IGC2024专访 | 新加坡A*Star Andy Tan教授：深入探讨CAR-NK细胞疗法的创新与挑战
IGC2024 | 会前专访系列
-IGC 2024-
随着免疫细胞疗法的不断突破，CAR-NK细胞治疗正吸引着投资者和医疗界的广泛关注。在当前市场条件下，这种创新的治疗方法展现出了巨大的潜力和希望。同时全球对创新医疗解决方案的需求日益增长，跨国界的科研合作也加速了CAR-NK细胞疗法的发展，为全球患者提供了更多治疗选择。
第八届IGC免疫基因及细胞治疗大会即将于9月6-7日在北京召开，大会特设“CGT国际监管与技术前瞻论坛”专场。 由此，IGC组委非常荣幸在会前邀请到新加坡科技研究局A*Star生物工艺科技研究院BTI，首席科学家、组长(新加坡)，Andy Tan教授，分享他在免疫细胞及基因治疗领域的最新进展、面临的挑战以及未来的发展方向。
采访嘉宾：Andy Tan，新加坡科技研究局A*Star生物工艺科技研究院BTI，首席科学家、组长(新加坡)
Andy Tan 教授领导着新加坡科技研究局 (A*STAR) 生物技术研究所 (BTI) 的免疫细胞制造小组，该小组专注于开发实验室和生物反应器规模工艺的深度能力，包括培养基优化，以便生产天然或嵌合抗原受体 (CAR) 工程同种异体 NK 和T 细胞，用于癌症免疫治疗。他已就这项研究提交了几项技术披露，并曾领导与当地合同开发和制造组织 (CDMO) 的联合实验室，以建立 CAR 病毒生产细胞和 CAR-T 细胞的可扩展扩增。他的研究得到了新加坡科技研究局 (A*STAR)、国家研究基金会 (National Research Foundation)、国家医学研究委员会 (National Medical Research Council) 和行业资金的支持，他是与生物技术公司合作项目的负责人或联合研究员。
Andy Tan 教授在新加坡国立大学获得理学学士、物理学硕士学位和免疫学博士学位。随后，他在澳大利亚国立大学完成了免疫基因组学博士后培训，之后加入 BTI 担任研究科学家，随后被任命为小组负责人。他目前还是新加坡理工学院的兼职副教授。
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IGC 组委会
Andy Tan教授，您作为新加坡科技研究局的资深研究员，在免疫细胞工艺技术领域有着深入研究。我想请教您一下，从您的专业视角来看，目前这一领域的发展和趋势有哪些显著特点？特别是在细胞治疗的个体化、精确性提升以及新靶点的发现方面，您认为未来有哪些创新点值得我们期待？
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Andy Tan 教授
目前发展和趋势的显著特点可以概括为以下三点：
多样化的细胞类型：除了传统的CAR-T细胞， 其他类型免疫细胞治疗的研究也迅速发展，比如NK细胞（自然杀伤细胞）、 CAR-NK、 TCR-T细胞（T细胞受体工程T细胞）以及iPSC衍生的免疫细胞等。这些不同种类的细胞疗法丰富了该领域的产品维度， 可以进一步提高治疗效果和适应症广度。
优化的细胞工程技术：随着CRISPR/Cas9等基因编辑技术的成熟，科学家们能够更精准地编辑细胞基因，提高细胞治疗的安全和有效性。利用iPSC作为种子细胞通过进一步分化获得的NK、T细胞提升了产品的制备效率和产量，克服了个体化制备的局限性。
组合治疗方案：细胞疗法与其他疗法（比如免疫检查点抑制剂、抗体疗法、化疗）联合使用，显著提高了治疗的协同效应，大大改善了患者预后。
The significant features of the current developments and trends can be summarized into the following three points:
Diverse Cell Types: In addition to traditional CAR-T cells, research on other types of immune cell therapies is also increasing, such as NK cells (natural killer cells), CAR-NK, TCR-T cells (T cell receptor-engineered T cells), and iPSC-derived immune cells. These different types of cell therapies enrich the product dimensions of the field, potentially increasing the efficacy and broadening the indications of treatments.
Optimized Cell Engineering Technologies: With the maturation of gene editing technologies like CRISPR/Cas9, scientists are able to edit cell genes more precisely and improve the safety and effectiveness of cell therapies. Using iPSCs as seed cells for further differentiation into T cells and NK cells through further differentiation has increased the efficiency and yield of product preparation, overcoming the limitations of individualized preparation.
Combination Therapy Strategies: The combination of cell therapy with other therapeutic modalities (such as immune checkpoint inhibitors, antibody therapy, and chemotherapy) significantly enhances the synergistic effects of treatment, greatly improving patient outcomes.
关于细胞治疗的个体化和精确性提升的进展方面，我认为有以下几个方面：
肿瘤新抗原预测和个性化疫苗：通过对患者的肿瘤基因组进行详尽分析并识别特异性的新抗原，可以制定个性化的肿瘤疫苗接种策略。
精准基因编辑：利用更精准的基因编辑技术（比如CRISPR/Cas9）来改造免疫细胞，增强其抗肿瘤杀伤力和体内持久性，同时减少可能的副作用。
生物标志物的监测与应用：通过高精度的生物标志物监测, 可以实时评估疾病进展和治疗反应，从而促进动态调整治疗方案，确保最佳的治疗效果。
Regarding advancements in personalization and precision of cell therapy, I think there are the following aspects:
Tumor neoantigen prediction and personalized vaccines: By thorough analysis of the patient's tumor genome to identify specific neoantigens, a personalized tumor vaccination strategy can be devised.
Precision gene editing: Utilizing more precise gene editing technologies (such as CRISPR/Cas9) to modify immune cells, thus enhancing their anti-tumor cytotoxicity and in vivo persistence while reducing potential side effects.
Biomarker monitoring and application: Through high-precision biomarker monitoring, disease progression and treatment response can be evaluated in real time, facilitating dynamic adjustments of treatment plans to ensure optimal therapeutic outcomes.
新靶点的发掘及创新方面主要表现在：
多靶点联合：探索和发现新的肿瘤细胞特异性靶点，通过多靶点联合的方式，提高治疗的有效性并减少肿瘤逃逸风险。
肿瘤微环境调控：除了靶向肿瘤细胞，也可研究如何调控肿瘤微环境，如针对抑制性免疫细胞（Tregs、MDSCs）、改变肿瘤代谢环境等，增强整体免疫反应。
合成生物学创新：通过合成生物学设计具有新功能的细胞，如自带环境感知能力和自杀开关的免疫细胞，增强治疗的安全和控制性。
总结起来，当前免疫细胞治疗领域有诸多令人振奋的进展，从多样化的细胞类型到精准的个体化治疗设计，再到新靶点的发现和应用。未来的创新将进一步推动这领域的发展，带来革命性的治疗手段。通过不断的科学探索和技术进步，我们可以期待更多突破性成果，为患者带来更有效和安全的治疗选择。
The main innovations in discovering new targets and aspects of innovation are reflected in:
Multi-Target Combination: Exploring and discovering new tumor cell-specific targets, using a multi-target combination approach could improve treatment effectiveness and reduce the risk of tumor escape.
Regulation of the Tumor Microenvironment: In addition to targeting tumor cells, research are focused on how to regulate the tumor microenvironment, such as targeting inhibitory immune cells (Tregs, MDSCs) and altering the tumor metabolic environment to enhance the overall immune response.
Synthetic Biology Innovations: Designing cells with new functions through synthetic biology, such as immune cells with inherent environmental sensing capabilities and self-destruction switches, to enhance the safety and controllability of therapies.
In summary, there have been many exciting advancements in the field of immune cell therapy, ranging from diverse cell types to precise personalized therapy designs, and the discovery and application of new targets. Future innovations will further drive development in this field, bringing revolutionary treatment methods. Through continuous scientific exploration and technological progress, we can anticipate more breakthrough results, providing patients with more effective and safer treatment options.
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IGC 组委会
Andy Tan教授，在免疫细胞治疗领域，异体自然杀伤（Allogeneic NK）细胞因其在治疗实体瘤方面的潜力而备受关注。您在CAR-NK细胞的工艺制造方面具有开创性意义。我想请您谈一谈，在您的研究中，针对实体瘤的异体CAR-NK细胞制造工艺面临哪些主要挑战？同时您在解决这些挑战方面进行了哪些关键性的研究以及这些研究成果如何推动了CAR-NK细胞疗法的发展？
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Andy Tan 教授
针对实体瘤的异体CAR-NK细胞制造工艺面临以下几个主要挑战：
种子细胞来源与扩增：原代NK细胞的获取和大量扩增仍然是当前的一个主要技术难题。一般来说，原代NK细胞需要从供体血液或脐带血中提取，然后进行大规模扩增，确保足够数量的活细胞用于治疗。虽然iPS-NK在一定程度上解决了这个问题，但是与原代NK相比，iPSC-NK的安全性还有待进一步的临床验证。
持久性和活性：与T细胞相比，NK细胞在体内的持久性和活性较短，需要解决如何在治疗中保持其长时间的抗癌活性。
异体细胞的免疫排斥：虽然NK细胞引发排异的风险与T细胞相比极低，但是在使用中依然有可能会引起宿主免疫系统的排斥反应，需要克服这方面的免疫障碍。
肿瘤微环境的抑制：实体瘤微环境往往具有抑制性，可以降低NK细胞的抗肿瘤活性，需要研究如何增强NK细胞在这种环境中的功能。
The manufacturing process of allogeneic CAR-NK cells targeting solid tumors faces the following major challenges:
Source of Seed Cells and Expansion: Obtaining and massively expanding primary NK cells remains a major technical challenge. Typically, primary NK cells need to be extracted from donor blood or umbilical cord blood and then undergo large-scale expansion to ensure a sufficient number of viable cells for treatment. Although iPS-NK cells have somewhat addressed this issue, the safety still requires further clinical validation.
Persistence and Activity: Compared with T cells, NK cells have shorter persistence and activity in the body. There is a need to address how to maintain their long-term anti-cancer activity during treatment.
Immune Rejection of Allogeneic Cells: Although NK cells have a much lower risk of triggering immune rejection compared to T cells, there is still a possibility of eliciting a rejection response from the host immune system. Overcoming this immune barrier is essential.
Inhibition by the Tumor Microenvironment: The microenvironment of solid tumors is often suppressive and can reduce the anti-tumor activity of NK cells. Researches are still needed to enhance the function of NK cells in such environments.
我们的关键性研究主要关注以下几个方面：
优化NK细胞扩增技术：开发新的培养基和生长因子组合，显著提升NK细胞的扩增效率和质量。
新型饲养层细胞的开发：采用CRISPR/Cas9等基因编辑工具让具有调控NK活性的分子在饲养层细胞内稳定表达，以筛选出具有更强NK活化功能的饲养层细胞进行NK制备，以延长NK在体内的生存时间和抗肿瘤活性。
条件性培养基组分的筛选：通过筛选不同来源的水解产物，化合物寻找更适合NK体外增殖的培养组分，从而开发出扩增效果更加的NK培养基用于NK的制备。
肿瘤微环境调控：通过利用条件性培养基模拟肿瘤内微环境，驯化NK对肿瘤免疫微环境的适应性，提高NK进入肿瘤内的抗肿瘤活性。
Our key research focuses primarily on the following aspects:
Optimizing NK Cell Expansion Techniques: Developing new combinations of culture media and growth factors to significantly enhance the efficiency and quality of NK cell expansion.
Development of Novel Feeder Cells: Using gene editing tools like CRISPR/Cas9 to stably express molecules that regulate NK activity in feeder cells. The goal is to screen and select feeder cells with stronger NK activation capabilities for NK cell preparation, thereby extending the survival time and anti-tumor activity of NK cells in the body.
Screening of Conditional Culture Medium Components: By screening hydrolysates and compounds from various sources to find culture components that are more suitable for NK cell proliferation in vitro, we aim to develop more effective expansion media for NK cell preparation.
Tumor Microenvironment Regulation: Utilizing conditional culture media to simulate the tumor microenvironment, we aim to condition NK cells to adapt to the immune microenvironment of tumors, enhancing their anti-tumor activity upon entry into the tumor.
这些关键性研究工作已经取得了一些显著成果，推动了CAR-NK细胞疗法的发展，主要包括：
新型饲养层细胞的筛选：目前我们已经构建了多株携带不同共刺激分子的饲养层细胞，并对这些细胞的NK激活与扩增能力进行评估。
优化制备工艺：我们还正在利用生物反应器研究同种异体NK细胞的扩大生产技术，旨在降低制造成本。
条件性培养基组分的开发：我们已经开展了对来自各种动物和植物来源的水解产物和小分子进行功能筛选，以进一步优化培养基功能，提高NK细胞的生产效率和产量。
总之，通过克服这些主要挑战，我们希望这些研究不仅在理论上推动了CAR-NK细胞疗法的发展，更在实践中提供了切实可行的方案，为实体瘤患者带来了新的希望。
These key research efforts have already achieved some significant results, advancing the development of CAR-NK cell therapy, including:
Screening of Novel Feeder Cells: We have constructed different feeder cell lines carrying different co-stimulatory molecules and evaluated their capabilities to activate and expand NK cells in vitro.
Optimization of Production Processes: We are also using bioreactors to study the scale-up technology for production of allogeneic NK cells, aiming to reduce manufacturing costs.
Development of Conditional Culture Medium Components: We have initiated functional screenings of hydrolysates and small molecules from various animal and plant sources to further optimize culture media that enhances NK cell production efficiency and yield.
In summary, by overcoming these major challenges, we hope that our research will not only theoretically advance CAR-NK cell therapy but also provide practical and feasible solutions, bringing new hope to patients with solid tumors.
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IGC 组委会
Andy Tan教授，您在免疫细胞治疗领域的深厚背景和前瞻性研究，期待您分享下，在未来的研究蓝图中，您有哪些具体的研究方向或项目计划，以及您认为哪些领域或技术将为免疫细胞治疗带来革命性的变革？
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Andy Tan 教授
目前，我们的具体研究方向和项目计划包括以下几个方面：
新型CAR-NK细胞疗法: 我们正在开发针对不同癌症类型的新型嵌合抗原受体NK细胞疗法，旨在提高疗效并减少副作用。
代谢微环境调控：研究如何优化培养基的功能组分，重塑NK细胞的能量代谢，使其进入实体瘤微环境之后，可以抵抗免疫抑制调空，以增强免疫细胞的抗癌能力。
异体NK的规模化培养：利用不同类型的生物反应器，研究NK培养的工艺放大技术，配合多种在线监测，实现NK培养的规模化，提高NK的制备效率。
Currently, our specific research directions and project plans include the following aspects:
Novel CAR-NK Cell Therapies: We are developing new chimeric antigen receptor NK cell therapies targeting different types of cancer, with the aim of increasing efficacy and reducing side effects.
Regulation of the Metabolic Microenvironment: We are researching how to optimize the functional components of culture media to remodel the energy metabolism of NK cells. This will enable them to resist immune suppression in the tumor microenvironment, thereby enhancing the anti-cancer capabilities of immune cells.
Scale-Up Cultivation of Allogeneic NK Cells: By utilizing different types of bioreactors, we are studying the scale-up technology for NK cell cultivation. Coupled with various online monitoring systems, this will achieve large-scale NK cultivation and improve the efficiency and the feasibility of NK cell preparation.
关于革命性变革的新技术和新领域对免疫细胞治疗领域的影响，我有以下几个看法：
合成生物学：通过合成生物学技术设计和制造具有新功能的免疫细胞，比如更强的杀伤力或更好的耐药性。
多模态组合疗法：将细胞疗法与其他治疗方法（例如放疗、化疗和抗体治疗）相结合，形成多层次、多途径的综合治疗策略。
新型生物标志物的发现：鉴定和利用新的生物标志物来预测和监控治疗反应，从而个性化和优化治疗方案。
人工智能和大数据：利用AI和大数据分析来识别新的治疗靶点、优化治疗方案以及个性化治疗计划的设计。
关于未来展望，我有以下两个观点：
研发新一代技术平台：如多功能免疫细胞、多靶点免疫调控等，全面提升免疫细胞治疗的能力和范围。
全球合作与临床试验：通过与全球领先的研究机构和临床中心合作，推动临床试验和实际应用，缩短科研成果向临床应用的转换时间。
Regarding the impact of revolutionary new technologies and new fields on the field of immune cell therapy, I have the following points:
Synthetic Biology: Using synthetic biology techniques to design and create immune cells with new functions, such as enhanced cytotoxicity or better drug resistance.
Multimodal Combination Therapies: Combining cell therapy with other treatment methods (such as radiation therapy, chemotherapy, and antibody therapy) to form comprehensive treatment strategies that are multi-layered and multi-pathway.
Discovery of Novel Biomarkers: Identifying and utilizing new biomarkers to predict and monitor treatment responses, thereby personalizing and optimizing treatment plans.
Artificial Intelligence and Big Data: Utilizing AI and big data analysis to identify new therapeutic targets, optimize treatment strategies, and design personalized treatment plans.
Regarding future prospects, I have the following two considerations:
Development of Next-Generation Technology Platforms: Such as multifunctional immune cells and multi-target immune regulation, to comprehensively enhance the capabilities and scope of immune cell therapies.
Global Collaboration and Clinical Trials: By collaborating with leading research institutions and clinical centers worldwide, we aim to advance clinical trials and practical applications, thus shortening the time required for translating research findings into clinical applications.
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IGC 组委会
Andy Tan教授，作为免疫细胞治疗领域的领军人物，在您即将展开的中国之行中，您有哪些特别的期待或目标？同时，您对于探索中国在免疫细胞工艺技术方面的最新进展和潜在合作机会有何展望？
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Andy Tan 教授
在即将展开的中国之行中，我有以下几点特别的期待和目标：
学术交流和知识分享：期待与中国顶尖的科研机构和大学进行深入的学术交流，分享我们在免疫细胞治疗领域的最新研究成果和技术创新，同时也听取和学习中国同行在这一领域所取得的进展。
实地考察和技术评估：如果有机会，访问中国的一些领先的生物技术公司和临床中心，实地考察他们的实验室和生产设施，评估他们在CAR-T、CAR-NK等细胞治疗技术的实际应用和临床成果。
凝聚合作机会：通过参加学术研讨会、行业展会以及与当地企业的对接会，辨识和探讨具体的合作机会。例如，联合研究项目、临床试验合作、技术转移和市场推广等。
In my upcoming trip to China, I have several specific expectations and goals:
Academic Exchange and Knowledge Sharing: I look forward to engaging in in-depth academic exchanges with top research institutions and universities in China, sharing our latest research findings and technological innovations in the field of immune cell therapy. I am also eager to hear about and learn from the progress made by Chinese counterparts in this field.
On-Site Visits and Technical Evaluation: If opportunities arise, I am also willing to visit some leading biotechnology companies and clinical centers in China, tour their laboratories and production facilities in person, and evaluate their practical applications and clinical outcomes in technologies such as CAR-T and CAR-NK cell therapy.
Building Collaborative Opportunities: By participating in academic symposiums, industry exhibitions, and engaging in meetings with local companies, I hope to identify and discuss specific collaboration opportunities. These may include joint research projects, collaboration on clinical trials, technology transfer, and market promotion efforts.
对于探索中国在免疫细胞工艺技术方面的最新进展，我有以下几点展望：
先进的制造工艺：中国在细胞治疗工艺的规模化生产方面有着显著的进步，尤其在高效扩增、纯化和质量控制等方面。我非常期待了解这些技术细节，并探讨如何将这些经验借鉴到我们的研究中。
临床试验和应用：中国在免疫细胞治疗的临床试验方面取得了多个突破，特别是在实体瘤和难治性血液病的治疗上。我希望能深入了解这些临床试验的设计、实施和结果，以便丰富我们的临床策略。
政策和法规环境：了解中国在生物技术领域的政策和监管环境，特别是关于细胞治疗的审批流程和临床应用指南，这对国际合作和市场进入策略至关重要。
When it comes to exploring the latest advancements in immune cell processing technologies in China, I have the following expectations:
Advanced Manufacturing Processes: China has made significant progress in the scale-up production of cell therapy processes, particularly in efficient expansion, purification, and quality control. I am eager to learn about these technical details and discuss how we can leverage this experience in our research.
Clinical Trials and Applications: China has made several breakthroughs in clinical trials of immune cell therapies, especially in the treatment of solid tumors and refractory hematological diseases. I hope to gain insights into the design, implementation, and outcomes of these clinical trials to enrich our clinical strategies.
Policy and Regulatory Environment: Understanding China's policies and regulatory environment in the field of biotechnology, especially regarding the approval process for cell therapies and clinical application guidelines, is crucial for international collaboration and market entry strategies.
在潜在合作机会方面，我有如下期待：
联合研究项目：希望能够与中国的领先科研机构共同发起一些具有前瞻性的研究项目，例如在新型免疫疗法的开发和优化方面展开合作，共同推动技术进步和科学创新。
临床试验合作：通过跨国合作开展更多多中心临床试验，结合不同地区的患者数据，提升研究结果的广泛性和适用性，加速新疗法的临床应用。
技术转移和生产合作：考虑与中国的生物技术公司合作，进行技术转移和生产，共同打造符合国际标准的细胞治疗产品。这样不仅有助于提升产品的质量和生产效率，也可以更好地服务于全球患者。
市场和商业合作：探讨在中国市场推广免疫细胞治疗产品的策略，与当地合作伙伴建立长期的商业合作关系，推动治疗方案在中国的应用和普及。
总之，我非常期待这次中国之行，通过与中国同行的紧密合作，共同探索和实现免疫细胞治疗领域的更多突破，造福全球患者。
In terms of potential collaboration opportunities, I have the following expectations:
Joint Research Projects: I hope to initiate forward-looking research projects in collaboration with leading research institutions in China, focusing on the development and optimization of novel immune therapies. By working together, we can drive technological advancements and scientific innovation.
Clinical Trial Collaboration: By engaging in multinational collaboration, conducting multicenter clinical trials combining patient data from different regions, we aim to enhance the breadth and applicability of research results, accelerating the clinical application of new therapies.
Technology Transfer and Production Collaboration: Considering partnerships with biotechnology companies in China for technology transfer and production, we aim to collaboratively develop cell therapy products that meet international standards. This will not only enhance product quality and production efficiency but also better serve global patients.
Market and Commercial Collaboration: Exploring strategies for promoting immune cell therapy products in the Chinese market, establishing long-term commercial partnerships with local collaborators to facilitate the application and popularization of treatment solutions in China.
In conclusion, I am looking forward to my trip to China and through close collaboration with Chinese counterparts, working together to explore and achieve more breakthroughs in the field of immune cell therapy, benefiting patients worldwide.
感谢Andy Tan 教授的解答，他还将受邀出席9月6-7日于北京举办的IGC 第八届免疫基因及细胞治疗大会 发表关于“治疗实体瘤的同种异体NK细胞生产的机遇与挑战”的精彩演讲，让我们敬请期待！
IGC 2024
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IGC 2024（第八届免疫基因及细胞治疗大会）将再度于北京国际会议中心升级启航！今年IGC将从12大细分论坛出发，探讨CGT热点赛道的投融策略、前瞻技术、创新疗法研发、领先转化、先进CMC、国内外申报策略，促进国内外产学研医的深入交流与合作，加快中国免疫治疗、基因治疗及细胞治疗的产业转化！
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