ACTO主席下坂皓洋教授：外泌体赋能免疫细胞疗法创新突破

摘要：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。《肿瘤瞭望-血液时讯》特邀大会主

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。《肿瘤瞭望-血液时讯》特邀大会主席、亚洲细胞治疗组织（ACTO）主席下坂皓洋（Akihiro Shimosaka）教授与我们分享他在免疫细胞疗法、再生医学、基因疗法和外泌体的应用方面的深刻见解。

请问您在细胞疗法和免疫疗法领域的研究重点是什么？

下坂皓洋教授：在细胞治疗和免疫治疗领域，我的研究方向涵盖了多种治疗策略和技术手段。我致力于开发包括免疫细胞疗法和再生医学的应用以及外泌体在内的多种细胞疗法。这些治疗方法的共同目标是利用细胞和分子机制来治疗血液系统恶性肿瘤，改善患者的生活质量。

此外，我在药物研发、药物申报和药物监管等领域拥有近50年经验，并与多个全球大型药企及多国政府药品监管部门建立了长期和深层的合作交流。这种合作对于确保我们的研究成果能够安全、有效地转化为临床应用至关重要。通过与监管部门的沟通和协作，我们可以确保新技术的开发遵循严格的科学标准和伦理规范。

具体而言，我专注于以下几个方面：

再生医学：旨在通过刺激或替换受损组织来恢复其功能。这涉及到干细胞技术，特别是诱导多能干细胞（iPS细胞）的应用，其具有分化成多种细胞类型的能力。

免疫疗法：主要利用患者的免疫系统来对抗恶性肿瘤，包括通过基因工程改造T细胞，使其能够识别并攻击癌细胞。

基因疗法：旨在利用健康的基因来填补或替代缺失或病变的基因，以治疗囊性纤维化、镰状细胞病、镰状细胞贫血等遗传性疾病。

外泌体：是由细胞分泌而来的小囊泡，携带蛋白质、RNA和其他分子，可以影响其他细胞的功能。外泌体可以穿过细胞膜和不易引起免疫反应的特点，使其在基因、抗肿瘤等药物的体内运送方面具有独特优势，因此极具应用潜力，美国抗衰老医学研究会主席Klatz博士称：“外泌体是干细胞技术的下一个发展方向”。

Oncology Frontier-Hematology Frontier：What's your current focus in research in the fields of cell therapy and immunotherapy?

Dr. Akihiro Shimosaka：In the field of cellular therapy and immunotherapy, my research focuses on a variety of therapeutic strategies and technical approaches. I am committed to developing a range of cell therapies, including immune cell therapies and applications in regenerative medicine, as well as exosomes. The common goal of these treatment methods is to use cellular and molecular mechanisms to treat hematological malignancies and improve patients' quality of life.

Furthermore, I have nearly 50 years of experience in drug development, drug submission, and drug regulation, and have established long-term and in-depth cooperation and exchange with multiple global large pharmaceutical companies and drug regulatory authorities in various countries. This cooperation is crucial to ensuring that our research findings can be safely and effectively translated into clinical applications. Through communication and collaboration with regulatory authorities, we can ensure that the development of new technologies follows strict scientific standards and ethical norms.

Specifically, I focus on the following areas:

Regenerative Medicine: Aiming to restore the function of damaged tissues by stimulating or replacing them. This involves stem cell technology, especially the application of induced pluripotent stem cells (iPS cells), which have the ability to differentiate into various cell types.

Immunotherapy: Primarily using the patient's immune system to combat malignant tumors, including genetically engineering T cells to recognize and attack cancer cells.

Gene Therapy: Aiming to use healthy genes to fill in or replace missing or diseased genes to treat genetic diseases such as cystic fibrosis, sickle cell disease, and sickle cell anemia.

Exosomes: These are small vesicles secreted by cells, carrying proteins, RNA, and other molecules that can affect the function of other cells. Their ability to cross cell membranes and not easily trigger immune responses gives them a unique advantage in the in vivo delivery of drugs such as genes and anti-tumor agents, making them highly application potential. Dr. Klatz, President of the American Academy of Anti-Aging Medicine, said, "Exosomes are the next direction for stem cell technology development."

你能分享一些你认为在细胞或免疫疗法中最创新的方向，并告诉我们为什么它给你留下了深刻印象吗？

下坂皓洋教授：在细胞或免疫疗法领域，我认为最创新的两个方向是外泌体在免疫细胞疗法中的应用以及CD133+/CD34+外周血干细胞在再生医学中的作用。

首先，外泌体在免疫细胞疗法中的应用是一个非常前沿新兴的领域。外泌体是树突状细胞（DC细胞）分泌的微囊泡，携带多种遗传物质，可影响受体细胞的功能。在免疫疗法中，外泌体可以作为抗原呈递的平台，激活免疫反应，同时也可以携带抑制免疫反应的分子，这使得外泌体在免疫激活和免疫抑制中都发挥作用。外泌体必须携带所需信息，如抗原或信号分子，才能发挥作用，这是其作为治疗工具的关键特性。

美国杜克大学（Duke University）前癌症中心主任Herbert Kim Lyerly教授是全球最早开展外泌体研究的学者之一，拥有超过20年DC肿瘤疫苗研究经验，积累了大量肿瘤新抗原和外泌体的研究经验和数据。此次会议，Lyerly教授带来了题为《Exosomes and mRNA as Novel Cancer Therapies》的演讲，研究数据证实了外泌体在免疫疗法中的有效性，我对此充满期待。我将与Lyerly教授展开合作，协力研发通用型DC+外泌体肿瘤疫苗，并在美国、日本和中国开展临床试验和药物申报，敬请期待。

其次，CD133+/CD34+外周血干细胞在再生医学中的应用也是创新的方向。在日本，CD133+/CD34+外周血干细胞被用于促进新血管的再生，这对于糖尿病患者腿部的保护以避免截肢至关重要，这种先进的新型疗法已被监管部门批准。这种疗法的成功应用展示了再生疗法在临床实践中的巨大潜力，并且强调了除了药物审批系统外，疗法批准系统的重要性。

这两个领域的发展不仅展示了细胞和免疫疗法的创新性，而且为患者提供了新的治疗选择，带来了临床获益。随着研究的深入，我们有望看到这些疗法在更广泛的疾病治疗中的应用。

Oncology Frontier-Hematology Frontier：Can you share something you consider to be the most innovative in cellular or immunotherapy and tell why it impresses you?

Dr. Akihiro Shimosaka：In the field of cell or immunotherapy, I believe the two most innovative directions are the application of exosomes in immune cell therapy and the role of CD133+/CD34+ peripheral blood stem cells in regenerative medicine.

Firstly, the application of exosomes in immune cell therapy is a very cutting-edge and emerging field. Exosomes are microvesicles secreted by dendritic cells (DCs), carrying a variety of genetic materials that can affect the function of recipient cells. In immunotherapy, exosomes can serve as a platform for antigen presentation, activating immune responses, and can also carry molecules that suppress immune responses, making exosomes play a role in both immune activation and immune suppression. Exosomes must carry necessary information, such as antigens or signals, to function effectively, which is a key characteristic of their use as therapeutic tools.

Professor Herbert Kim Lyerly, former director of the Cancer Center at Duke University, is one of the earliest scholars in the world to conduct exosome research, with over 20 years of experience in DC tumor vaccine research, accumulating a wealth of research experience and data on tumor neoantigens and exosomes. At this conference, Professor Lyerly presented a lecture titled "Exosomes and mRNA as Novel Cancer Therapies," and the research data confirmed the effectiveness of exosomes in immunotherapy, which I am very much looking forward to. I will collaborate with Professor Lyerly to jointly develop a universal DC+ exosome tumor vaccine and conduct clinical trials and drug submissions in the United States, Japan, and China, so please stay tuned.

Secondly, the application of CD133+/CD34+ peripheral blood stem cells in regenerative medicine is also an innovative direction. In Japan, CD133+/CD34+ peripheral blood stem cells are used to promote the regeneration of new blood vessels, which is crucial for the protection of diabetic patients' legs and to avoid amputation, and this advanced new therapy has been approved by regulatory authorities. The successful application of this therapy demonstrates the great potential of regenerative therapy in clinical practice and emphasizes the importance of a therapy approval system in addition to the drug approval system.

The development of these two fields not only demonstrates the innovation of cell and immunotherapy but also provides new treatment options for patients, bringing clinical benefits. As research deepens, we can expect to see the application of these therapies in the treatment of a broader range of diseases.

您从参加这次国际细胞或免疫疗法会议中获得了哪些特别的见解或经验？

下坂皓洋教授：我深刻认识到了学习最新前沿进展与现有技术手段相结合的重要性。此次会议涉及到的技术众多，我们需要将多种技术融合，以满足复杂多变的治疗需求，制定更全面的治疗方案，从而更有效地应对各种疾病挑战。此外，这次会议也是一个分享信息的宝贵平台。我们有幸与行业领袖和监管部门代表对话，这种多方参与的交流对于推动细胞和免疫疗法的发展至关重要。

Oncology Frontier-Hematology Frontier：What special insights or experiences do you gain from participating in this international conference on cellular or immunotherapy?

Dr. Akihiro Shimosaka：I have come to deeply appreciate the importance of combining the latest cutting-edge advancements with existing technological methods. The conference covered a multitude of technologies, and it is essential for us to integrate various techniques to meet the complex and changing therapeutic needs, devising more comprehensive treatment plans to more effectively address the challenges of various diseases. Additionally, this conference served as a valuable platform for sharing information. We were fortunate to engage in dialogue with industry leaders and representatives from regulatory agencies; such multi-party engagement is crucial for propelling the development of cell and immunotherapies.

展望未来，您对细胞或免疫疗法的未来有什么期望或愿景？

下坂皓洋教授：首先，我期望这些疗法更加精准和个性化。目前的治疗模式往往类似于药物分发，即一种药物适用于所有患者，而未来的细胞或免疫疗法应转变为针对每例患者具体情况的个性化治疗。这意味着治疗方案将根据患者的遗传信息、肿瘤特征和免疫状态来制定，以实现最佳的治疗效果和最小的副作用。

其次，为了实现这种个性化治疗，我们需要相应的法规和政策支持。这包括建立和完善细胞治疗的监督框架，以确保患者能够接受更安全、更有效、更个体化的创新治疗。

最后，我们也期待未来细胞治疗能被纳入公共医疗保险体系中，进一步提升治疗的可及性与公平性，确保患者能够广泛受益于这些创新的研究成果。

总之，我对细胞或免疫疗法的未来充满期待，希望它们能够成为更加精准、个性化的治疗选择，并得到政策和保险系统的支持，从而惠及每一位患者。

自20世纪90年代以来，我便与中国医生展开紧密合作。我的研究成果推动了以粒细胞集落刺激因子为代表的造血调控因子在临床实践中的应用，使得上世纪90年代以后，外周血造血干细胞移植逐渐取代骨髓造血干细胞移植，也推动了造血干细胞移植技术在全世界范围内的开展，使众多中国患者受益。

在此基础上，北京大学血液病研究所自主研发的半相合移植技术在治疗儿童急性淋巴细胞白血病（ALL）和儿童急性髓系白血病（AML）方面取得了显著成效。这一技术的重要性在于，允许在没有同胞间人类白细胞抗原（HLA）全相合供者的情况下进行移植，解决了以往许多患者因找不到匹配供体而无法接受治疗的问题。我对于能够与他们合作，共同推动这一重要医学发展感到非常高兴。

Oncology Frontier-Hematology Frontier：As we are looking to the future, what's your expectation or wishes for the future of cellular or immunotherapy?

Dr. Akihiro Shimosaka：First and foremost, I anticipate that these therapies will become more precise and personalized. Current treatment models often resemble drug distribution, where one drug is applied to all patients. However, future cell or immunotherapies should shift towards personalized treatments tailored to the specific conditions of each patient. This means that treatment plans will be designed based on the patient's genetic information, tumor characteristics, and immune status to achieve the best therapeutic effects and minimize side effects.

Secondly, to achieve this level of personalized treatment, we need the support of corresponding regulations and policies. This includes the establishment and improvement of a regulatory framework for cell therapies to ensure that patients can receive safer, more effective, and more individualized innovative treatments.

Lastly, we also look forward to the future integration of cell therapies into public medical insurance systems, further enhancing the accessibility and equity of treatments and ensuring that patients can widely benefit from these innovative research outcomes.

In summary, I am filled with anticipation for the future of cell and immunotherapies, hoping they will become more precise and personalized treatment options, supported by policies and insurance systems, thus benefiting every patient.

Since the 1990s, I have been working closely with Chinese doctors. My research outcomes have facilitated the application of hematopoietic regulatory factors represented by granulocyte colony-stimulating factor in clinical practice. This has led to the gradual replacement of bone marrow hematopoietic stem cell transplantation with peripheral blood hematopoietic stem cell transplantation since the 1990s and has promoted the global development of hematopoietic stem cell transplantation technology, benefiting many Chinese patients.

Building on this foundation, the half-identical transplantation technology independently developed by the Hematology Institute of Peking University People's Hospital has achieved significant results in the treatment of children with acute lymphocytic leukemia (ALL) and acute myeloid leukemia (AML). The importance of this technology lies in its ability to perform transplantations without the need for a fully matched human leukocyte antigen (HLA) donor from siblings, solving the problem that many patients in the past could not receive treatment due to the lack of a matching donor. I am very pleased to collaborate with them in advancing this significant medical development.