美国费城儿童医院Stephan A. Grupp教授

　　《肿瘤瞭望》：对于儿童难治复发ALL有哪些新的治疗药物？

　　Grupp教授：本次会议上，我们介绍了CAR（嵌合抗原受体）-T细胞治疗，一种利用转染的T细胞的免疫治疗。所用T细胞包含基因重组嵌合抗原受体，该受体针对白血病肿瘤细胞所特异表达的CD19抗原而设计，该抗原几乎在所有B细胞肿瘤和ALL细胞上表达，这是一种非常好的靶向治疗。T细胞从患者体内收集，经由病毒转染稳定表达CD19受体后成为CAR-T细胞，再输回患者体内，这些CAR-T细胞在体内生长、扩散，并最终控制疾病。我们通过研究发现，利用CAR-T细胞治疗复发难治性ALL患者，患者最终的完全缓解率约94%。这一结果非常让人振奋。随访显示，3/4的患者在6个月时仍处在缓解状态，81%的患者到现在仍然生存，目前最长的患者生存已达到3年，而且该患者仍处于缓解状态，大多数患者不需要进一步治疗，例如造血干细胞移植。

　　What we are talking about at this conference is CAR (chimeric antigen receptor) T-cell therapy， which is engineered T-cell therapy. T-cells are genetically engineered with a chimeric antigen receptor. This receptor attacks CD19 which is found on almost all B-cell malignancies and almost all ALL. It’s a really good target. These T-cells are engineered using a virus. They are collected from each patient and given back to that patient and those cells then grow in the body and expand enormously ultimately controlling the disease. What we have seen is that 94% of patients that we have treated with refractory or relapsed ALL have gone into complete remission. We are very excited about that. Three-quarters of these patients remain in remission at six months and 81% of them are still alive. So the data now have a little bit of a long-term follow-up. The first patient we treated three years ago is still in remission and most of these patients have not required any further therapy such as bone marrow transplant.

　　《肿瘤瞭望》：您能概述一下适用于ALL的免疫治疗吗？

　　Grupp教授：ALL的免疫治疗方面的研究十分令人鼓舞。目前有相当多的抗体介导治疗，例如美国FDA获批的blinatumomab，是一种T细胞参与的双特异性抗体，虽然活性CAR-T细胞没有强，但由于不用从患者体内获取细胞，因而其治疗可及性强；其他正在开发的药物还有moxetumomab、inotuzumab，它们是针对CD22抗原的包括免疫毒性的共轭抗体，目前看来这两种药物的治疗反应也非常好。总体说来，抗体类药物比CAR-T细胞更容易耐受，但是毒性较高，尽管可以控制，我们仍希望看到更好的治疗反应。

　　The area of immunotherapy for ALL has really gotten very exciting. There are certainly antibody-mediated therapies out there. Approved in the United States is blinatumomab， which is a bispecific T-cell engaging antibody that is also very active (although not as active as CAR T-cells). It is easier to access though because you don’t need to make cells from the patient.

　　Other treatments that are being developed include moxetumomab and inotuzumab， which are conjugate antibodies with immunotoxins which then attack the antigen CD22. There have been excellent responses seen with both of those. In general， I would say the antibody products are better tolerated than CAR T-cells where the toxicities are higher， but even those are manageable and we are seeing much higher response rates.

　　《肿瘤瞭望》：ALL治疗中相应的最佳治疗时机？

　　Grupp教授：目前我们正在治疗疾病进展阶段的患者，我们发现即使肿瘤负荷较高，我们仍然可以较好的控制疾病，但是其相应的毒性增加。而使用抗体治疗，对于高肿瘤负荷的患者控制不佳。因此，如果我们希望动员患者尽早治疗，并且使用毒性相对低、效果更好的CAR-T细胞治疗。在儿童ALL中，我们主要的挑战在于确定高危患者，由于该类患者预后不良，因此需要尽早开始治疗。

　　Right now we are treating very advanced stage patients and we are learning in the CAR T-cell field that the higher the tumor burden， we can still get excellent control of the disease but there is higher toxicity. With the antibodies， the control of disease with very high disease burdens is not as good. So if we can move patients into treatment earlier， I think we will have better toxicity outcomes with the CAR T-cells and better efficacy outcomes with the various antibodies. I do believe that in pediatric ALL， the challenge is to define high-risk patients， which we can do genetically or with minimal residual disease testing. In adults， the outcomes are not as good and it will probably be easier to deploy these therapies earlier.