CAR-T细胞疗法作为医学界的璀璨新星，虽疗效显著却如潘多拉之盒般充满未知。从治疗成功到长期监护，每一步都需精心策划。近期，在第十二届陆道培血液病学术论坛上，《肿瘤瞭望-血液时讯》有幸特邀美国梅奥诊所血液移植中心Shahrukh Hashmi教授，深入分享了CAR-T疗法后长期监护策略的优化方向与实践经验。
《肿瘤瞭望-血液时讯》您在讲座中提到的“潘多拉盒子”比喻，似乎暗示了CAR-T细胞治疗可能带来的未知和潜在风险。请问您如何理解这一比喻，并在您的临床实践中如何应对这些挑战？
Shahrukh Hashmi教授：潘多拉之盒，一旦开启，其内容便难以预料。这一比喻恰如其分地适用于那些极具疗效但同时又属全新且复杂的疗法，如CAR-T细胞疗法，以及几十年前的骨髓移植术。以分娩为例，在人类世界中，女性需历经长达九个月的艰辛妊娠过程，然而，当婴儿呱呱坠地之时，一个新的、长期的篇章才刚刚拉开序幕。接下来该怎么办？谁将承担起从婴儿出生到青春期的全程监护责任？这不仅是医学界新疗法、复杂疗法面临的根本问题，也是所有治疗过程结束后需要深思的议题。我们固然能够治愈白血病、淋巴瘤等患者，但随之而来的问题是，谁将负责长期监测这些患者，以应对已知的及未知的并发症？这正是潘多拉之盒这一比喻的深刻寓意所在。
Oncology Frontier-Hematology Frontier：The metaphor of "Pandora's box" you mentioned seems to imply the unknown and potential risks thatCAR-Tcell therapy may bring. How do you understand this metaphor and how do you address these challenges in your practice?
Dr. Shahrukh Hashmi：Pandora's box. When you open it, you have no idea what's coming up. That is true for anything which is very, significantly curative, but also a brand new therapy and a complex therapy like CAR-T cells. And a few decades ago, a bone marrow transplant. I'll give you an example of a childbirth. The pregnancy of 9 months in humans is a laborious task for a female and kudos to all the women in the world carrying the baby for 9 months. When the baby is born, the question is, that's when another story starts a long term story. What next?Now who's gonna follow the baby from childbirth till the teenage? That's gonna be the fundamental question for any new therapy and a complex therapy that comes in medical world as well. Not that we cured a patient with leukemia lymphoma, but then what who is going to monitor those patients for the knowns and unknown complications in long term. So that's where the analogy of Pandora's box comes in.
《肿瘤瞭望-血液时讯》：CAR-T细胞治疗在血液肿瘤中取得了显著的疗效，但长期并发症仍是关注焦点。请问您如何看待CAR-T治疗后患者长期生存率的改善及其相关并发症的管理？
Shahrukh Hashmi教授：在CAR-T细胞治疗后，评估并预防患者并发症的基本原则在于采取有组织、系统化的方式。为此，我们设立了“幸存者诊所”，专门服务于接受CAR-T细胞治疗的幸存者，以便我们能够细致入微地监测CAR-T细胞已知及未知的影响。这包括但不限于对新发癌症的监测筛查，以及对心脏、脑部等可能出现的并发症的严密观察，同时也不能忽视癌症本身复发的可能性。
当前对于长期随访诊所或特殊诊所的需求比以往任何时候都更为迫切。全球范围内，尤其是像中国这样拥有众多城市的国家，患者纷纷涌向少数能够开展CAR-T细胞治疗的中心，以寻求治疗白血病、淋巴瘤或骨髓瘤等疾病。患者在接受治疗后，首年的随访工作通常较为完善，但关键在于我们需要建立机制，确保能够年复一年地持续监测他们的综合状况。
这一原则同样适用于接受CAR-T细胞治疗的儿童患者。当这些孩子长大成人，面临生育问题时，谁来评估他们未来生育健康孩子的风险？谁将从他们15岁起，直至50岁甚至更久，持续进行健康评估？我构想的解决方案是，在开展CAR-T细胞治疗的医院中，建立高度组织化的CAR-T幸存者管理项目，以确保患者能够得到全面、长期的关怀与监测。
Oncology Frontier-Hematology Frontier：CAR-T cell therapy has shown remarkable efficacy in hematologic malignancies, yet long-term complications remain a focal point. How do you perceive the improvement in long-term survival rates postCAR-Ttherapy and the management of related complications?
Dr. Shahrukh Hashmi：The the fundamental principle of assessing the complications and preventing them in a patient after a CAR-T cell is to have an organized, systematic fashion, a clinic called survivorship clinic for these survivors who got a CAR-T cell so that we can monitor the known and the unknown effects of the CAR-T cells very carefully, whether it be new cancers to have an eye on those to screen them, or the heart complications or the brain complications or anything else, or the cancer itself may be coming back.
We have to monitor that and those kind of clinics called long term follow up clinic, or survivorship clinics are needed much more today than ever. Because people from all over the world are travelling to few centres, which can do CAR-T cell, for example, from hundreds of thousands of cities in China. They go to a few selected centers to get CAR-T cells for their leukemia, lymphomas or myeloma. When they go back, the first year follow up is great, but we need to have mechanisms to follow them up year after year, after year, after year.
And this is true even for the young kids who get the CAR-T cells, because what's gonna happen when they're going to have babies who's going to actually assess the risk of them having normal kids in the future, who's gonna assess these patients from the age of 15 all the way up to the 50. It's our responsibility. The way I envision this is having a very organized CAR-T survivorship program in the hospitals which perform CAR-T cells.
《肿瘤瞭望-血液时讯》有哪些新策略或方法可以预测和降低CAR-T治疗后的长期并发症风险？
Shahrukh Hashmi教授：幸运的是，目前开展CAR-T细胞治疗的各大洲都在积极建立注册登记系统。从骨髓移植领域的经验中，我们了解到这些注册登记系统能够为我们提供关于CAR-T细胞治疗后并发症及远期效应的线索。我们期望国际上的各个注册登记系统能够实现相互整合，例如某组患者接受CAR-T细胞治疗后的十年随访数据，我们便能拥有更加丰富的数据资源。
随后，我们将能够利用人工智能方法和机器学习技术，基于患者既往接受的化疗、CAR-T细胞治疗等暴露因素，更好地预测其个体化风险。这将有助于基于精准医学模型预测患者可能面临的心血管、脑部并发症或新发癌症等风险，而这一切的实现都离不开我们目前正在积累的庞大数据库。
Oncology Frontier-Hematology Frontier：what new strategies or methods have been proposed to predict and reduce the risk of long-term complications followingCAR-Ttherapy?
Dr. Shahrukh Hashmi：Fortunately, most of the continents where we're doing CAR-T cells, we're forming workhouse registries. We've learned from bone marrow transplant fields that these registries will give us a clue about the complications and late effects that happen after the CAR-T cells.
Now, once you've got mega data from them, for example, 10 year data of the CAR-T cell of a group of patients, we would hope that the international registries will merge with each other so that we have more data.
And then we be able to better predict by artificial Intelligence methodologies, machine learning, methodologies, that what are the individualized risks of patients based on the exposures, which is the chemotherapy, the CAR-T cells that they had in the past? To predict what kind of complication they may have for this cardiovascular, which is a heart or brain complications or new cancer development. It will come from those precision medicine models based on machine learning, deep learning methodologies, which is AI once we have the mega data simulated, which we're accumulating now.
会议回放
请扫描下方二维码以观看会议回放，其中Shahrukh Hashmi教授的讲座及讨论环节位于166:30至202：40。