编者按：干细胞基础研究、再生医学、细胞治疗以及临床研究指南的应用，是当前全球血液学与转化医学领域最受瞩目的前沿方向。以此为核心议题，第十届国际干细胞论坛（IFSC）隆重召开，汇集了来自世界各地的顶尖专家学者，共同探讨科学发现与技术创新，集中展示造血干细胞基础、临床及转化研究的最新进展，推动全球干细胞领域协同创新发展。会议期间，《肿瘤瞭望-血液时讯》特邀日本大阪大学Naoki Hosen教授，围绕“突破CD19/BCMA：血液肿瘤CAR-T与NK细胞治疗的新型靶点盘点”分享其最新研究成果与学术思考。现将精粹整理成文，以飨读者。

《肿瘤瞭望-血液时讯》：目前CAR-T疗法在B细胞淋巴瘤和多发性骨髓瘤中取得了巨大成功，主要归功于CD19和BCMA靶点。然而，对于急性髓系白血病（AML）和T细胞肿瘤，目前仍缺乏理想靶点。您的团队长期致力于发现白血病干细胞的安全新靶点，请问在AML领域，有哪些靶点具有较好的“疗效与安全性”平衡潜力？

Naoki Hosen教授：目前用于AML的靶点主要包括CD33、CD123及CLL-1等。上述靶点虽具备良好的抗白血病活性，但由于其在成熟髓系细胞中亦有表达，不可避免会带来较高的靶向毒性。

为此，本团队研发了靶向HLA-DRB1分子的新型CAR-T细胞。该靶点可精准区分AML受者与移植供者，对AML具有高度特异性，相关临床试验即将启动。然而，该策略的局限性在于其高度依赖于患者与供者间的HLA配型，仅适用于特定人群。因此，针对无法使用HLA-DR靶向CAR-T细胞的患者，仍需开发更为通用的靶点。

目前本团队正尝试应用CLL-1靶点。该靶点虽会清除成熟粒细胞，但在CAR-T细胞清除白血病细胞后，拟通过异基因移植重建造血系统以作补充。综合而言，目前尚无既能靶向AML细胞，又不影响正常干细胞的绝对理想靶点。

Oncology Frontier-Hematology Frontier：Currently, CAR-T therapy has achieved great success in B-cell lymphomas and multiple myeloma, mainly due to CD19 and BCMA targets. However, for acute myeloid leukemia (AML) and T-cell tumors, ideal targets are still lacking. Your team has long been committed to discovering safe novel targets for leukemia stem cells. In the AML field, which targets have good potential for balancing "efficacy and safety"?

Professor Naoki Hosen: I see so the several types of targets is used as the targets for AML. For example CD33 CD123 or CLL-1. These are all good targets, but it's also expressed in the mature myeloid cells. So it should be effective but it's also very toxic. So we can never avoid that using such target. So today we will we invented a new CAR-T cell targeting the HLA-DRB1 molecule. Which discriminate from recipient AML recipient and transplant donor. So that one is very specific for AML. So it should work. We will test in a clinical trial very soon. But the problem is this type of CAR-T cells can be used for a very specific condition about the HLA selection between patients and donors. So we really need a more universal target for the patients who cannot use HLA-DR targeting CAR-T cells. So currently we try to use the CLL-1. This target will deplete mature granulocyte. But after we deplete all the leukemia cells using CAR-T cells we attempt to reconstitute the hematopoietic system using the allo-transplant. So that's another strategy. So I don't think very ideal target on that for the AML cells but not on normal stem cell.

《肿瘤瞭望-血液时讯》：与自体CAR-T相比，NK细胞治疗（尤其是通用型NK）在移植物抗宿主病（GVHD）风险上具有天然优势。在血液肿瘤的新靶点开发上，您认为CAR-NK和CAR-T在靶点选择策略上有何不同？

Naoki Hosen教授：CAR-T细胞属于自体细胞，可在患者体内长期存续，甚至可能永久存在。相比之下，CAR-NK细胞属于异基因细胞，其会在数周至数月内被同种异体免疫反应所清除。

基于此特性，即使以CLL-1为靶点，其所致的粒细胞减少亦呈一过性。由于CAR-NK细胞被免疫反应耗竭后，患者体内不表达CLL-1的正常造血干细胞可促使粒细胞恢复。因此，对于此类患者，应用CAR-NK细胞具备一定的治疗潜力。

Oncology Frontier-Hematology Frontier：Compared to autologous CAR-T, NK cell therapy (especially universal NK) has a natural advantage in the risk of graft-versus-host disease (GVHD). In the development of new targets for hematological malignancies, how do you think the target selection strategies differ between CAR-NK and CAR-T?

Professor Naoki Hosen: Yeah that's a good question. So basically CAR-T cell is an autologous cell so it persists in the patients body for long sometimes forever. In contrast CAR-NK cell it's allogeneic cells it's basically a good thing and bad thing it's basically eliminated in a few weeks or months by the allogeneic immune reaction. So in this case even if you use for example CLL-1 as a target so the granulocytes decrease but it's transient because CAR-NK cell is depleted by immune reaction so the patients granulocytes is coming back because the hematopoietic stem cell normal hematopoietic stem cell does not express the CLL-1. So there is some chance to use CAR-NK cells for such patients.

《肿瘤瞭望-血液时讯》：中日两国在细胞治疗领域的交流日益频繁。您认为在新型细胞治疗靶点的早期发现、专利授权以及后续的临床开发方面，中日两国的科研机构与企业之间有哪些理想的合作模式？

Naoki Hosen教授：在细胞治疗领域，中国在临床开发方面较日本具有显著优势。因此，探讨中日两国间的深度合作具有重要战略意义。理想的合作模式为：在日本学术机构完成首次人体试验（first-in-human trial）后，进一步联合中国的学术机构或企业，在中国开展规模化扩展与受试者入组。这一模式有助于快速推进新疗法的临床验证。

Oncology Frontier-Hematology Frontier：Exchanges between China and Japan in the field of cell therapy are becoming increasingly frequent. In terms of early discovery of novel cell therapy targets, patent licensing, and subsequent clinical development, what ideal collaboration models do you think exist between research institutions and enterprises in China and Japan?

Professor Naoki Hosen：Yeah actually China is in this field in this cell therapy field China is much more advanced compare with Japan especially for clinical development. So I'm really thinking about a good collaboration between China and Japan. So my attempt is in Japan we perform the first in human trial in an academia setting and then we can expand in China collaborating with China academic or company. And it may be very easy to expand and test in a huge numbers of people. So I really think about it recently.

专家简介

Naoki Hosen（保仙直毅）教授

日本大阪大学

大阪大学大学院医学系研究科 血液・肿瘤内科学 教授

Hosen教授现任大阪大学血液・肿瘤内科学教授。他于1994年毕业于大阪大学医学部，2002年获大阪大学医学博士学位，2004至2007年赴美国斯坦福大学从事博士后研究，2020年起出任现职。

其研究聚焦血液恶性肿瘤的免疫治疗与细胞治疗，致力于鉴定血液肿瘤干细胞特异性抗原并开发相关靶向疗法。代表性成果包括发现整合素β7可作为多发性骨髓瘤CAR-T治疗的新靶点（Nature Medicine, 2017），以及开发靶向HLA-DR分子的CAR-T/NK细胞疗法（Nature Cancer, 2025）