Finally, in the case where one knows what is important to be recognized, the field of vaccinations against tumor-associated antigens can be applied.

 

Dr Fridman: As you say, HCC is a difficult tumor to target because of the fact that the liver is an organ that manipulates degrees of tolerance. Its role is to take care of a lot of control mechanisms within the body. Consequently, we need to understand deeply what type of microenvironment we have around a given liver tumor cell in order to determine the appropriate immunotherapy. That may be different from the immunotherapy used in other cancers to take into account the specific immune situation of the liver.

 

Dr Fridman: You need to understand that if the immune system is to control tumors, it is a matter of equilibrium between the tumor mass and the immune reaction. Ablation therapies that diminish the tumor mass can help this balance in favor of the immune reaction. That is one of several approaches that may help to change this equilibrium that previously favored the developing cancer to be in the favor of the controlling immune reaction. Other ways to modify this interaction include cytokines, interferon and so on.

 

Dr Fridman: Tumor immunotherapy induces a particular type of toxic effects, which I define as iatrogenic immunotherapy, producing autoimmune syndromes with the potential destruction of cells in the colorectal region, the liver, as well as thyroiditis, skin rashes and so on. The response to this is multilevel. First, is to follow the patients very closely in the days following treatment. Secondly, when a symptom appears, it should be treated, and corticosteroids are a good approach to management. Third is to control the effects when they occur and keep them as minimal as possible. Finally, if there is destruction of the thyroid, for instance, then replacement therapy to replace the thyroid hormones is required. On one hand, you are treating a deadly disease that is cancer.  And on the other hand, we have to cope with toxicities, which is important but is secondary to keeping the patient alive and being treated in the best way.

 

Dr Fridman: I think the future of immunotherapy will be based on a better understanding of the interactions of a given tumor to its host immune system. It is not so much about liver versus colon versus skin, but it will depend on the intimidate and intricate relationship between both. Once this is better understood, a targeted personalized precise type of immunotherapy will be applied to the patient rather than the non-specific, very expensive and toxic treatments that are still being used today.