Oncology Frontier: In recent years， we have seen the gradual rise of immuno-biological cancer therapy. Can you summarize the current status of immune therapy in the treatment of colorectal cancer and its clinical applications?

　　《肿瘤瞭望》：近年来，我们可以看到肿瘤免疫治疗的逐步发展。您能总结一下目前肿瘤免疫治疗在结直肠癌领域的发展和它的临床运用吗？

　　Dr Arnold: We are in the beginning of the decade of immunotherapy and in colorectal cancer I have the feeling that this decade hasn’t really started. There is only some very premature data on checkpoint inhibitors been used in clinics on very few patients. We have more data on immune stimulants like TLR9 (toll-like receptor 9) agonists that activate the immune system by different mechanisms. This has recently shown such interesting data that we are about to start a phase III trial which will use this approach in a randomized trial for maintenance treatment in patients who underwent chemotherapy in the beginning， are under control and then will receive this new compound which will be randomized against standard of care.

　　Arnold教授：我们正处在免疫治疗时代的开端，我感觉在结直肠癌领域，这个时代还没有真正的开始。目前仅有一些用于少数患者的免疫检查点阻断剂（checkpoint inhibitors）的初步研究数据。对于以其他方式激活免疫系统的免疫刺激剂（immune stimulants），如TLR-9 （toll-like receptor 9）激动剂，我们拥有更多的研究数据。目前已获得一些有趣的数据，我们准备开展一项Ⅲ期临床试验，对初治使用化疗并取得疾病控制，进而换用该类药物维持或以标准方案维持的患者进行随机比较研究。

　　Oncology Frontier: Do all toxicities related to immunotherapy require permanent discontinuation of treatment?

　　《肿瘤瞭望》：是不是当毒性反应出现时，就应该永久地停止相应的免疫治疗？

　　Dr Arnold: Actually those compounds are quite well tolerated. This is true for the very few instances of checkpoint inhibitors as well as the TLR9 agonists. We do have data from about ninety patients from a randomized phase II trial and the only toxicity was a local toxicity at the injection site and only a few had immune system stimulating adverse events (fever， sweats) but nothing of a serious nature. So that is a benefit and adds weight to these therapies.

　　Arnold教授：事实上这些药物的耐受性都较好。只有极少数的例子在使用免疫检查点阻断剂或TLR-9激动剂时，出现严重的免疫治疗毒性反应，需要停药。我们一项有90例患者的随机临床II期试验数据显示，唯一的毒性反应出现在注射部位周边，并且只有少数人出现免疫系统刺激的不良事件（发热，大汗），但本质都不严重。因此，这些药物更具优势和价值。

　　Oncology Frontier: What should we do in patients who do experience signs of toxicity?

　　《肿瘤瞭望》：当患者出现毒性反应时，我们应当如何处理？

　　Dr Arnold: The local injection reaction is difficult to avoid as the drug has to be administered some way. It would be assumed that if the patient had been treated previously with chemotherapy， toxicities would have been substantially greater. I think these events have to be accepted. Sweats from immune system stimulation can be treated with paracetamol or something similar but this was not necessary in the majority of patients.

　　Arnold教授：注射局部出现的反应是无法避免的，因为药物总需要通过某种途径进入患者体内。可以确定的是，先前使用过化疗的患者，毒性反应发生的机会相对较高。我认为这些不良事件是可以接受的。因免疫刺激出现大汗的患者，可以用扑热息痛或类似药物治疗，但对大多数患者而言不是必须的。

　　Oncology Frontier: What changes can immune therapy targeting immune checkpoints bring to cancer patients?

　　《肿瘤瞭望》：运用免疫检查点阻断剂的免疫治疗可以给癌症患者带来哪些改变？

　　Dr Arnold: What we would like to see in colorectal cancer is the same as the signals we get from lung cancer and the classical indications for melanoma is that we would like to see long responses to the treatment. Generally， responses to chemotherapy or chemotherapy plus antibody are relatively short (several months). We would like to see prolonged control of the disease even in incurable patients by administering those drugs. Stimulating the immune system really brings the disease under control and the patient is then not in need of chemotherapy for a long time. How these treatments will react with chemotherapy in terms of resistance developing is a matter for further research. For example， one principle that is quite often used in metastatic colorectal cancer is anti-angiogenesis. It is not exactly chemotherapy but a more targeted approach and this works nicely in colorectal cancer. There is preclinical data that shows that checkpoint inhibition as well as TLR9 stimulation may be synergistic with anti-angiogenic drugs so we look forward to early developmental trials to see whether these do provide additional benefits for the patient.

　　Arnold教授：我们希望在结直肠癌中看到在肺癌以及经典的黑色素瘤中获得的相同的效果，即治疗的长期有效性。一般来说，化疗或化疗联合抗体的治疗方案的有效性都相对较短（几个月）。我们希望即使无法治愈患者，也能长期控制疾病。激活免疫系统后，疾病能得到长期的控制，患者也在可以在较长的一段时间里不再需要化疗。至于这些药物如何和化疗相互作用，进而产生耐药，这是未来的研究方向之一。例如，在转移性结直肠癌里较常用的一种药物是血管生成抑制剂。它并不是实际意义上的化疗，而是更偏向于靶向治疗，在结直肠癌里有很好的效果。初步临床前研究数据显示，免疫检查点阻断剂与TLR-9激动剂能协调增强抗血管生成抑制剂的疗效。因此我们期待能有相关的早期临床试验加以证实，以为患者提供更好的治疗选择。