美国宾夕法尼亚大学费城儿童医院Stephan A. Grupp教授

　　CSCO之行·大会印象

　　本届CSCO大会首次邀请到美国宾夕法尼亚大学费城儿童医院Stephan A. Grupp教授进行专题报告，这也是Grupp教授的首次中国之行。他对此次会议表示出很高的评价，认为会议举办得非常成功。Grupp教授在22日的国际淋巴瘤论坛的主题会上进行了关于CAR-T细胞治疗的精彩演讲。他指出，论坛上介绍了很多具有划时代意义的研究进展，也涌现出了一些优秀的临床研究结果。总之，这次会议给他留下了深刻的印象。

　　Grupp教授的主要研究领域为CAR-T细胞治疗。目前，CAR-T细胞治疗已被证实对于B细胞恶性肿瘤具有较好疗效，并且其最好的临床数据并非来源于淋巴瘤的治疗，而是急性淋巴细胞白血病（ALL）的治疗。

　　CAR-T细胞治疗在ALL中的应用

　　Grupp教授首先介绍了CAR-T治疗在ALL中的应用。由于CAR-T细胞治疗在ALL中疗效显著，目前美国正在进行一些大型临床试验以验证CAR-T细胞治疗的疗效。作为美国3个主要CAR-T研究团队其中之一，Grupp教授所在团队“Kite and Juno”拥有治疗ALL的CAR-T细胞产品专利，他们已与诺华制药公司合作开发相关产品（CTL019），借助CAR-T细胞治疗，可使80%~90%的难治复发性ALL患者获得完全缓解。

　　Grupp教授表示：“这项结果使我们非常兴奋。目前，我们面临的主要问题之一是短期的毒性反应，即细胞因子释放风暴（CRS）。CRS通常在肿瘤负荷比较高，即体内白血病细胞数目较多的患者可能表现非常显著，而且极有可能威胁生命。所幸的是，我们发现可通过使用托珠单抗（tocilizumab）控制炎症因子白介素-6（IL-6）的释放，从而抑制CRS。该药物能够重建机体对严重毒性反应的控制能力。”

　　根据Grupp教授介绍，他们通过长期的治疗随访结果，显示出CTL019的应用前景非常令人瞩目。除外需要移植的患者，使用CTL-019治疗后患者，其1年无复发生存率可达到55%。因此，我们可以期待CAR-T细胞治疗方法在不久的将来应用到临床上一些复发难治的ALL患者中。

　　CAR-T细胞治疗在弥漫大B细胞淋巴瘤（DLBCL）中的应用

　　虽然CAR-T细胞治疗应用于淋巴瘤的进展滞后于ALL研究1~2年，但是我们也看到了研究的飞速进步。根据目前所取得的初步临床数据，Grupp教授认为CAR-T细胞治疗极有可能应用于DLBCL的治疗中，但是他认为疗效有限，可能仅有ALL的一半。他解释说：“如果CAR-T细胞治疗在ALL患者中的总反应率可以达到80%~90%，那么在DLBCL患者中的总反应率可能只有40%~50%。所以我们能够看到未来应用CAR-T治疗弥漫大B有可能获得显著疗效，但是却不能达到ALL的治疗效果。”

　　除此之外，另一项具有提示性意义的结果来自于针对早期进展的DLBCL患者，研究发现部分患者在CAR-T治疗3个月时可获得部分缓解，而6个月时候则达到了完全缓解。这种现象我们在ALL的患者中没有观察到。因此，Gruppo教授认为这是一项非常有趣的发现。

　　前景及展望

　　从现有数据我们可以看到，CAR-T细胞治疗中常见的严重毒副反应在DLBCL患者中比较少见。这将令我们将来应用CAR-T细胞治疗于淋巴瘤患者倍添信心。在今年12月份召开的美国血液学协会（ASH）年会上，我们也许将看到更多的来自这些团队的研究成果，并且我们期待看到更加长期的随访结果。除此之外，研究人员也正在努力探索CAR-T细胞治疗在慢性淋巴细胞白血病以及多发性骨髓瘤中的应用，我们期待在不久的将来CAR-T细胞治疗的应用更加广阔。

　　Interviewer:This is Oncology Frontier and today we have the honor of doing a short interview with Professor Grupp. Can you share with us what impressions CSCO has given you? Thank you.

　　Dr. Grupp: Yes， so my name is Stephan Grupp. I’m a pediatric oncologist at the University of Pennsylvania and Children’s Hospital of Philadelphia. And my area of expertise is CAR T-cells and immunotherapy. This is my first trip to CSCO， and by the way， my first trip to China. I have enjoyed the meeting greatly. We were， of course， all very concerned about the storm that had hit Xiamen before I arrived， but the city is beautiful and in great shape， and the meeting has been fantastic. I have attended a number of the lymphoma sessions and those have had some really cutting edge research and some excellent clinical results as well.  So， I’ve been fascinated by the meeting.

　　Interviewer: Could CAR T cells play an important role for the treatment of diffuse large B cell lymphoma?

　　Dr. Grupp: Right. So， CAR T-cells， right now， have proved to be efficacious in patients with B-cell malignancies. And， I would say the best data right now are actually not in lymphoma—but I’ll get to lymphoma—but in ALL (acute lymphoblastic leukemia). So， that’s where a lot of the large clinical trials in the United States are focused. And the reason for that is because the efficacy in ALL is quite high. So there are three groups in the United States: the group that works with the drug company Novartis—which is the group that I work with—Kite and Juno， all of whom have CART T-cell products in the ALL space. And we’re all seeing complete response rates in patients with highly refractory disease in the 80-90 percent range. So， we’re very excited by these results in ALL. Now， in ALL， one of the problems that we have is toxicity， short term， from a toxicity called cytokine release syndrome (CRS). Cytokine release syndrome can be very significant in patients who have high disease burden， have a great deal of leukemia in their body， and can be life-threatening in those patients. But we have learned how to control the toxicity by blocking a particular inflammatory protein called IL-6 (interleukin 6). And the drug that does that is called tocilizumab and that has really revolutionized our ability to control this very significant toxicity. Again， in ALL， the longer term results have also been very promising with the product that we have developed， called CTL019， which is the Novartis product. And we see relapse-free survival rates at one year of 55 percent without those patients requiring transplant. So， we’re very hopeful about the possibility of this being definitive therapy for some patients with relapse refractory disease.

　　Now， what about diffuse large B-cell lymphoma? So， those studies are accruing rapidly but are a year or two behind the ALL studies. What I would say about the data so far—which are highly preliminary—is that， probably， the CAR T-cells have significant efficacy in diffuse large B-cell lymphoma， but probably at about half the rate that we see in ALL. So， if the ALL response rates are in the 80-90 percent range， the diffuse large B-cell response rates are closer to 40-50 percent. So， we’re definitely seeing very significant efficacy， but not at the ALL levels. The other interesting hints that we take from the early data are that some of these patients have evolving responses， which is to say， they’re in partial responses at 3 months， and then in complete responses in 6 months. In ALL， that never happens， but we see it in diffuse large B-cell. So， we’re finding that to be very interesting.

　　And then the other aspect is that—again， with very preliminary data—we think that the risk of that severe toxicity called cytokine release syndrome (or CRS) is less in the lymphoma patients. So， we are very hopeful for diffuse large B-cell lymphoma. I think at the hematology meetings in December we’ll see more data from these groups and we’ll have a better idea of slightly longer term outcome. So I would say ALL is very promising while diffuse large B-cell is also quite promising， but not at the same response levels. And then beyond that， people are also studying CLL (chronic lymphocytic leukemia) and multiple myeloma with more data to be seen in the next year or so.