Graft-versus-host disease (GvHD), a life-threatening complication of allogeneic hematopoietic stem cell transplantation (HSCT), presents a significant clinical challenge. While mesenchymal stromal cells (MSCs) hold promise as an immunomodulatory therapy for GvHD, their inconsistent efficacy stems from the limitations of using primary donor-derived MSCs. The variability in MSC populations from different donors, coupled with the need for extensive ex vivo expansion to achieve therapeutic doses, leads to unpredictable product quality and suboptimal outcomes. The process of ex vivo expansion often results in functional changes and replicative senescence in MSCs, limiting their therapeutic potential. Induced pluripotent stem cell (iPS)-derived MSCs offer a potential solution by providing a scalable and consistent source of cells. This study investigates the long-term safety profile of iPS cell-derived MSCs (CYP-001) in treating steroid-resistant acute GvHD, addressing the limitations of donor-derived MSCs and paving the way for a readily available and consistent MSC-based therapy.

Existing literature highlights the inconsistencies in the efficacy of MSC therapies for GvHD, primarily due to the challenges associated with using donor-derived MSCs. The significant variability in MSC populations across donors, coupled with the requirement for extensive ex vivo culture expansion to achieve therapeutic cell numbers, introduces unpredictability and compromises therapeutic outcomes. The inherent inter-donor variability in MSCs affects their immune modulatory capabilities, impacting their ability to express crucial factors like indoleamine 2,3-dioxygenase, which plays a key role in suppressing T cell proliferation. Studies using MSCs from various tissue sources have demonstrated varying degrees of success in treating steroid-resistant acute GvHD, with 2-year overall survival rates ranging widely from 0% to 40%. The Janus kinase inhibitor ruxolitinib has shown promise, but its long-term survival data remains limited. The use of iPS cells offers a promising alternative for consistent, large-scale manufacturing of MSCs, overcoming limitations associated with donor variability and the need for extensive culture expansion.

This Phase I, multicenter, open-label, dose-escalation study (ClinicalTrials.gov registration: NCT02923375) evaluated the safety and efficacy of CYP-001 in adults with steroid-resistant acute GvHD after allogeneic HSCT. Fifteen participants were enrolled across seven centers in the UK and Australia. Participants were divided into two cohorts (A and B) receiving two intravenous infusions of CYP-001 on days 0 and 7 at doses of 1 × 10⁶ cells/kg and 2 × 10⁶ cells/kg, respectively. All participants received standard-of-care aGvHD medications. The primary evaluation period concluded at day 100, followed by a 2-year extended follow-up period with 6-monthly assessments of survival status, GvHD grade, additional treatments, malignancy status, and adverse events. Data analysis was performed using SAS v.9.4, and Kaplan-Meier curves were generated using Prism 10. The study was conducted in accordance with ICH-GCP guidelines and ethical principles.

CYP-001 was well-tolerated with no serious adverse events, tumors, or safety concerns related to treatment observed during the two-year follow-up. At two years post-infusion, nine of fifteen participants (60%) survived. Causes of death were consistent with common complications seen in allogeneic HSCT recipients, including relapse, pneumonia, GvHD, and sepsis. The two-year survival rate observed in this study compares favorably with previous reports on steroid-resistant acute GvHD treated with MSCs from other sources (survival rates ranging from 0% to 40%). While three participants experienced acute GvHD symptoms at the 6-month visit, none showed symptoms at 12 months or beyond. Three participants had chronic GvHD at 12 and 24 months, and two at 18 months, receiving additional treatment as needed.

The findings demonstrate the long-term safety and tolerability of iPS cell-derived MSCs (CYP-001) in treating steroid-resistant acute GvHD. The observed two-year survival rate is encouraging and compares favorably to other reported treatments. This suggests that CYP-001 could represent a significant advancement in GvHD treatment, offering a scalable and consistent therapeutic option compared to donor-derived MSCs. The absence of treatment-related serious adverse events, tumors, or other safety concerns supports the safety profile of CYP-001 over a two-year period. This study lays the groundwork for larger-scale clinical trials to further validate these findings and investigate the efficacy and long-term effects of this innovative therapy.

This study provides compelling evidence for the long-term safety and sustained efficacy of CYP-001, an iPS cell-derived MSC therapy, in treating steroid-resistant acute GvHD. The two-year survival rate and absence of treatment-related adverse events highlight the potential of this approach. Further research, particularly larger-scale clinical trials (such as the ongoing global phase II trial, NCT05643638), is needed to confirm these findings and fully elucidate the therapeutic potential of iPS cell-derived MSCs in GvHD management.

This study had a small sample size, limiting the statistical power to detect subtle differences in outcomes. The open-label design could introduce bias. Furthermore, the comparison of survival rates across different studies should be made with caution, given the variability in patient populations, treatment regimens, and assessment methods. Longer-term follow-up would be valuable to assess potential late-onset effects.