编者按：第54届国际实验血液学会年度科学会议（ISEH 2025）于9月24日至27日在日本熊本盛大召开。大会汇聚全球血液学领域的顶尖专家，共话基础血液学、免疫学、干细胞及细胞与基因治疗等前沿进展。会议期间，《肿瘤瞭望-血液时讯》特邀中国医学科学院血液病医院（中国医学科学院血液学研究所）王建祥教授与大阪大学Naoki Hosen教授，就CAR-T治疗白血病的最新进展展开深度对话。双方从基础机制、临床应用、疗效优化及未来发展等多维度进行交流，旨在推动CAR-T疗法的创新发展与国际合作，提升全球患者的可及性与治疗获益。
《肿瘤瞭望-血液时讯》近年来，CAR-T疗法在血液肿瘤治疗中取得了突破性进展。请两位分别谈谈在白血病CAR-T治疗领域的主要进展，以及目前仍面临的关键挑战。
Naoki Hosen教授：CAR-T细胞治疗在日本已开展约五年时间，目前已成为临床常规手段，广泛应用于白血病、淋巴瘤及骨髓瘤患者，并显著改善预后。其不良反应如细胞因子释放综合征（CRS）和免疫效应细胞相关神经毒性综合征（ICANS）的发生率已大幅降低，但复发问题依然突出。因此，我认为我们需要在更早期使用CAR-T治疗。
王建祥教授：对于急性淋巴细胞白血病（ALL），CD19 CAR-T疗法在复发/难治患者中显示出较高缓解率；然而在急性髓系白血病（AML）中，因缺乏理想靶点，疗效受限，同时可能引发长期骨髓抑制，目前全球范围内尚无获批用于AML的CAR-T药物。长期生存是CAR-T治疗的另一重要挑战，部分ALL患者在CAR-T治疗后仍需依赖异基因造血干细胞移植以降低复发风险。未来需探索提高CAR-T疗效的新策略，尽可能减少对移植的依赖，从而推动其在急性白血病中的更广泛应用。
Oncology Frontier-Hematology Frontier：In recent years, CAR-T therapy has achieved breakthrough advances in the treatment of hematologic malignancies. Could you each discuss the major achievements of CAR-T therapy in leukemia and the key challenges that remain?
Prof.Naoki Hosen：CAR-T cell therapy, implemented in Japan for about five years, has become a standard clinical approach, widely used for leukemia, lymphoma, and myeloma patients, significantly improving prognosis. Adverse events like cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) have markedly decreased, but relapse remains a significant issue. Therefore, I believe CAR-T therapy should be applied at earlier stages.
Prof. Jianxiang Wang：For acute lymphoblastic leukemia (ALL), CD19 CAR-T therapy shows high remission rates in relapsed/refractory patients. However, in acute myeloid leukemia (AML), the lack of ideal targets limits efficacy, and long-term myelosuppression is a concern, with no CAR-T therapies globally approved for AML. Long-term survival is another major challenge, as some ALL patients still rely on allogeneic hematopoietic stem cell transplantation post-CAR-T to reduce relapse risk. Future strategies should focus on enhancing CAR-T efficacy, minimizing transplant dependency, and promoting broader application in acute leukemias.
《肿瘤瞭望-血液时讯》您主导了首个中国原研CD19 CAR-T产品纳基奥仑赛的研发和上市，请您谈谈该药物在机制上有哪些独特优势或创新之处？
王建祥教授：我们的CD19 CAR-T采用独特的单链抗体，结合CD19抗原的不同表位，可避免因表位重叠导致的交叉耐药，为其他CD19 CAR-T治疗失败的患者提供新选择。我们还采用了创新的CAR-T结构设计，这使其能够很好地发挥作用。临床试验及实践数据表明，该疗法安全性和疗效均表现优异。关键性II期研究显示，3级及以上不良事件发生率低于10%，3级及以上ICANS发生率同样较低，证明该疗法不仅高效而且耐受性良好。基于这些数据，我国监管机构批准了纳基奥仑赛（Inaticabtagene autoleucel，简称Inati-cel）用于成人ALL患者。此外，我们也已在儿童患者中开展了相关临床试验，这一适应症有望在不久后获批。
Oncology Frontier-Hematology Frontier：You led the development and approval of Inaticabtagene Autoleucel, the first domestically developed CD19 CAR-T product in China. Could you share what unique advantages or innovations this therapy offers in terms of mechanism of action?
Prof. Jianxiang Wang：Our CD19 CAR-T utilizes a unique single-chain antibody targeting a distinct epitope on the CD19 antigen, avoiding cross-resistance due to epitope overlap and providing a new option for patients who have failed other CD19 CAR-T therapies. We also adopted an innovative CAR-T structure design, enabling it to function effectively. Clinical trials and real-world data demonstrate excellent safety and efficacy. Pivotal Phase II studies show that grade 3 or higher adverse events and ICANS occur in less than 10% of cases, confirming the therapy’s high efficacy and tolerability. Based on these results, China’s regulatory authority approved Inaticabtagene autoleucel (Inati-cel) for adult ALL patients. Additionally, clinical trials in pediatric patients are underway, with approval for this indication expected soon.
《肿瘤瞭望-血液时讯》您在报告中介绍了CAR-T和NK细胞治疗的探索。与传统疗法相比，这两种策略在AML治疗中展现出了哪些独特优势或潜在突破？
Naoki Hosen教授：正如王教授所言，目前尚无针对AML的CAR-T细胞疗法获批，因此相关研究本身已具备突破意义。我们的产品迄今仅在异基因造血干细胞移植后的患者中被证实有效，这也是当前的局限。这源于我们最初试图寻找在AML细胞上特异性表达的表面抗原，但尚未完全成功，因此选择了现有抗原作为AML的首个靶点。目前，我们正致力于将该CAR-T疗法的适用范围扩展至非移植患者。由于HLA-DR并不在人类真正的造血干细胞上表达，我们正在积极验证该CAR-T不会对正常造血干细胞造成损伤。如果这一点得以证实，该疗法的应用有望进一步拓展，覆盖所有AML患者。
Oncology Frontier-Hematology Frontier：In your talk, you introduced CAR-T and NK cell therapies. Compared with conventional treatments, what unique advantages or potential breakthroughs do these approaches offer in AML?
Prof.Naoki Hosen：As Professor Wang noted, no CAR-T cell therapy for AML has been approved, making such research inherently groundbreaking. Our product has so far only been validated in patients post-allogeneic transplantation, which is a current limitation. This stems from our initial attempts to identify surface antigens specifically expressed on AML cells, which have not been fully successful, leading us to select existing antigens as the first AML target. We are now working to expand the application of this CAR-T therapy to non-transplant patients. Since HLA-DR is not expressed on true human hematopoietic stem cells, we are actively verifying that this CAR-T does not harm normal hematopoietic stem cells. If confirmed, this could broaden the therapy’s application to all AML patients.
《肿瘤瞭望-血液时讯》继关键临床研究后，2025 EHA进一步公布了纳基奥仑赛的真实世界研究数据，结合这些研究结果，您如何看待CAR-T在ALL治疗中的地位和未来前景？
王建祥教授：自CD19 CAR-T疗法获批上市以来，已在中国成功治疗了超过100名患者。其在真实世界研究中的疗效优于II期临床试验结果，且安全性特征与试验数据相符，进一步验证了其在临床中的有效性和安全性。此外，该疗法在微小残留病（MRD）阳性患者中表现出色，能够有效清除MRD，使患者转为MRD阴性。这表明，针对完全缓解但仍存在MRD的患者，CD19 CAR-T细胞可作为一种有效的治疗手段。
针对是否将这款CAR-T疗法应用于前线治疗，以减少化疗周期或减少异基因移植的需求，我们已经设计并开展了针对成人ALL的一线治疗临床试验。目前，针对Ph+或Ph-患者，这款CAR-T疗法已被证明具有良好的效果，能够显著清除MRD，并有望在长期生存方面带来益处。我们仍在对患者进行长期随访，期待最终结果能够进一步验证其作为一线治疗方案的潜力，并为ALL治疗提供一种有前景的选择。
Oncology Frontier-Hematology Frontier：Following the pivotal clinical studies, the 2025 EHA Congress further presented real-world data on Inaticabtagene Autoleucel. Based on these findings, how do you evaluate the role of CAR-T therapy in the treatment of ALL and its future prospects?
Prof. Jianxiang Wang：Since its approval and market launch, our CD19 CAR-T therapy has successfully treated over 100 patients in China. Real-world studies demonstrate superior efficacy compared to Phase II clinical trial results, with safety profiles consistent with trial data, further validating its effectiveness and safety in clinical practice. Notably, the therapy excels in minimal residual disease (MRD)-positive patients, effectively eliminating MRD and achieving MRD-negative status, making it a valuable treatment for patients in complete remission with persistent MRD.
To address whether this CAR-T therapy can be used as a frontline treatment to reduce chemotherapy cycles or the need for allogeneic transplantation, we have designed and initiated clinical trials for frontline treatment of adult acute lymphoblastic leukemia (ALL). Currently, for both Ph-positive and Ph-negative patients, this CAR-T therapy has demonstrated promising efficacy, significantly clearing minimal residual disease (MRD) and showing potential for long-term survival benefits. Long-term follow-up is ongoing, and we anticipate that the final results will further validate its potential as a frontline treatment, offering a promising option for ALL therapy.
《肿瘤瞭望-血液时讯》AML的免疫逃逸机制复杂多样，您认为在CAR-T和NK细胞治疗的研发中，最需要重点解决的科学或临床难题是什么？
Naoki Hosen教授：目前，AML治疗面临的主要障碍是缺乏特异性表达于AML细胞但不表达于造血干细胞的理想靶点。尽管多年来全球研究者持续探索，但至今仍未能取得显著突破。因此，现阶段解决这一问题的主要策略是将CAR-T疗法与异基因造血干细胞移植相结合，彻底清除白血病细胞，甚至包括部分正常造血细胞，然后利用移植重建造血系统。因此，CAR-T与异基因造血干细胞移植的联合应用对AML患者至关重要。
此外，另一种潜在的策略是采用短期的CAR-NK细胞治疗。由于CAR-NK细胞在治疗后会迅速被异体免疫系统清除，因此可将其作为AML的巩固治疗手段，而不依赖异基因造血干细胞移植，这可能成为未来的一种有效治疗方案。
Oncology Frontier-Hematology Frontier：AML presents diverse immune evasion mechanisms. In your opinion, what are the most critical scientific or clinical hurdles that need to be addressed in developing CAR-T and NK cell therapies for AML?
Prof.Naoki Hosen：The primary challenge in AML treatment is the lack of an ideal target antigen specifically expressed on AML cells but not on hematopoietic stem cells. Despite extensive global research, significant breakthroughs remain elusive. Currently, the main strategy to address this is combining CAR-T therapy with allogeneic hematopoietic stem cell transplantation to eliminate leukemia cells, and sometimes normal hematopoietic cells, followed by hematopoietic system reconstitution via transplantation. Thus, the integration of CAR-T and allogeneic transplantation is critical for AML patients.
Additionally, a promising alternative is short-term CAR-NK cell therapy. As CAR-NK cells are rapidly cleared by the allogeneic immune system, they can serve as a consolidation therapy for AML, potentially bypassing the need for allogeneic transplantation. This approach may offer an effective treatment option in the future.
《肿瘤瞭望-血液时讯》展望未来，您认为细胞治疗领域还有哪些潜在突破？同时，如何进一步提升国际协作与转化效率，更高效地推动CAR-T及其他细胞疗法的全球应用？
王建祥教授：目前，CAR-T疗法面临的主要挑战包括高昂的成本及较长的制备周期，导致部分患者在CAR-T制备期间病情进展。为此，降低成本并加快制备效率成为亟需解决的问题。全球正在探索多种应对策略。例如，“快速CAR-T”技术可将制备时间缩短至一天，而质量控制约需七天，从而使患者在七至十天内即可接受回输。另一种前沿方法是体内CAR-T技术，通过脂质纳米颗粒（LNP）或逆转录病毒将CAR构建体直接递送至体内，无需体外制备，初步数据已显示可行性，但仍需长期疗效验证。
鉴于不同国家在CAR-T研发水平及经济条件方面存在差异，推动国际合作尤为重要。一方面，可通过国际多中心临床试验实现技术全球化应用；另一方面，应合理控制CAR-T价格，保障各经济水平国家患者均能获得该先进疗法。此外，持续开发新一代CAR-T技术，尤其是体内CAR-T，有望显著降低成本并提升可及性，从而使更多患者受益。然而，全球免疫疗法发展存在不平衡，需通过协作与创新持续优化。当前仍缺乏成熟解决方案，该领域仍为未来研究与国际合作的重点方向。
Naoki Hosen教授：王教授已做了全面阐述，我想从不同角度讨论。目前，CAR-T疗法面临的最大挑战是将该技术应用于实体瘤。我的实验室也在积极探索，但依然面临很大困难。AML的CAR-T治疗因缺乏特异性靶点受限，而实体瘤的CAR-T开发则面临更为复杂的问题，包括T细胞如何有效浸润肿瘤组织以及如何克服肿瘤微环境的免疫抑制等。若能突破这些瓶颈，CAR-T疗法有望惠及更广泛的癌症患者。
Oncology Frontier-Hematology Frontier：Looking ahead, what potential breakthroughs do you foresee in the field of cell therapy? At the same time, how can international collaboration and translational efficiency be further enhanced to accelerate the global application of CAR-T and other cell-based therapies?
Prof. Jianxiang Wang：Currently, CAR-T therapy faces major challenges, including high costs and lengthy preparation cycles, leading to disease progression in some patients during manufacturing. Reducing costs and accelerating production are urgent priorities. Globally, several strategies are being explored. For instance, "fast CAR-T" technology shortens production to one day, with quality control taking about seven days, enabling infusion within seven to ten days. Another cutting-edge approach is in vivo CAR-T, delivering CAR constructs directly into the body via lipid nanoparticles (LNP) or retroviruses, bypassing ex vivo preparation. Preliminary data show feasibility, but long-term efficacy requires validation.
Given disparities in CAR-T development and economic conditions across countries, international collaboration is crucial. Multicenter clinical trials can facilitate global technology application, while reasonable pricing ensures accessibility for patients in diverse economies. Additionally, advancing next-generation CAR-T, particularly in vivo approaches, could significantly lower costs and enhance availability, benefiting more patients. However, global immunotherapy development remains uneven, requiring ongoing collaboration and innovation. No mature solutions exist yet, making this a key focus for future research and international cooperation.
Prof.Naoki Hosen：Professor Wang has provided a comprehensive overview, and I would like to discuss from a different perspective. Currently, the greatest challenge for CAR-T therapy is its application to solid tumors. My laboratory is actively exploring this, but significant difficulties persist. AML CAR-T therapy is limited by the lack of specific targets, while developing CAR-T for solid tumors faces more complex issues, including how T cells can effectively infiltrate tumor tissue and overcome immunosuppression from the tumor microenvironment. Overcoming these barriers could enable CAR-T therapy to benefit a broader range of cancer patients.
专家简介
王建祥 教授
中国医学科学院血液病医院（中国医学科学院血液学研究所）临床首席专家
国家血液系统疾病临床医学研究中心主任；
教授，主任医师，博士生导师；
中国医学科学院北京协和医学院首批长聘教授；
国家百千万人才工程国家级人选；
中华医学会血液学分会第十届主任委员；
中国医师协会内科医师分会副会长、血液科医师分会副会长等职务；
天津授衔专家、海河医学学者、首届天津名医、获天津市“十佳”医务工作者、“中国好医生”月度人物；
从事血液病临床与基础工作多年，对各种血液病的诊治具有丰富的临床经验，现主要从事白血病及血液肿瘤的临床与基础研究。
Naoki Hosen 教授
大阪大学
研究领域：血液学，癌症免疫学
研究与职业经历
2003年12月—2007年3月：斯坦福大学医学院，博士后研究员
2007年5月—2009年3月：大阪大学医学研究科，副教授
2009年4月—2014年3月：大阪大学医学研究科健康科学部
2014年4月—2019年12月：大阪大学医学研究科健康科学部，副教授
2020年1月至今：大阪大学医学研究科医学部，教授
2020年11月至今：大阪大学免疫前沿研究中心，教授
获奖经历
2007年：白血病研究基金青年研究者奖
2018年：高松宫妃癌症研究基金研究资助