Black教授在采访中指出，对于BCG灌注治疗失败的患者，目前还有许多争议，但同时也有很多处理的方法。人们讨论最多的恐怕是免疫检查点抑制剂，它可以通过静脉注射作为一种全身治疗。除此之外，还有其他临床试验，包括病毒疗法，如一项试验测试一种能表达干扰素的病毒，另一种则是溶瘤细胞病毒。此外，还有肿瘤疫苗的试验。总的来说，目前对于BCG灌注无效的膀胱癌在免疫治疗方面有多种治疗方法。

 

Prof. Black: There is a lot going on in the field right now with patients who fail BCG and there are different approaches. The ones most talked about are the immune checkpoint inhibitors， which are given intravenously as a systemic therapy. But there are other trials with viral therapy. There is one trial testing a virus that expresses interferon， and another with oncolytic viruses. There is a vaccine trial also. So there are a lot of immunotherapy approaches for non-responsive bladder cancer.

 

 

免疫检查点抑制剂的原理是肿瘤自身产生许多肿瘤抗原，而免疫系统会识别为外源性物质，从而对其发生免疫反应。但当T淋巴细胞介入准备杀伤肿瘤细胞的时候，肿瘤细胞通过PD-1/PD-L1途径抑制自身的肿瘤抗原来躲避T细胞杀伤。据Black教授介绍，免疫检查点抑制剂的作用就是解除这种抑制作用，让免疫细胞重新激活工作，消灭癌细胞。当然，它仅在检查点激活时起作用，这就是为什么只有20%～25%的患者对此类药物有效的原因。

 

Prof. Black: The idea behind the checkpoint inhibitors is that the tumor is making tumor antigens that the immune system recognizes as foreign and actually develops a response to them. But when the T-cells come in to actually kill the tumor cells， they are turned off by the checkpoint PD-1/PD-L1 access. By introducing an inhibitor， we can release that inhibition and the immune system is free to destroy the tumor. Of course， it only works if the checkpoint activation occurs in the first place， which is why only 20-25% of patients show a response.

 

 

Black教授认为，在研究初期，必须把免疫检查点抑制剂用作单药治疗，以确认其安全性和有效性，但最终还是需要了解联合用药的效果是否理想。目前的试验仅仅是对于BCG灌注治疗失败的患者给予单药治疗。在美国，FDA指示这些药物在用于早期肿瘤患者之前必须在BCG灌注治疗失败的患者中进行临床试验。John Hopkins医院的Noah Hahn教授正在筹划一项临床研究，在同时行放疗的患者中，对比BCG灌注和BCG+PD-1/PD-L1抑制剂和BCG+其他一种免疫检查点抑制剂三组的疗效。

 

Prof. Black: We have to test them as monotherapy first to make sure they are safe and show evidence of activity. But ultimately， we want to see how they work in combination. The trials right now are primarily single agent in BCG-unresponsive patients. In the US， the FDA is saying that we have to test the drugs in those patients first before looking at earlier stage disease. There will be trials in combinations. Noah Hahn at John Hopkins has a trial in development where there will be multiple arms with BCG alone versus BCG plus PD-1/PD-L1 versus BCG plus any other checkpoint inhibitor， and radiation will fit in there as well.