Meyer Everett H, Pavlova Anna, Villar-Prados Alejandro, Bader Cameron, Xie Bryan, Muffly Lori, Kim Paige, Sutherland Katherine, Bharadwaj Sushma, Dahiya Saurabh, Frank Matthew, Arai Sally, Johnston Laura, Miklos David, Rezvani Andrew, Shiraz Parveen, Sidana Surbhi, Shizuru Judy, Weng Wen-Kai, Agrawal Vaibhav, Putnam Amy, Fernhoff Nathaniel, Tamarisis John, Lu Ying, Pawar Rahul D, McClellan J Scott, Lowsky Robert, Negrin Robert S
Stanford Blood and Marrow Transplantation and Cellular Therapy Division, Stanford School of Medicine, Stanford University, Stanford, CA.
Cellular Immune Tolerance Program, Stanford Department of Medicine, Stanford University, Stanford, CA.
Blood. 2025 May 1;145(18):2012-2024. doi: 10.1182/blood.2024026446.
Allogeneic hematopoietic cell transplantation is a curative therapy limited by graft-versus-host disease (GVHD). In preclinical studies and early-phase clinical studies, enrichment of donor regulatory T cells (Tregs) appears to prevent GVHD and promote healthy immunity. We enrolled 44 patients in an open-label, single-center, phase 2 efficacy study investigating if a precision selected and highly purified Treg therapy manufactured from donor-mobilized peripheral blood improves 1-year GVHD-free relapse-free survival (GRFS) after myeloablative conditioning. We compared this study arm with a concomitant standard-of-care (SOC) cohort. All donor Treg products were successfully manufactured and administered without cryopreservation within 72 hours. Participants had a 1-year incidence of acute grade 3 to 4 GVHD of 7%, moderate to severe chronic GVHD of 11%, and nonrelapse mortality rate of 4.5%. The primary end point of significantly improved 1-year GRFS was achieved at 64% evaluated against a predicted incidence of 40% (P = .002) with a realized incidence of 36% in the SOC comparator. For those trial patients who developed grade 2 to 4 acute GVHD, 91% responded to front-line corticosteroid therapy, whereas 50% responded in the SOC comparator group. Trial participants had a reduced incidence and burden of GVHD and improved GRFS, compared with rates common to highly variable unmanipulated donor grafts and multiagent immune suppression. This trial was registered at www.clinicaltrials.gov as #NCT01660607.
异基因造血细胞移植是一种受移植物抗宿主病（GVHD）限制的治愈性疗法。在临床前研究和早期临床研究中，富集供体调节性T细胞（Tregs）似乎可预防GVHD并促进健康免疫。我们招募了44名患者参加一项开放标签、单中心的2期疗效研究，该研究旨在调查由供体动员外周血制备的经过精确选择和高度纯化的Treg疗法是否能改善清髓性预处理后1年无GVHD无复发生存率（GRFS）。我们将该研究组与同期的标准治疗（SOC）队列进行了比较。所有供体Treg产品均成功制备并在72小时内无需冷冻保存即可给药。参与者1年急性3至4级GVHD的发生率为7%，中度至重度慢性GVHD的发生率为11%，非复发死亡率为4.5%。与预测发生率40%相比，1年GRFS显著改善这一主要终点实现率为64%（P = 0.002），而SOC对照组的实际发生率为36%。对于那些发生2至4级急性GVHD的试验患者，91%对一线皮质类固醇治疗有反应，而SOC对照组中这一比例为50%。与高度可变的未处理供体移植物和多药免疫抑制常见的发生率相比，试验参与者的GVHD发生率和负担降低，GRFS得到改善。该试验已在www.clinicaltrials.gov上注册，编号为#NCT01660607。
