黄河教授、Didier Blaise教授：中法视角下细胞疗法的探索与突破

健康 2024-10-03 11:10 山西

编者按

近日，中国医师协会第十一届中法血液学学术会议在天津顺利召开，吸引到数百名国内外血液学领域的权威专家和学者齐聚一堂。会议期间，《肿瘤瞭望-血液时讯》特邀浙江大学医学院附属第一医院黄河教授与法国马赛大学血液学研究所Didier Blaise教授展开中外对话，畅谈血液恶性肿瘤领域中新细胞疗法的挑战与机遇。现将精粹整理成文，以飨读者。

从中法视角阐释细胞治疗的发展轨迹

Tracing the Development Trajectory of Cellular Therapy from a Sino-French Perspective

Didier Blaise教授

法国马赛大学血液学研究所

细胞治疗既是一个古老的故事，也是一个崭新的篇章。之所以称其为“老故事”，是因为它始于近70年前的异体移植。铭记这一点至关重要，因为我们从中学到了很多。大约30年前，细胞治疗的发展基础和前景已经形成，这也就是我们现在所说的定向或靶向细胞治疗，尤其是CAR-T细胞。这两种疗法的发展均至关重要，而黄教授团队已证实，两者可成功结合应用。目前，在法国及欧洲地区，这两种细胞治疗的使用都在增加。尤其是鉴于老年患者数量的不断上升，异体移植的应用显著增长。我们之所以提出此类治疗需求，是基于细胞治疗领域亦取得了相应的进展。然而，法国的情况与中国有所不同，与美国相比也有所不及。这是因为法国在CAR-T等新型细胞治疗的研究发展方面，并未拥有相同的学术发展水平。

（上下滑动查看英文原文）

Professor Didier Blaise：Cellular therapy is begin to be an old story and a new story in the same time. Old story because it all started with allogeneic transplantation and nearly 70 years ago. It's very important to keep that in mind because we learn a lot from that 30 years ago, there was a promise and the premise of development, of what we call now cellular therapy, and directed cellular therapy and targeted cellular therapy. And namely, it's the CAR-T cells. And is both development are very important. And it has been demonstrated by professor Huang’s team that you can combine both of them very successfully. So the situation now in France and in Europe is the fact that you have an increase use of both kind of cellular therapy. Both allogeneic transplantation is dramatically increased, because we treat more and more older patients. We request this kind of treatment, because we have also a development in cellular therapy. However, we are not in the same situation than in china and at a lesser degree with the us because we have not the same kind of academic development concerning the develop as a new form of CAR-T cells.

黄河教授

浙江大学医学院附属第一医院

诚如Didier Blaise教授所言，细胞治疗和造血干细胞移植在全球范围内已经实施多年。CAR-T疗法作为新兴技术，约在15年前开始应用，主要通过基因编辑技术改变T细胞，以治疗如血液系统恶性肿瘤等疾病。截至目前，中国和美国已有约12种商业化CAR-T产品可用于临床实践。此外，中国、美国和欧洲也开展了大量临床试验，旨在开发新的治疗手段，以改善治疗效果、降低毒性，让更多患者受益。细胞治疗、干细胞移植和CAR-T疗法的发展需要与欧洲及全球同道进行广泛的合作与交流。目前，我们与欧洲血液与骨髓移植学会（EBMT）合作已超过20年，建立了紧密的学术联系，促进了双方在临床和科研领域的共同进步。正如Didier Blaise教授所给予我们的诸多宝贵建议那样，我们与欧洲同仁之间的紧密合作极为重要且令人鼓舞。

（上下滑动查看英文原文）

Professor Huang：Just as Professor Didier Blaise mentioned, cellular therapy and stem cell transplantation have been performed worldwide for many years. However, CAR-T therapy is a more recent development, approximately 15 years old, and involves the use of gene editing to modify T cells for the treatment of hematological malignancies.So far, China and the United States have about 12 commercial products that can be used in clinical practice. Additionally, China, the United States, and Europe have many clinical trials underway. We aim to develop novel products that can improve outcomes, reduce toxicity, and make these treatments available to more patients. I believe that in the fields of cellular therapy, stem cell transplantation, and CAR-T therapy, we will see increased cooperation, and we are actively exchanging knowledge with our European colleagues. I recall that we have been collaborating with the EBMT for over 20 years. Just as Didier Blaise has provided us with many valuable suggestions and comments, our close cooperation with all European colleagues is also greatly appreciated and significant.

细胞治疗新纪元：多元化靶点与高效CAR-T疗法的前沿探索

Advancing Cellular Therapy: Pioneering Diversified Targets and Enhanced CAR-T Therapies

黄河教授

浙江大学医学院附属第一医院

既往，商业CAR-T产品的开发主要聚焦于CD19和BCMA这两个特定靶点。然而，鉴于血液系统恶性肿瘤的复杂多样性，涵盖了诸如T系与髓系等广泛的细胞谱系，因此我们当前的首要任务在于探索并拓展更为多元化的治疗靶点。此外，细胞疗法在针对实体瘤及自身免疫性疾病等广泛疾病谱中的应用亦展现出巨大的潜力，寻找新的治疗靶点无疑将惠及更多超出传统血液系统恶性肿瘤范畴的患者群体。

其次，鉴于当前淋巴瘤领域商业CAR-T产品的疗效局限性，即仅有约半数患者能实现完全缓解，我们亟须开发更为高效的CAR-T疗法。这要求我们直面基因编辑、代谢调节等关键性挑战，通过技术创新与科学突破，寻求更为强有力的治疗手段，以显著提升治疗反应率与长期生存率。

最后，通用型CAR-T产品的开发成了一个极具吸引力的探索方向。鉴于当前CAR-T治疗均为个体化定制，不仅耗时冗长且成本高昂，严重限制了其临床应用范围。因此，研发一种既经济又适用于更广泛患者群体的通用型CAR-T疗法，对于推动细胞治疗领域的进步与普及具有深远意义。中国正积极携手国内外医药企业，致力于这些新型细胞治疗产品的开发与研究，共同迎接新型细胞疗法时代的到来。

（上下滑动查看英文原文）

Professor Huang：We used to say that the commercial products focused on CD19 and BCMA. Now, what we need first is more targets, just like T-lineage and myeloid, because hematological malignancies include different lineages.

Another point is that, I think, just like other diseases, solid tumors and other cancers need to be treated with cellular therapy. We need new targets and to include more and more patients beyond those with hematological malignancies, such as autoimmune diseases, which also require cellular therapy. So, I think we'd like to develop new targets for cellular therapy.

Secondly, I believe we should develop more enhanced CAR-T therapies, because, for example, in lymphoma patients, commercial CAR-T therapies achieve complete remission in about 50% of patients. I think we need to be more effective, and so we will investigate methods such as gene editing and altering metabolism, to improve their function.

Furthermore, I think we need universal CAR-T, because, until now, CAR-T is individually manufactured. This takes a long time and is costly, so we need a cheaper option that can be used for more patients. This approach represents a novel cellular therapy, and we have developed it, working in cooperation with companies, to create new cellular therapies.

Didier Blaise教授

法国马赛大学血液学研究所

我们研究团队将聚焦于相对特定的领域——侵袭性淋巴瘤，展开深入探索。尽管相较于肿瘤学整体对该类治疗方法的迫切需求，目前的患者基数显得较为有限，但针对难治性病例，我们目前已能够循序渐进地推进创新疗法，其治疗策略亦已显著超越初期模式。

这一进步离不开众多国际研究者的不懈努力，特别是浙江大学医学院附属第一医院黄河教授及其团队所取得的杰出成果。广大同仁的贡献使我们能够在疾病发展的早期阶段就介入更多患者的治疗，从而显著提升治疗效果。然而，我们仍需持续探索，以获取新的洞见并推动领域的发展。

黄河教授强调的通用性治疗策略具有举足轻重的意义，它将是针对高度侵袭性疾病实施一线治疗的必由之路。鉴于疾病进展的迅速性，延误治疗往往意味着失去治愈的可能，因此，这一策略的重要性不言而喻。同时，针对多样化的治疗靶点进行研究亦至关重要，而中国在此领域的研究工作已展现出卓越成就。此外，髓系恶性肿瘤的治疗因其复杂性和严峻性，成为未来学习与探索的重点，尽管挑战重重，但同样十分重要。

此外，中国的研究人员在多个领域内开展的研究工作均展现出了广阔的前景，特别是针对实体瘤的细胞治疗研究。对于肝癌与胰腺癌等侵袭性极强的疾病，亟需我们加大研究力度。同时，亦不应忽视自身免疫性疾病等同样重要的领域，这些疾病同样能从细胞治疗中获益匪浅。

综上所述，我对细胞治疗的未来充满了信心与期待。得益于以黄教授为首的众多中国研究团队不懈探索，为患者点亮了治疗的新希望，也为该领域的发展注入了无限活力与可能性，使其发展前景愈发引人入胜。

（上下滑动查看英文原文）

Professor Didier Blaise：We will started with very restricted area. It was aggressive lymphoma. It's a low number of patients as compared to the extent of oncology needed this kind of treatment. But now step after step, we can treat. We don't do exactly the same things are initially. First, it was really a refractory patient. And thanks to the work made by many people, notably in china and notably in Hangzhou（the first affiliated hospital, Zhejiang university school of medicine）， we are more and more treated patient earlier in the course of disease, but we still need new insights and new development.

And you mentioned very important of that. The universal donor is critical, because it will be the only way to go to first line therapy for very aggressive disease. Because when you wait too long, you cannot cure the disease. So it's very important. The different target also and you are doing a great job on the different target. For example, for myeloid malignancies is very important, is more tricky that what we have seen for or to learn for it malignancies, but it's very important. And developments that you conduct also in china are very promising in both in different areas. For the solid tumors, we desperately need to have cellular therapy for very aggressive disease as hepatic cancer or pancreatic cancer, and also something that perhaps we neglect, which is very important as the autoimmune disease. Because these diseases are really can benefit from this kind of treatment.

So I do feel that the future is really promising, because thanks to teams as the one directed by professor Huang, there is an exploration of many parameters making this future very interesting for the patient suffering from this disease.

从交流到实践：国际合作加速细胞治疗创新与应用

From Exchange to Practice: International Collaboration Accelerates Innovation and Application of Cellular Therapy

黄河教授

浙江大学医学院附属第一医院

在未来，多种治疗方法将在临床实践中迎来日益广泛的应用，其应用范围将显著拓宽，不仅深耕于血液学领域，更将跨越至血液系统恶性肿瘤以外的广泛疾病谱系。展望未来，细胞治疗不仅被寄予厚望成为自身免疫性疾病治疗的有力手段，其潜力更将延伸至实体肿瘤患者的治疗领域，开启全新的治疗篇章。

此外，细胞治疗作为一种极具前景的治疗方法，其效能的进一步释放或将通过与其他先进治疗策略的深度融合展现。期待在未来，能够将细胞治疗与单克隆抗体、小分子靶向治疗等手段有机结合，通过这种多模态治疗的协同作用，显著提升临床治疗效果，为患者带来更加显著的治疗获益。

在此过程中，国际合作的重要性不言而喻。正如在干细胞移植领域与EBMT等权威机构的紧密合作所展现的成效，我们同样期待在细胞治疗领域构建更为广泛的国际合作网络。我们热切希望能够与像Didier Blaise教授这样的国际知名专家携手并进，共同探索细胞治疗的无限可能，他们的卓越指导和宝贵建议将为我们提供前行的重要指引。

因此，有理由相信，随着技术的不断进步和国际合作的持续深化，未来将有越来越多的患者能够从细胞治疗中获得显著的治疗效益，迎来生命的转机与希望。

（上下滑动查看英文原文）

Professor Huang：I think several therapies will be increasingly used in clinical practice, not just in hematology but also beyond hematological malignancies. I believe that in the future, for autoimmune diseases and even solid tumors, patients may be treated with cellular therapy.

Furthermore, I would like to add that cellular therapy is a very good method, but we will combine it with other strategies, such as monoclonal antibodies and small molecular targets. We will combine these to improve clinical outcomes. In this process, I think international cooperation is extremely important. Just as with stem cell transplantation, we will collaborate with EPMT. I think for cellular therapy too, we hope for more international cooperation, perhaps with experts like Professor Didier Blaise. Professor Didier Blaise will give us excellent guidance and suggestions.So, in the future, I think more and more patients will benefit from this cellular therapy.

Didier Blaise教授

法国马赛大学血液学研究所

法国及欧洲在医学发展方面与中国存在一定差异，主要归因于缺乏相应的学术发展环境。这并非意味着法国缺乏具备智慧与才能的医学人才，而是指当前在资源和组织架构层面尚不足以充分支撑这一领域的深入探索。尤为值得注意的是，某些关键的治疗技术在实际应用中并未能为法国及欧洲的医学进步提供有力支持。我们目前的治疗手段主要局限于已注册产品的应用，这在一定程度上限制了我们在医学道路上的探索与发展。

正因如此，国际合作显得尤为重要。黄教授或许仍记得，在我首次尝试CAR-T细胞疗法治疗患者之前，我曾专程前往贵中心拜访，并在您的科室深入学习了十天。通过亲眼见证临床操作的全过程，我满怀希望与憧憬地返回工作岗位。尽管未能完全复制您的成功经验，但我将您所传授的治疗方案与操作精髓带给了我的患者，这一经历对我而言具有不可估量的价值。自那次交流以来，我们始终保持着紧密的合作关系，共同分享经验，探讨问题，这一点对于推动中法医学进步具有至关重要的意义。因此，我相信，无论身处世界的何处，未来我们都将是携手共进的合作伙伴。我们将充分利用各自的优势资源，共同努力，将这种先进的治疗方法惠及更多需要的患者，为他们的健康与福祉贡献我们的力量。

（上下滑动查看英文原文）

Professor Didier Blaise：I believe we are not in the same situation in France, or in Europe as a whole, as I mentioned initially. This is because we do not have this kind of academic development. I don't mean to say that we lack individuals with the intelligence to achieve it, but rather that we lack the resources and the organizational structure to enable us to do so. Additionally, certain types of therapy, which are crucial, have not been helpful to us in this particular context.

Therefore, I feel that we are constrained by the fact that we must currently rely on registered products. Doing so limits the avenues we can explore.

This is precisely why it is so crucial to engage in the international collaboration you have mentioned. You may recall that prior to treating my first patient with CAR-T cell therapy, I visited you and spent ten days in your department. Through observing the clinical procedures, I returned with a great deal of enthusiasm and inspiration. Although we were unable to replicate your exact approach, I did bring back to my patients the subtleties and methodologies you had developed. This has been invaluable. Since then, we have collaborated and exchanged ideas, which has been of great significance.

So, I truly believe that no matter where in the world we are or what the future holds, we are all part of a collaborative effort. We will harness the strengths of one place and combine them with the advantages of another. Together, we will strive to bring this type of treatment to the patients under our care.

携手跨越挑战，细胞治疗领域的未来展望

Hand in Hand Across Borders: Future Prospects in Cellular Therapy

Didier Blaise教授

法国马赛大学血液学研究所

黄教授已阐述了通用型疗法或新靶点探索的潜力，这些要素对于精准预测并引领医学新纪元的发展具有不可估量的重要性。与治疗初始阶段相比，当前医学界面临的核心挑战已不再是毒性管理，而是尚未能够精准锁定针对每位患者、每种疾病的特异性治疗策略。

我们正全力以赴，致力于降低患者的疾病复发率。通过实施更为早期的干预措施，我们有望克服患者治疗无应答的难题，为患者带来治疗希望。此外，我们的关注点已不仅局限于难治性患者的挑战，更将复发问题置于同等重要的位置，力求在这一领域取得突破性进展。

为了达成这一目标，我们亟须加强跨学科、跨团队的紧密合作，共同探索多元化的治疗路径。其中，特殊联合方案的序贯治疗以及与异体移植技术的巧妙结合，正如黄教授团队所展现的卓越实践，无疑为我们提供了宝贵的启示与借鉴。这些努力不仅展现了医学研究的无限可能，更预示着细胞治疗领域未来的光明前景。

因此，我们有理由相信，细胞治疗的未来充满了希望与机遇。我们应充分利用在多个医学领域内积累的深厚知识，通过知识的整合与创新，以及研究者的团结协作，共同推动这一领域的持续进步与发展。

（上下滑动查看英文原文）

Professor Didier Blaise：I think it has been already mentioned by professor Huang, the new possibility of universal donor or new target are very important, because with this kind of thing, you can envision, clearly new development, we have to realize that contrary to the beginning, the main problem is not the toxicity, is clearly the fact that we have not find the real key for every patient and every disease.

We are fighting to decrease the relapse rate in this patient. We will probably solve the problem of a patient not responding because we will treat the patient earlier on. And we will not more address the question in a refractory patient, we remain at the present time. With the problem of relapse. We have to work together and probably many things can be imagined even sequential treatment of the special or combination with allogeneic transplantation, as you did in your team, which is very important.

So once again, as I said previously, future is very promising because we will use the knowledge we have in the in many area and try to put together that when I said together is to put together the knowledge, but also to put together the investigators in order to progress.

黄河教授

浙江大学医学院附属第一医院

我完全赞同Didier Blaise教授的观点。我认为细胞疗法目前仍处于初级阶段，展现出的未来前景无疑是光明的。在聚焦于新靶点设计与创新细胞疗法等核心要素的同时，我们亦需深刻认识到整个医疗体系构建的重要性，这涵盖了增强患者对于新兴治疗手段的认知与接受度，以及医院与政府、制药企业间紧密合作，共同致力于新型细胞疗法的研发、审批及临床应用的推广。我认为，社会各界对于此类新型疗法的深刻理解与广泛认同，是确保其能够真正惠及患者、实现治疗价值最大化的关键所在。唯有通过社会各界的携手努力与不懈探索，方能推动细胞疗法领域迈向更高水平，并实现医学科技的进步与长足发展。

（上下滑动查看英文原文）

Professor Huang：I totally agree with Professor Didier Blaise. I think cellular therapy is still in its initial stages, and it holds a bright future. Beyond aspects such as the design of new targets and novel cellular therapies, I believe the importance also lies in the entire system, involving patient awareness, as well as government and industrial pharmaceutical companies, who are working to develop and approve new cellular therapies for commercial use.I think it is crucial that society as a whole understands these new therapies and recognizes the benefits they can bring to patients. Together, I believe we will drive progress and development in this field.

专家简介

黄河教授

浙江大学求是特聘教授

浙江省特级专家

973首席科学家

主任医师博士生导师

现任浙江大学医学院附属第一医血液科骨髓移植中心主任

浙江大学血液学研究所所长

干细胞与细胞免疫治疗浙江省工程中心主任

任国家重点研发计划“干细胞及转化研究”重点专项专家组成员

中华骨髓库专家委员会副主任委员

中华医学会血液学分会常务委员

亚洲细胞治疗组织学术委员会副主席

亚太血液与骨髓移植学会执行委员会委员

欧洲血液与骨髓移植学会国际学术委员会委员

浙江省免疫学会理事长

主要研究方向为干细胞基础研究与造血干细胞移植临床应用、细胞免疫治疗前沿技术与转化研究

先后于2003年及2015年2次荣获国家科技进步奖二等奖

作为负责人承担973 863 国家自然科学基金重点项目

国家自然科学基金国际合作与交流项目等27项

以通讯作者在New England Journal of Medicine, Nature, Cell Research, Lancet Haematology等期刊发表SCI论文278篇

获省部级以上科技奖项15项授权发明专利21项

近5年在国际大型会议担任主席、特邀报告和口头报告百余次

主编人民卫生出版社出版的国内首部CAR-T细胞治疗学专著《CAR-T细胞免疫治疗学》

共同主编人民卫生出版社全国研究生《血液内科学》教材

参编著作及教材11部

任国际造血干细胞移植领域权威杂志Bone Marrow Transplantation Journal of Hematology and Oncology编委

专家简介

Didier Blaise 教授

法国马赛大学血液学研究所

Paoli Calmettes 学院血液和骨髓移植和细胞治疗项目主任

血液病科医疗主任

欧洲肿瘤内科学会（ESMO）与欧洲血液学会（EHA）会员

（来源：《肿瘤瞭望–血液时讯》编辑部）

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ioncology

《肿瘤瞭望》于2014年初创刊，由著名肿瘤科专家徐兵河院士担任总编辑，以“同步传真国际肿瘤进展”为办刊宗旨，以循证医学理念为指导思想，采用全媒体组合报道模式，致力于为国内广大肿瘤临床、教研人员搭建一座与国际接轨的桥梁。