A phase 1b study on the safety of Wharton's jelly mesenchymal stromal cells in the treatment of acute graft-versus-host disease.

Abstract

Steroid-refractory (SR) and high-risk (HR) acute graft-versus-host disease (aGVHD) is a major complication of allogeneic hematopoietic stem cell transplantation. Mesenchymal stromal cells (MSCs) possess immunomodulatory potential, and Wharton's jelly MSCs, a rapidly expanding subset of cells that exhibit potent in vitro suppression of T-cell proliferation, may benefit patients in the setting of SR/HR aGVHD. The objective of this study was to evaluate the safety and preliminary efficacy signals of multiple-dose MSCTC-0010, an umbilical cord-derived Wharton's jelly MSC product, in patients with SR or HR aGVHD. This was a prospective, single-center, open-label phase 1b trial (NCT03158896). Adults (18-76 years old) with de novo HR or SR aGVHD unresponsive to ≥1.6 mg kg⁻¹ day⁻¹ methylprednisolone were enrolled. Three sequential cohorts received 2 × 10⁶ (low dose [n = 5]), 10 × 10⁶ (high dose [n = 5]) or 10 × 10⁶ cells kg⁻¹ on day 0, day 7, day 14 and day 21 (extended high dose [n = 14]) intravenously. The primary endpoint was the absence of treatment-related adverse events (TRAEs) (Common Terminology Criteria for Adverse Events grade ≥3 persisting >24 h) by day 42. Secondary endpoints included overall response (OR) and complete response (CR) at day 28 and day 90, need for additional immunosuppression and ectopic tissue formation as detected by computed tomography (CT) on day 90. Analyses were descriptive in intention-to-treat (all treated) and at-risk (alive/on-study) populations. Twenty-four patients received an infusion; median age was 59 years and 66% were male. No TRAEs were observed. One patient experienced transient infusion-related dyspnea. No ectopic tissue formation was detected on CT imaging at day 90. By day 28, 71% of patients demonstrated clinical improvement: 33% achieved CR and 38% achieved a partial response (PR). By day 90, 54% of patients showed improvement (CR 42%, PR 13%). Median time to additional systemic therapy (ruxolitinib ± extracorporeal photopheresis) was 15 days; 75% ultimately required escalation. Median overall survival was 7.0 months for all patients and 30 months for those completing all planned doses. MSCTC-0010 demonstrated an excellent safety profile with no grade ≥3 TRAEs and no ectopic tissue formation. Promising early efficacy-including 71% day 28 OR and 42% day 90 CR in a population with historically poor outcomes-supports further investigation. A randomized multicenter phase 2 trial combining or sequencing MSCTC-0010 with ruxolitinib is warranted to clarify its therapeutic contribution in HR/SR aGVHD.