2024年11月14日至17日，国际细胞与免疫治疗（CTI）大会在中国杭州盛大举行，汇聚了全球细胞治疗和免疫治疗领域的顶尖专家、学者和行业领袖。此次大会不仅是一个学术交流的国际平台，更是一个展示最新科研成果、推动领域发展的重要窗口。此次会议，以色列特拉维夫大学舍巴医疗中心Arnon Nagler教授带来了题为《Academic CAR-T Cell Therapy in NHL or ALL：The Sheba Experience》的演讲，《肿瘤瞭望-血液时讯》特邀Arnon Nagler教授，为我们分享了CAR-T细胞疗法治疗非霍奇金淋巴瘤（NHL）和急性淋巴细胞白血病（ALL）的研究成果、所面临的挑战、以及舍巴医疗中心的治疗经验对临床实践产生的深远影响。

Q1

您在研究中发现CAR-T细胞疗法治疗NHL和ALL有哪些显著成果？这些成果对临床实践有何影响？

自2016年起，我们的学术性CAR-T细胞疗法率先在儿童ALL领域展开，并在2017年扩展至成人NHL。至今，我们已经为350例患者提供了治疗。虽然这个数字对于中国来说可能不算多，但对于以色列这样的小国家而言，已经是相当重要的成果了。

我们的研究结果显示，CAR-T细胞疗法极大地改变了恶性淋巴肿瘤的治疗格局，尤其是在NHL的治疗上，其次是ALL，最后是多发性骨髓瘤（MM）。CAR-T细胞疗法不仅提高了CAR-T细胞的可及性和经济性，还增加了治疗CD19阳性恶性肿瘤的灵活性。在疗效方面，我们实现了约70%的客观缓解率（ORR）。长期随访结果显示，我们实现了约50%的总生存期（OS）和无病生存期（DFS），这一成果是通过我们自主制备的CAR-T细胞达成的。特别是在ALL患者中，约三分之二的患者在桥接异体移植后复发，但我们的CAR-T疗法使完全缓解（CR）率达到了约70%，其中微小残留病（MRD）阴性率达到了70%。这意味着对于那些原本治疗选择有限的患者来说，CAR-T疗法不仅给予了他们新的希望，还带来了显著的治疗效果。对于那些复发或对CAR-T细胞疗法没有应答的患者，尤其是在ALL领域，我们也为他们提供了其他治疗方案。

Oncology Frontier-Hematology Frontier：What are the significant outcomes of CAR-T cell therapy in treating NHL and ALL in your research? And what are the implications of these outcomes for clinical practice?

Professor Arnon Nagler：First of all, I would like to say how happy I am to be in Hangzhou and to express my gratitude for the hospitality, friendship, and collaboration. I am from Sheba Medical Center in Ramat Gan, Israel. Our academic CAR-T program started in 2016 in pediatric ALL and then moved to adult non-Hodgkin lymphoma in 2017. We have treated 350 patients, which I guess is not a huge number for China, but for a small country like Israel, it is significant. I would say that CAR-T has revolutionized treatment in lymphatic malignancies, mainly non-Hodgkin lymphoma.

And to a lesser extent, ALL, and to an even lesser extent in multiple myeloma. Our academic program increases the accessibility and affordability of CAR-T cells and also gives us flexibility to treat CD19-positive malignancies that are not yet approved.

We have achieved an overall response rate of about 70%, and for long-term, about 50% overall survival and disease-free survival with our in-house CAR-T cells.

And in ALL, where 2/3 of our patients have relapsed after allogeneic transplantation, the CR rate is about 70% and out of this, MRD negativity is 70%. So I would say that for patients who had no hope, CAR-T really gives them hope and really good results. For patients who relapse or do not respond to CAR-T cells, especially in ALL, we have other means to treat these patients.

Q2

在您的经验中，CAR-T细胞治疗在NHL或ALL中面临的最大挑战是什么，您是如何应对这些挑战的？

对于CAR-T细胞治疗领域而言，当前的主要挑战是如何预测可能不会对CAR-T细胞疗法产生应答，或者在治疗后可能会复发的患者。为了应对这一挑战，我们需要提前识别这些患者，并为他们制定相应的治疗计划，或者尽早采取干预措施。

为此，我们正在使用一组替代标记物来构建患者档案。此次会议，我也展示了这些标记物如何帮助我们区分炎症性和非炎症性的细胞因子集群。我们的研究表明，具有炎症性细胞因子集的患者往往对CAR-T细胞疗法的应答较差。因此，我们可以提前制定相应的治疗方案，比如使用特定的抗体、T细胞衔接器（TCE），或者考虑桥接异体移植和其他免疫疗法，以应对那些可能对CAR-T疗法应答不佳的患者。

Oncology Frontier-Hematology Frontier：In your experience, what are the biggest challenges faced by CAR-T cell therapy in NHL or ALL, and how do you address these challenges?

Professor Arnon Nagler：The biggest challenge for me is the affordability and accessibility of CAR-T cells. This is why we have the academic in-house non-commercial program. But for the whole field, the challenge now is predicting the patients who will either not respond to CAR-T cells or will relapse after CAR-T cells, how we can predict them ahead of time and then plan what to do with them or how we can catch them early.

So we are now working with a profile of surrogate markers that I will show tomorrow in my talk, which can try to separate the clusters of inflammatory cytokines, the non-inflammatory. And we have shown that patients with an inflammatory set of cytokines tend to respond less to CAR-T cells, so we can come and prepare what to do, either to go with a specific antibody, T cell engagers, or allogeneic transplantation or other immunotherapies for those that will predict failure with CAR-T.

Q3

Arnon Nagler教授：CAR-T细胞的毒性相对有限，主要毒性是细胞因子释放综合征（CRS）。作为欧洲联盟的一部分，我们已经发布了关于如何处理以及如何预测CRS患者的建议。在350例接受CAR-T细胞疗法的患者中，没有任何患者因CRS死亡，这得益于我们对CRS的严格监控和管理。我们的CAR-T细胞疗法中CRS的发生率相对较低，且对3到4级CRS的数量有所限制，使得CAR-T细胞的毒性可控，低于自体移植的毒性。因此，CAR-T细胞疗法目前被用于淋巴瘤的二线治疗，患者对CAR-T治疗的应答良好，出乎我们的意料。

Oncology Frontier-Hematology Frontier：In response to the potential side effects or challenges of CAR-T cell therapy, what measures has Sheba Hospital taken to ensure patient safety and comfort?

Professor Arnon Nagler：The toxicity of CAR-T cells is rather limited. The main toxicity, which was not so discussed before, is cytokine release syndrome (CRS). We are a part of a European consortium that has published some recommendations on how to approach patients with CRS toxicity and how to predict them. As for the cytokine release syndrome (CRS), the percentage of CRS is rather low, and out of 350 or so patients, we didn't lose any patient to CRS. But again, we have a limit in the number of grade 3 to 4 CRS. So I would say that the toxicity of CAR-T cells is manageable. It's lower than the autologous transplantation. And this is why CAR-T cells are now being given to patients in the second line of therapy in lymphoma and in the last patients that we never expected would respond, and they are responding very nicely to CAR-T therapy.

Q4

总之，虽然CAR-T疗法在其他恶性肿瘤的治疗中面临诸多挑战，但我们对这一疗法的未来应用前景持乐观态度，并正在积极研究以克服这些挑战。

Oncology Frontier-Hematology Frontier：Do you think CAR-T therapy can be used for other cancers?

Professor Arnon Nagler：One of the big challenges now is moving CAR-T cells to other non-lymphatic and myeloid malignancies, and the other solid tumors.

So, I will show again tomorrow that we found out that in patients with AML with a 21 translocation, there is expression of CD19, and we just published on six patients. It's a real disease in which they use the CD19 for treating AML. All patients responded, but the response is short-lived. So it gives you a window of opportunity to come with allogeneic transplantation. And we also started the program in autoimmune diseases. We treated four patients, it just sent to publication, so I think there are many patients with autoimmune diseases more than hematological malignancies. We are very excited about our new program of CAR-T in autoimmune diseases. You can also give BCMA or combine the two for autoimmune malignancy for autoimmune diseases.