在造血干细胞移植（HSCT）领域，免疫调节机制至关重要，不仅影响移植的成功率，还决定了受体对移植物的耐受性以及移植后的长期健康情况。在第十二届陆道培血液病学术论坛中，斯坦福大学血液和骨髓移植科主任Robert S.Negrin教授分享了关于免疫调节机制与移植的精彩讲座。《肿瘤瞭望-血液时讯》特邀Robert Negrin教授接受专访，从国际视角为我们解读移植物抗宿主病（GVHD）、移植物抗肿瘤效应（GVT）与免疫耐受等前沿话题。
《肿瘤瞭望-血液时讯》在造血干细胞移植中，如何通过调节免疫调节机制来降低移植物抗宿主病的发生率，同时保持移植物抗肿瘤效应？
Robert Negrin教授：在移植领域，在降低GVHD发生率的同时保持GVT是一项重大挑战。GVHD是HSCT的潜在不利后果，而GVT则是移植治疗中对抗肿瘤的关键积极因素。在本次学术会议上，我介绍了一种创新的方法——基于在动物模型研究中的发现，通过设计移植物来培育特定的细胞群体，这一策略显示出实现上述平衡的巨大潜力。
此外，其他研究团队也在积极探索不同的策略。例如，来自西雅图的弗雷德·哈钦森癌症研究中心（Fred Hutchinson Cancer Research Center）的一项引人注目的研究，聚焦于初始T细胞（naive T cell）的消耗，其被认为与GVHD的发生密切相关。在欧洲，另一种广泛采用的策略是消耗αβ T细胞，同时保留其他类型的T细胞群体。
在众多策略中，确定哪一种最为有效是一项颇具挑战性的任务，因为它们可能均具备一定的治疗效果。最终，这些策略的有效性需要通过严谨的临床试验来验证。然而，需要注意到一个主要的挑战是，动物模型并不能完全预测某种治疗或策略的优越性，必须通过临床试验来明确。
造血干细胞移植是一项复杂的医疗程序，提高无复发生存率（GRFS）是我们追求的终极目标。我们面临的挑战不仅包括对患者的长期随访以确保疾病不复发，还包括缺乏一种可靠的方法来衡量移植物对肿瘤的持续效果。克服这些挑战可能需要长期而艰苦的研究工作，而且可能需要多种策略的结合才能取得成功。
Oncology Frontier-Hematology Frontier：How can we modulate the immune regulatory mechanisms to reduce the incidence of graft-versus-host disease (GVHD) in allogeneic hematopoietic stem cell transplantation while maintaining graft-versus-leukemia (GVT) effects?
Dr. Robert Negrin：This is one of the major challenges of our field. How do we modulate graft versus host disease? The negative consequence of the transplant yet retain graft versus tumor effects, the positive aspects of the transplant. I showed you one approach of engineering, the graft to bring out certain cell populations. We think that has great potential to do exactly what we hope to achieve, which is what we learned from animal modeling. There are other strategies that other investigators are exploring. One particular one from Seattle from the Fred hutchin Cancer Institute involves depleting so called naive t cells, which we think are responsible for causing graft versus host disease.
Another strategy of done widely in Europe is to deplete so called Alpha beta t cells and retain the other t cell populations. So there are a number of different strategies, and it's very difficult to know which one is the perfect strategy and they may all work and that's fine. The end result has to be documented in clinical trials.
However, one of our challenges has been that the animal modeling is useful for dividing concepts, but it is not prove that a particular therapy or strategy is better than the next.
That has to be done through clinical trials. I showed you one example of taking that forward into a randomized clinical trial. That's the type of evidence that we need to really document that a particular strategy is better as you can appreciate. Bone marrow transplantation is complicated. You're trying to do different things. What we ultimately want is what we call grfsgdhd relapse, Free survival. And that's the ultimate goal. A big part of our Challenge is that we have no way to measure whether you've retained the graft versus tumor effect other than following patients and making sure they don't relapse. It's hard work. It takes a long time, takes a difficult studies. And there probably is more than one strategy that will ultimately work is just a matter of defining and rigorously testing these different strategies.
《肿瘤瞭望-血液时讯》近期有哪些新的发现或策略可以增强移植后的免疫耐受，从而改善患者的长期生存率？
Robert Negrin教授：免疫耐受是一种移植后受体对供体移植物抗原的耐受状态，这在移植医学中是一项极具挑战性的任务。这个过程可能需要数月时间，在这期间，患者不仅要面对感染的风险，还需定期回访移植中心接受严格的随访监测，并服用多种免疫抑制药物。因此，了解免疫耐受的发生机制以及如何加速这一过程，是当前亟待解决的关键问题之一。
免疫耐受的概念至关重要，许多研究人员已经探索了多种策略，例如如何加速恢复。但迄今为止，这些尝试尚未取得显著成果。免疫耐受的研究是一个不断发展的领域，仍有许多工作需要完成，以便我们能够更深入地理解并解决这一难题。
值得关注的是，斯坦福大学的Samuel Strober博士在其研究中提出了一个创新的概念，即将骨髓移植与实体器官移植相结合，以诱导对实体器官的耐受性。这种方法可能为免疫耐受提供了新的视角。然而，根据目前的认识，免疫耐受的形成确实需要较长时间，我们对于如何有效地影响或控制这一过程的了解仍然有限。
Oncology Frontier-Hematology Frontier：What new findings or strategies have been identified to enhance immune tolerance post-transplant and thereby improve long-term survival rates in patients?
Dr. Robert Negrin：Where you bring up a very interesting question, you brought up the concept of immune tolerance.So that's what something remarkably happens after a transplant is that the donor becomes tolerant of the recipient. And I think that's one of the truly black boxes of what we do in transplantation. We know it happens over a period of months. During that time patients are at great risk for various infections. They have to be followed to the transplant center there on lots of different medications. They can reactivate all kinds of infections. So that's really one of the major unmet questions of how does immune tolerance occur. How do we accelerate it? And i'll be honest, there are relatively few important. It's a very important concept, but there's been relatively little success. Various strategies that have been looked at are various site of kinds to try to accelerate new recovery. But to date, none of them have really born much fruit. It's an area of ongoing investigation, and still a lot of a lot of work that needs to be done to try to figure that out.
Now, that could have obvious relevance in other settings. For example, we at Stanford have developed a concept based upon work from one of my colleagues, doctor Samuel stripper, who combines bone marrow transplantation with solid organ transplantation. The idea being you induced tolerance to the solid organ. So there's lots of areas that could be helpful in. But we're left now with recognizing this occurs, it takes months for it to occur, and we don't yet know how to really influence it.
《肿瘤瞭望-血液时讯》鉴于个体间免疫反应的差异性，您认为个性化医疗在移植中的重要性如何，以及如何实现个性化的目标？
Robert Negrin教授：骨髓移植是个性化医疗的典范，它根据患者独特的遗传特征，即人类白细胞抗原（HLA）基因，来匹配合适的供体。这一过程已经高度体现了个性化的医疗实践。然而，如何将这一概念进一步普及是一个复杂的问题，这要求我们为每位特定患者寻找到匹配的供体。这不仅凸显了个性化医疗的重要性，也揭示了我们面临的挑战。
随着我们对疾病理解的不断深化，一个关键的未解之谜是移植物抗肿瘤效应。我们如何识别出哪些患者的疾病特征更容易受到GVL的影响，以及哪些患者可能具有更强的抵抗作用？解决这些问题将帮助我们更精准地筛选患者人群，预测哪些人可能从骨髓移植治疗中获得更大的益处，代表了我们未来研究和发展的方向。
当然，不应忽视我们已经在移植领域取得了一项重大成就——建立了国家骨髓库。目前，全球约有3300万志愿者愿意成为他们从未见过的人的供体，不仅彰显了人类互助的精神，也提醒我们为了识别出适合特定患者的个性化供体，我们必须不懈努力，继续寻找更有效的方法来评估疾病风险，并为患者匹配更合适的供体，以降低整体治疗的风险。
此外，所有这些策略都必须通过精心设计的临床试验来验证，数据收集在这一过程中至关重要。移植领域在数据收集与管理方面走在了前列。例如，在美国，根据联邦法律的要求，医生必须收集并报告所有治疗相关的结果给国家骨髓库。这种做法使医生能够准确地评估治疗表现，并与其他中心进行比较，这对于领域内的持续改进和发展至关重要。这种对数据的重视和透明度在其他疾病领域并不常见，但它对于医学的进步至关重要。
Oncology Frontier-Hematology Frontier：Given the variability in immune responses among individuals, how important do you think personalized medicine is in post-transplant immune regulation, and how can this goal be achieved?
Dr. Robert Negrin：That's a very big question, very important question. I would say that bone marrow transplantation is a great example of personalized medicine and meaning that we identify a donor based upon the personal genes, hla genes that the patient expresses.So that's very much already a personalized medicine. How do we go? How do we more generalize those concepts? It is very difficult because it does require very specific donors for a particular patient. I think that highlights how important doing personalized medicine really is. I think as we learn more about disease, one of the unmet questions is, what is the graft versus tumor effect? How do we how do we know which characteristics of the patient's disease is more susceptible to graft versus tumor effects versus other patients who may be more resistant? Will allow us to pick patients better, which patients would benefit from these therapies better than other patients.
And I think that's a really a direction we could go in. But I would say the bone transplantation a is a great example of personalized medicine because of the need for finding a specific donors. Let's not forget that in this field, one of the great achievements was developing so called national marrow donor program. There are now 33 million people around the world who volunteered to be a donor for someone they've never met before, which highlights how far you have to go to identify the personalized donor for a particular patient. So it's a complicated problem. And we made a lot of progress. And we continue to search for better ways to identify disease risk and better donors for individual patients to reduce risk. All that has to be characterized by very well constructive clinical trials.
The other piece that I would want to mention is that it's very important that we collect outcomes. I think that's another area where the transplant field has been far ahead of other comparative fields. For example, in the United States, we are required by federal law to report our outcomes, so we collect Information, we collect data, and then we reported to centralize the repositories that allows us to really assess how we're doing, how we compare to other centers. I think that's critically important. And at least in North America, in the United States, not very commonly practiced, except in very isolated areas. And transplant is one of those areas that we really collect data.
会议回放
请扫描上放二维码以观看会议回放，其中Robert S.Negrin教授的讲座及讨论环节位于90:50至123:50。