Salvage treatment of steroid-refractory acute GVHD with the off-the-shelf product of human umbilical cord mesenchymal stromal cells: a multicenter, open label, phase Ib/IIa trial

Le résumé fourni par la source

Acute graft-versus-host disease (aGVHD) is a life-threatening complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT), particularly if treatment is refractory. Mesenchymal stromal cells (MSCs) have demonstrated promising therapeutic effects in aGVHD, due to their well-described immunomodulatory properties. Based on the importance of maternal-fetal interface immune tolerance, the umbilical cord may provide a superior tissue source of MSC. This study aimed to investigate the safety and efficacy of human umbilical cord derived MSCs (hUC-MSCs) delivered as salvage therapy for steroid-refractory (SR)-aGVHD. This phase Ib/IIa, multicenter, open-label clinical trial of a third-party, off-the-shelf preparation of hUC-MSCs enrolled grades II to IV SR-aGVHD patients. This trial consist of 2 parts: a phase Ib dose escalation part using a standard 3 + 3 design, which planed twice weekly i.v. infusions of hUC-MSCs, at 0.5 × 106 per kg, 1.0 × 106 per kg and 2.0 × 106 per kg for 3 weeks, to determine the maximum tolerated dose and recommended phase 2 dose (RP2D). Phase IIa of this work is an expansion cohort study of hUC-MSCs at RP2D. The primary endpoint of the study was safety and RP2D. The key secondary endpoints were efficacy of the overall response rate (ORR) at Day 28. The study enrolled 25 patients with SR-aGVHD who received different doses of hUC-MSCs treatment. Safety analysis showed that no dose-limiting toxicity was observed in all dose groups. An ORR of 80.0% was achieved by day 28, with a complete response rate of 40.0% and a partial response rate of 40.0%. The incidence, severity, and type of adverse events (AEs) were similar across different dose groups, showing no obvious correlation with dose. The RP2D was determined to be 1.0 × 106 per kg. The 1-year overall survival rate was 74.3%. The 1-year incidence of non-relapse mortality and relapse of the underlying malignancy after SCT was 17.0% and 8.4%, respectively. Biomarker analysis showed that in responding patients, the proportion of CD8 + central memory T cells and CXCR-10 levels significantly increased at 24 h after hUC-MSCs infusion. The remarkable efficacy and favorable safety profile of hUC-MSCs offer a promising salvage therapy for patients with severe SR-aGVHD. CTR20221330. Registered 06 June 2022, http://www.chinadrugtrials.org.cn/clinicaltrials.searchlistdetail.dhtml .

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.