Department of Internal Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA, United States.
Abramson Cancer Center and the Division of Hematology and Oncology, Hospital of the University of Pennsylvania, Philadelphia, PA, United States.
Front Immunol. 2024 May 16;15:1358668. doi: 10.3389/fimmu.2024.1358668. eCollection 2024.
Allogeneic hematopoietic cell transplantation (HCT) has transformed over the past several decades through enhanced supportive care, reduced intensity conditioning (RIC), improved human leukocyte antigen (HLA) typing, and novel graft-versus-host disease (GVHD)-prevention and treatment strategies. Most notably, the implementation of post-transplantation cyclophosphamide (PTCy) has dramatically increased the safety and availability of this life-saving therapy. Given reductions in nonrelapse mortality (NRM) with these advances, the HCT community has placed even greater emphasis on developing ways to reduce relapse - the leading cause of death after HCT. When using RIC HCT, protection from relapse relies predominantly on graft-versus-leukemia (GVL) reactions. Donor lymphocyte infusion (DLI), adoptive cellular therapy, checkpoint inhibition, and post-HCT maintenance strategies represent approaches under study that aim to augment or synergize with the GVL effects of HCT. Optimizing donor selection algorithms to leverage GVL represents another active area of research. Many of these strategies seek to harness the effects of T cells, which for decades were felt to be the primary mediators of GVL and the focus of investigation in relapse reduction. However, there is growing interest in capitalizing on the ability of natural killer (NK) cells to yield potent anti-tumor effects. A potential advantage of NK cell-based approaches over T cell-mediated is the potential to reduce NRM in addition to relapse. By decreasing infection, without increasing the risk of GVHD, NK cells may mitigate NRM, while still yielding relapse reduction through identification and clearance of cancer cells. Most T cell-focused relapse-prevention strategies must weigh the benefits of relapse reduction against the increased risk of NRM from GVHD. In contrast, NK cells have the potential to reduce both, potentially tipping the scales significantly in favor of survival. Here, we will review the role of NK cells in GVL, optimization of NK cell match or mismatch, and burgeoning areas of research in NK cell therapy such as adoptive transfer and chimeric antigen receptor (CAR) NK cells.
异基因造血细胞移植 (HCT) 在过去几十年中发生了转变，这得益于强化支持治疗、降低强度的预处理 (RIC)、改进人类白细胞抗原 (HLA) 分型以及新型移植物抗宿主病 (GVHD) 预防和治疗策略。最值得注意的是，移植后环磷酰胺 (PTCy) 的应用极大地提高了这种救命疗法的安全性和可用性。鉴于这些进展降低了非复发死亡率 (NRM)，HCT 社区更加重视开发降低复发的方法 - 这是 HCT 后死亡的主要原因。在使用 RIC HCT 时，预防复发主要依赖于移植物抗白血病 (GVL) 反应。供者淋巴细胞输注 (DLI)、过继性细胞治疗、检查点抑制以及 HCT 后维持策略是正在研究的旨在增强或协同 HCT 的 GVL 作用的方法。优化供者选择算法以利用 GVL 是另一个活跃的研究领域。这些策略中的许多都旨在利用 T 细胞的作用，几十年来，T 细胞被认为是 GVL 的主要介导物，也是降低复发的研究重点。然而，利用自然杀伤 (NK) 细胞的能力引起了越来越多的兴趣，这些细胞有可能产生强大的抗肿瘤作用。与 T 细胞介导的方法相比，NK 细胞方法的一个潜在优势是除了降低复发外，还可能降低非复发死亡率。通过减少感染，而不增加 GVHD 的风险，NK 细胞可以降低非复发死亡率，同时通过识别和清除癌细胞来降低复发率。大多数以 T 细胞为中心的预防复发策略必须权衡降低复发的益处与 GVHD 增加的非复发死亡率风险。相比之下，NK 细胞有可能降低两者，从而使生存率显著提高。在这里，我们将回顾 NK 细胞在 GVL 中的作用、NK 细胞匹配或不匹配的优化，以及 NK 细胞治疗中新兴的研究领域，如过继转移和嵌合抗原受体 (CAR) NK 细胞。
