Dipartimento di Oncologia ed Ematologia, Ospedale Papa Giovanni XXIII, Bergamo, Italy.
Molecular and Translational Medicine Doctoral Program (DIMET), University of Milano-Bicocca, Monza, Italy.
Front Immunol. 2024 Oct 24;15:1459175. doi: 10.3389/fimmu.2024.1459175. eCollection 2024.
Although allogeneic hematopoietic cell transplantation (HCT) represents a curative approach for many patients with hematological diseases, post-transplantation relapse occurs in 20-50% of cases, representing the primary cause of treatment failure and mortality. Alloreactive donor T cells are responsible for the graft versus leukemia (GvL) effect, which represents the key mechanism for the long-term curative effect of HCT. However, the downside is represented by graft versus host disease (GvHD), largely contributing to transplant-related mortality (TRM). Multiple factors play a role in regulating the delicate balance between GvL and GvHD, such as the optimization of the donor HLA and KIR match, the type of graft source, and the adaptive use of post-transplant cellular therapy. In addition to the standard donor lymphocyte infusion (DLI), several attempts were made to favor the GvL effect without increasing the GvHD risk. Selected DLI, NK DLI, activated DLI and more sophisticated genetically engineered cells can be employed. In this scenario, cytokine-induced killer (CIK) cells represent a suitable tool to boost GvL while minimizing GvHD. CIK cells are T lymphocytes activated in culture in the presence of monoclonal antibodies against CD3 (OKT3), interferon-gamma (IFN-g), and interleukin-2 (IL-2), characterized by the expression of markers typical of NK cells and T cells (CD3, CD56, with a prevalent CD8 phenotype). CIK cells can mediate cytotoxicity through both MHC and non-MHC restricted recognition, which is the so-called "dual-functional capability" and display minimum alloreactivity. Allogeneic CIK cells showed a favorable rate of response, especially in the setting of minimal residual disease, with a rate of GvHD not exceeding 25%. Finally, the CIK cell platform can be adapted for chimeric antigen receptor (CAR) cell strategy, showing promising results in both preclinical and clinical settings. In this review, we describe the main immunological basis for the development of the GvL and the possible cellular therapy approaches used to boost it, with a particular focus on the use of CIK cells.
虽然异基因造血细胞移植（HCT）代表了许多血液系统疾病患者的一种治愈方法，但移植后复发发生在 20-50%的病例中，这是治疗失败和死亡的主要原因。同种异体反应性供体 T 细胞负责移植物抗白血病（GvL）效应，这是 HCT 长期疗效的关键机制。然而，其缺点是移植物抗宿主病（GvHD），这在很大程度上导致移植相关死亡率（TRM）。多个因素在调节 GvL 和 GvHD 之间的微妙平衡中发挥作用，例如供体 HLA 和 KIR 匹配的优化、移植物来源的类型以及移植后细胞治疗的适应性使用。除了标准供体淋巴细胞输注（DLI）外，还尝试了几种方法来促进 GvL 而不增加 GvHD 风险。可以使用选择的 DLI、NK DLI、激活的 DLI 和更复杂的基因工程细胞。在这种情况下，细胞因子诱导的杀伤（CIK）细胞是一种促进 GvL 同时最小化 GvHD 的合适工具。CIK 细胞是在存在针对 CD3（OKT3）、干扰素-γ（IFN-g）和白细胞介素-2（IL-2）的单克隆抗体的培养中激活的 T 淋巴细胞，其特征是表达 NK 细胞和 T 细胞的典型标志物（CD3、CD56，具有占主导地位的 CD8 表型）。CIK 细胞可以通过 MHC 和非 MHC 限制识别介导细胞毒性，这就是所谓的“双重功能能力”，并显示出最小的同种异体反应性。同种异体 CIK 细胞显示出有利的反应率，尤其是在微小残留疾病的情况下，GvHD 率不超过 25%。最后，CIK 细胞平台可以适应嵌合抗原受体（CAR）细胞策略，在临床前和临床环境中均显示出有前途的结果。在这篇综述中，我们描述了 GvL 发展的主要免疫学基础以及用于增强它的可能细胞治疗方法，特别关注 CIK 细胞的使用。
