Cellular Therapy and Immunology, Manashi Chakrabarti Foundation, Kolkata, India; BMT Research Lab, Department of Blood and Marrow Transplantation & Hematology, Dharamshila Narayana Superspeciality Hospital and Research Centre, New Delhi, India.
Department of Transplant Immunology & Immunogenetics, All India Institute of Medical Sciences, New Delhi, India.
Transplant Cell Ther. 2021 Feb;27(2):144-151. doi: 10.1016/j.jtct.2020.10.005. Epub 2020 Dec 10.
Adaptive or memory natural killer (NK) cells with epigenetic imprints similar to memory T cells have been shown to develop in response to cytomegalovirus (CMV) infection with upregulation of activating receptor NKG2C. These cells have been shown to possess strong anti-tumour efficacy both in-vitro as well as in-vivo.
To determine if reconstitution of adaptive NK cells (CD56NKG2CNKG2A) in patients with advanced leukemia undergoing haploidentical HCT had any impact on disease progression (DP).
The study cohort comprised of 60 patients with advanced acute leukemia, aged 2-65 years, receiving myeloablative PTCy based haploidentical transplantation from CMV seropositive donors, followed by CTLA4Ig-primed donor lymphocyte infusions (DLI). They were evaluated for the kinetics of reconstitution of adaptive NK cells, both phenotypic and functional, at days +30,+60, +90 and at regular intervals, to 3 years of follow-up, in relation to DP. Reconstitution of adaptive NK cells was compared with a retrospective cohort of patients in the same protocol receiving DLI without CTLA4Ig.
Non-relapse mortality, acute and chronic GVHD were 5.1%, 10.3% and 14.5%. DP was 17.5% at a median follow-up of 28 months. Adaptive NK cells were significantly higher in patients without DP at days+30, +60 and +90 (p = 0.0001), irrespective of CMV reactivation and remained elevated until 36 months post-HCT. These cells maintained their functional competence as measured by robust interferon-gamma production with higher expressions of KIR, NKG2D and CD57, without any increase in PD1 expression. Grafts from donors with higher adaptive NK cells were associated with a lower risk of DP (p = 0.0001). In multivariate analysis, adaptive NK cell recovery at day +90 had the most favorable impact on DP (HR-0.7). Tregs reconstituted briskly along with the adaptive NK cells and were sustained as well, without compromising the GVL effect. Comparison with a retrospective cohort receiving the same protocol with DLI without CTLA4Ig, showed a superior reconstitution of adaptive NK cells in those receiving CTLA4Ig-DLI (p < 0.0001).
Our study suggests that myeloablative transplantation from CMV seropositive haploidentical donors augmented with CTLA4Ig-primed DLI might favor early and sustained expansion of functionally competent adaptive NK cells irrespective of CMV reactivation, with a favorable outcome.
已证实，巨细胞病毒（CMV）感染可诱导具有与记忆 T 细胞相似的表观遗传印记的适应性或记忆自然杀伤（NK）细胞的发育，并上调激活受体 NKG2C。这些细胞在体外和体内均显示出强大的抗肿瘤功效。
确定在接受半相合造血干细胞移植（haploidentical HCT）的晚期白血病患者中，适应性 NK 细胞（CD56dimNKG2C+NKG2A+）的重建是否会对疾病进展（DP）产生影响。
该研究队列包括 60 例年龄在 2-65 岁的晚期急性白血病患者，他们接受了基于 PTCy 的半相合移植，来自 CMV 血清阳性供者，随后进行 CTLA4Ig 预激的供者淋巴细胞输注（DLI）。他们在第 30、60、90 天以及 3 年的随访期间评估适应性 NK 细胞的表型和功能重建情况，与 DP 相关。将适应性 NK 细胞的重建与同一方案中接受无 CTLA4Ig 的 DLI 的患者的回顾性队列进行比较。
非复发死亡率、急性和慢性移植物抗宿主病（GVHD）分别为 5.1%、10.3%和 14.5%。中位随访 28 个月时 DP 为 17.5%。在第 30、60 和 90 天，无 DP 的患者的适应性 NK 细胞明显更高（p=0.0001），与 CMV 再激活无关，并在 HCT 后 36 个月仍保持升高。这些细胞通过产生更强的干扰素-γ来保持其功能能力，同时表达更高的 KIR、NKG2D 和 CD57，而 PD1 表达没有增加。来自具有更高适应性 NK 细胞供者的移植物与 DP 风险降低相关（p=0.0001）。多变量分析显示，第 90 天适应性 NK 细胞的恢复对 DP 的影响最有利（HR-0.7）。Tregs 与适应性 NK 细胞一起迅速重建并持续存在，而不会影响 GVL 效应。与接受相同方案但无 CTLA4Ig 的 DLI 的回顾性队列相比，接受 CTLA4Ig-DLI 的患者的适应性 NK 细胞重建更优（p<0.0001）。
我们的研究表明，来自 CMV 血清阳性半相合供者的清髓性移植，联合 CTLA4Ig 预激的 DLI，可能有利于适应性 NK 细胞的早期和持续扩增，而与 CMV 再激活无关，并带来有利的结果。
