Ghosh Arnab, Smith Melody, James Scott E, Davila Marco L, Velardi Enrico, Argyropoulos Kimon V, Gunset Gertrude, Perna Fabiana, Kreines Fabiana M, Levy Emily R, Lieberman Sophie, Jay Hillary V, Tuckett Andrea Z, Zakrzewski Johannes L, Tan Lisa, Young Lauren F, Takvorian Kate, Dudakov Jarrod A, Jenq Robert R, Hanash Alan M, Motta Ana Carolina F, Murphy George F, Liu Chen, Schietinger Andrea, Sadelain Michel, van den Brink Marcel R M
Department of Medicine and Immunology Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
Center of Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
Nat Med. 2017 Feb;23(2):242-249. doi: 10.1038/nm.4258. Epub 2017 Jan 9.
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative therapy for hematological malignancies. However, graft-versus-host disease (GVHD) and relapse after allo-HSCT remain major impediments to the success of allo-HSCT. Chimeric antigen receptors (CARs) direct tumor cell recognition of adoptively transferred T cells. CD19 is an attractive CAR target, which is expressed in most B cell malignancies, as well as in healthy B cells. Clinical trials using autologous CD19-targeted T cells have shown remarkable promise in various B cell malignancies. However, the use of allogeneic CAR T cells poses a concern in that it may increase risk of the occurrence of GVHD, although this has not been reported in selected patients infused with donor-derived CD19 CAR T cells after allo-HSCT. To understand the mechanism whereby allogeneic CD19 CAR T cells may mediate anti-lymphoma activity without causing a significant increase in the incidence of GVHD, we studied donor-derived CD19 CAR T cells in allo-HSCT and lymphoma models in mice. We demonstrate that alloreactive T cells expressing CD28-costimulated CD19 CARs experience enhanced stimulation, resulting in the progressive loss of both their effector function and proliferative potential, clonal deletion, and significantly decreased occurrence of GVHD. Concurrently, the other CAR T cells that were present in bulk donor T cell populations retained their anti-lymphoma activity in accordance with the requirement that both the T cell receptor (TCR) and CAR be engaged to accelerate T cell exhaustion. In contrast, first-generation and 4-1BB-costimulated CAR T cells increased the occurrence of GVHD. These findings could explain the reduced risk of GVHD occurring with cumulative TCR and CAR signaling.
异基因造血干细胞移植（allo-HSCT）是治疗血液系统恶性肿瘤的一种潜在治愈性疗法。然而，allo-HSCT后的移植物抗宿主病（GVHD）和复发仍然是allo-HSCT成功的主要障碍。嵌合抗原受体（CAR）可指导过继转移T细胞对肿瘤细胞的识别。CD19是一个有吸引力的CAR靶点，它在大多数B细胞恶性肿瘤以及健康B细胞中均有表达。使用自体靶向CD19的T细胞进行的临床试验在各种B细胞恶性肿瘤中显示出显著的前景。然而，使用异基因CAR T细胞存在一个问题，即它可能会增加发生GVHD的风险，尽管在allo-HSCT后输注供体来源的CD19 CAR T细胞的特定患者中尚未有相关报道。为了了解异基因CD19 CAR T细胞在不显著增加GVHD发生率的情况下介导抗淋巴瘤活性的机制，我们在小鼠的allo-HSCT和淋巴瘤模型中研究了供体来源的CD19 CAR T细胞。我们证明，表达共刺激分子CD28的CD19 CAR的同种反应性T细胞受到增强的刺激，导致其效应功能和增殖潜能逐渐丧失、克隆性缺失，以及GVHD的发生率显著降低。同时，大量供体T细胞群体中存在的其他CAR T细胞根据T细胞受体（TCR）和CAR均需参与以加速T细胞耗竭的要求，保留了它们的抗淋巴瘤活性。相比之下，第一代和4-1BB共刺激的CAR T细胞增加了GVHD的发生率。这些发现可以解释随着累积的TCR和CAR信号传导，GVHD发生风险降低的原因。
