韩国成均馆大学医学院  Won Seog Kim教授

　　《肿瘤瞭望》：由于基因表达谱分析的迅速发展，越来越多的信号通路和基因异常被发现与血管免疫母T细胞淋巴瘤（AITL）相关。您认为哪一类分子靶向药物最具发展前景？ 

　　Kim教授：目前对TET2和IDH2的研究比较深入，其突变率大概在50%~60%左右。在AITL方面，其他调控表观遗传的药物如HDAC抑制剂也显示出较好的疗效。根据我们目前对AITL的基因测序的研究发现，RHOA位点和CD28分子存在突变，因此未来CD28信号通路可能成为新的治疗靶点，同时我们也在探索能够修饰调控RHOA的药物。我们仍需对AITL进行更深入的探索以了解其分子生物和遗传学的特点，从而指导靶向治疗。

　　Prof. Kim:TET2 and IDH2 have been around for a while. The mutation rate is around 50-60%， but still the HDAC inhibitors or other epigenetic modifiers can be good drugs in these disease subtypes. Based on our sequencing data， we found new mutations in RHOA and some genetic changes in CD28， so maybe in the future， CD28 signaling can also be a good target. We are also looking for drugs that can modify RHOA signaling pathways. But we still don’t know much about the biological and genetic changes in AITL and we need to develop a deeper understanding in this disease subtype.

　　《肿瘤瞭望》：关于mTOR抑制剂依维莫司联合CHOP方案治疗新诊断外周T细胞淋巴瘤，在您新近的研究中显示AITL患者获得了100%的完全缓解。这是否意味着针对于AITL这一特定亚型，依维莫司联合CHOP有望成为一线标准治疗方案？

　　Kim教授：我们选择依维莫司联合CHOP方案的主要原因在于其与柔红霉素具有协同作用。因此可以预期二者联合能获得更高的有效率。尤其在血管免疫母T细胞淋巴瘤中，依维莫司具有调节免疫的独特优势。在AITL疾病进展过程中，微环境中的免疫作用扮演极重要的角色，因此联合依维莫司将有助于打断肿瘤微环境的病理生理循环。在我们的研究招募了3名AITL患者，结果显示患者均获得了完全缓解，这证明依维莫司联合CHOP具有一定的发展前景。但由于病例数量较少，我们仍需要进一步的临床试验进行证实，目前做任何肯定的结论都为时尚早。 

　　Prof. Kim: The reason we chose everolimus in combination with CHOP was because everolimus is synergistic with doxorubicin. By adding everolimus to CHOP， we can expect a higher response rate. Especially in AITL， everolimus can also contribute to immunomodulation. In AITL， the microenvironment and immune interactions are important parts of disease progression， and with the addition of everolimus， we can expect some synergy with the CHOP regimen allowing us to control the microenvironment. We enrolled three AITL cases， and all patients showed a complete response. So it looks promising. But the number of cases is still small and we need more evaluation from future clinical trials. We may be able to change our approach but we need more data and it is too early to come to any concrete conclusions.

　　《肿瘤瞭望》：一些研究表明AITL的预后与肿瘤微环境密切相关，来那度胺作为一种免疫调节剂和血管生成抑制剂，是否对AITL患者有益？ 

　　Kim教授：AITL瘤细胞来源于滤泡辅助性T细胞，与周围的B细胞、树突状细胞及其他免疫细胞存在活跃的相互作用，这就是微环境在这类疾病中至关重要的原因。既往的研究验证了干扰素、环孢素及其他一些免疫抑制剂和沙利度胺的治疗活性，同时，第二代微环境调节剂来那度胺较比沙利度胺有更强的效果，总反应率达30%，其缺点在于缓解持续时间短暂。目前，法国学者正在进行一项关于来那度胺联合CHOP方案的II期临床试验，该项研究的数据将为我们提供有效的循证医学证据，以明确来那度胺在AITL治疗中的地位。

　　Prof. Kim: AITL is derived from follicular helper T-cells and these are interacting with surrounding B-cells， dendritic cells and other immune cells. That is why the microenvironment is important in this disease subtype. Previously， trials with interferon， cyclosporin A and other immune modulators gave some positive results. Also， thalidomide showed efficacy at times. Lenalidomide appears to be more effective than thalidomide and gives us around a 30% response， but the duration of response is very short. Currently， the French group is conducting a phase II trial with CHOP plus lenalidomide. Once that data is published， we can review the responses and reconsider the role of lenalidomide in this subtype.

　　《肿瘤瞭望》：如何看待其与小分子靶向药物的关系，并构建合理的联合治疗方案？

　　Kim教授：根据目前的研究，AITL在表观遗传学方面存在多个位点的基因突变，例如TET2、IDH2和DNMT3。正如我们所预料的，HDAC抑制剂获得了非常好的效果，总反应率达50%，其中完全缓解率占30%。关于HDAC抑制剂联合CHOP或其他方案的研究正在进行，但均显示出较大的毒副作用，限制了其应用。一项大型的III期临床试验比较了单纯CHOP和CHOP联合罗米地辛的效果，我们非常期待其研究结果的公布。同时，中国自主研发的西达本胺也具有良好的发展前景。而另一方面，brentuximabvedotin在AITL方面的疗效也比较肯定。除此而外，在确定新的治疗靶点上，我们仍需要更深层的基础研究支持。当前，任何单药治疗方案都不成熟，也许在复发难治患者中我们可以进行一些谨慎的尝试，但在一线治疗中，尤其对那些年轻患者而言，我们仍将获得完全缓解乃至治愈作为首要目标，谈及单药或单纯靶向药物治疗为时尚早。在HDAC抑制剂或其他类似去甲基化药物的疗效进一步明确之前，联合化疗仍是首选。

　　Prof. Kim: Based on current knowledge， AITL has many genetic changes in epigenetic modifiers including TET2， IDH2 and DNMT3. As expected， the HDAC inhibitors produce a very high response rate， around 50% and including a 30% complete response rate. One drug in particular from China， chidamide， seems to be a very interesting drug. Currently， HDAC inhibitors plus CHOP or other chemotherapy regimens are under evaluation， but are proving to be too toxic. There is a large phase III trial ongoing with CHOP plus romidepsin versus CHOP alone where the data will be very helpful. Otherwise， brentuximab vedotin can be effective， but we need new knowledge to develop new targets. For the chemotherapeutic agents， a single agent regimen is not on the horizon. In recurrent/refractive cases we can try， but for front-line therapy and especially in young patients， we have to expect a complete response and cure. It is too early for the single or targeted agents. We may have to use combination chemotherapy temporarily until we can be using chemo-free regimens like the HDAC inhibitors or other epigenetic modifiers like demethylating agents.