2025年8月22日至23日，由中国北京健康促进会与广州市红棉肿瘤和罕见病公益基金会联合主办、北京陆道培血液病研究院承办的第十三届陆道培血液病学术大会在京隆重召开。本次会议汇集全球顶尖血液学专家，聚焦造血干细胞移植、细胞治疗、血液肿瘤精准诊疗等核心议题，为千余名参会者呈现了一场高规格、深层次的学术盛宴。会议期间，候任美国血液学会（ASH）主席、美国斯坦福大学血液和骨髓移植科主任Robert Negrin教授分享了“改善移植结局的免疫调节机制（Immunoregulatory Mechanisms to Improve Transplant Outcomes）”的精彩报告。《肿瘤瞭望-血液时讯》特邀Robert Negrin教授围绕临床的核心问题展开深入解读，以期为优化移植管理策略提供重要的实践指导与理论参考。

PART.1
 

在临床异体造血干细胞移植中，诱导或输注调节性T细胞（Tregs）已显示可显著降低GVHD风险。请问您如何在真实世界的临床方案里权衡：通过外源性Treg补充或体内选择性扩增（例如低剂量IL-2/工程化IL-2）来实现免疫耐受，同时尽量保留或不损害GvL（graft-versus-leukemia）效应？您认为现阶段哪类证据最能指导临床实践？

Robert Negrin教授：问题核心在于如何利用调节性T细胞（regulatory T cells）于临床应用中。目前已有多种策略正在探索中。其中一个基本难题是，尚无能够特异性扩增调节性T细胞的药物。这类细胞在行为上与普通T细胞颇为相似，因此许多旨在激活和扩增调节性T细胞的药物也会同时扩增常规T细胞。例如，尽管白细胞介素-2（IL-2）是一种有吸引力的候选因子，但它也会影响其他免疫细胞群体。
 

本次我所展示的研究数据主要集中在分离调节性T细胞，并将其以纯化群体形式用于过继转移。这并不是说这是发挥生物学效应的唯一途径，但它可视为一种最直接且已在临床前研究中得到验证的策略。最终的关键在于，何种策略能够带来最佳的临床结局，而这只能通过精心设计的临床试验来确定。我们认为，目前的研究数据为一种策略奠定了基础，其他策略亦可在此基础上继续探索，以期获得更优疗效。最终我们必须将这些理念推向临床实践。

In allogeneic hematopoietic stem cell transplantation, adoptive Treg transfer or in-vivo Treg expansion has reduced GVHD in studies. Clinically, how do you weigh adoptive Treg supplementation versus in-vivo selective expansion strategies (e.g., low-dose IL-2 / engineered IL-2) to induce tolerance while preserving graft-versus-leukemia (GvL) effects? Which types of evidence should guide practice today?
 

Pro. Robert Negrin: The central question addressed herein pertains to strategies for harnessing regulatory T cells for clinical application. Currently, multiple approaches are under investigation; however, a fundamental challenge lies in the absence of pharmacological agents that specifically target and expand regulatory T cells. These cells exhibit functional and behavioral similarities to conventional T cells, meaning that agents designed to activate and expand regulatory T cells often concomitantly stimulate effector T cells. For instance, interleukin-2 represents a promising cytokine for this purpose, yet it exerts broad effects on various immune cell populations, thereby complicating its selective application.

The research presented here focuses on an alternative strategy: the isolation and adoptive transfer of purified regulatory T cells. While this may not be the only method to achieve a biological effect, it represents a direct and empirically validated approach in preclinical models. Ultimately, the determination of which strategy yields optimal clinical outcomes will depend on rigorously designed clinical trials. The current data provide a foundational framework for one such strategy and set the stage for comparative evaluation with other emerging approaches. Translating these concepts into clinically viable therapies remains an essential direction for future research.

PART.2

工程化CAR-Tregs与特异性Treg工程化正在进入临床试验阶段（例如针对HLA/移植物抗原的CAR-Tregs）。您怎么看CAR-Treg在器官/移植免疫耐受中的现实可行性？在推进到临床时，您最担心的安全或制造相关问题是什么？

Robert Negrin教授：目前，研究人员正在开发多种不同策略以增强调节性T细胞的活性，例如通过引入嵌合抗原受体（CAR）或尝试分离抗原特异性的调节性T细胞。我们提出的一种思路是导入一种新型受体，使其仅对某些形式的白细胞介素-2（例如“正交IL-2”）产生响应，从而特异性增强表达该正交IL-2受体的细胞功能。这些策略各有优势，而我们希望已完成的研究能够证实调节性T细胞具备生物学功能，今后的重点在于进一步优化其性能。
 

在安全性方面，并无过多担忧，因为我们已具备多种细胞群体应用的丰富经验，更关键的问题在于哪种方法能表现出最佳疗效。个人更倾向于探索如何在体内刺激调节性T细胞并促进其扩增的策略。无论是通过CAR还是正交IL-2受体实现这一目标，均为具有潜力的研究方向。

然而需要注意的是，为将这类新型受体导入CAR-T细胞，必须进行体外操作：将细胞从体内取出，经激活后通过载体转导目标基因。这一过程有时可能改变其生物学活性。因此，一个重要前提是如何验证经过操作的CAR-T细胞仍保持与原始细胞相同的生物学功能。在推进至临床试验阶段时，这一问题必须予以高度重视。

Engineered CAR-Tregs and antigen-specific Treg engineering are moving into clinical trials (e.g., HLA-A2 CAR-Tregs). What is your assessment of the practical feasibility of CAR-Tregs for transplantation tolerance? When moving to the clinic, what are the top safety or manufacturing concerns you would highlight?

Pro. Robert Negrin: Numerous strategies are currently under investigation to enhance the activity of regulatory T cells. These include engineering them with chimeric antigen receptors (CARs) or isolating antigen-specific regulatory T cell populations. One promising approach involves equipping these cells with a novel receptor that enables selective responsiveness to specific forms of interleukin-2, referred to as orthogonal IL-2, thereby selectively expanding only those cells expressing the corresponding orthogonal IL-2 receptor. While many of these strategies show substantial promise, our work contributes to the growing evidence that regulatory T cells possess significant biological functions—now the focus turns to further refining their efficacy.

From a safety standpoint, I have few concerns, largely due to extensive prior experience working with various cell populations. The primary consideration remains identifying which strategy yields the greatest therapeutic efficacy. Personally, I favor approaches aimed at stimulating and expanding regulatory T cells within the body. Both CAR-based systems and orthogonal IL-2 receptor strategies represent valid and compelling avenues toward this goal.

One important caveat, however, is that introducing these novel receptors into T cells requires extensive in vitro manipulation—including cell extraction, activation, and genetic transduction—which may alter their biological properties. A key question is how to ensure that the modified CAR-T cells retain functional equivalence to their native counterparts. This issue warrants careful evaluation as we advance toward clinical trials.

PART.3

除了Tregs，近期工作也探索了先天免疫（如NKT）或联合免疫调节策略以促进“传染性耐受”（infectious tolerance）。在您看来，哪些“组合策略”最有希望在保留抗肿瘤活性同时降低GVHD/排斥？这些组合在哪些模型或早期临床证据中最有说服力？

Robert Negrin教授：我对调节性T细胞的相关数据尤为认可，因其研究已推进至随机试验阶段，标志着临床转化取得实质性进展。关于恒定自然杀伤T细胞的研究亦具有显著的科学价值。然而，该类细胞在体内含量极为稀少，因此在分离并获取足够数量用于临床应用方面存在诸多技术限制。这一问题既涉及生物学特性，也受到当前技术条件的制约。

尽管这些研究具有重要的科学意义，但其最终价值仍需通过临床试验予以验证，而这一过程既耗时又充满挑战。希望今日所展示的数据能够激励我们开展更深入的研究，因其证实了此类研究在获得积极临床结局方面的可行性。当前的重点应是在此基础上进一步优化策略，不断提升其临床适用性与疗效。

Beyond Tregs, recent work explores innate immune players (e.g., NKT cells) or combination immunoregulatory approaches to promote “infectious tolerance.” Which combination strategies do you find most promising to reduce GVHD/rejection while preserving anti-tumor activity? Which models or early clinical data are most persuasive?

Pro. Robert Negrin: The data on regulatory T cells are particularly compelling, as this work has advanced to randomized trials, demonstrating tangible clinical progress. The research on invariant natural killer T cells, which you mentioned, is also highly promising. However, a significant challenge lies in the extreme rarity of these cell populations, which imposes substantial technical limitations on their isolation for clinical applications. Thus, the situation involves both biological constraints and practical technical hurdles.

While these studies possess considerable scientific merit, their ultimate validation must come from clinical trials, which are time-consuming and complex. It is my hope that the findings presented today will stimulate further investigation, as they illustrate the feasibility of conducting such studies and achieving positive clinical outcomes. Moving forward, we must build upon this foundation to refine and enhance these approaches.