Safety of autologous freshly expanded mesenchymal stromal cells for the treatment of graft-versus-host disease

Abstract

Despite the curative potential of hematopoietic cell transplantation (HCT) for hematologic malignancies, graft-versus-host disease (GVHD) remains a substantial cause of morbidity and mortality, particularly if treatment is refractory. Treatment with additional immunosuppression including steroids often leads to opportunistic infections and organ dysfunction. Novel therapies are greatly needed, specifically ones that lead to responses in treatment-refractory patients and are better tolerated. Mesenchymal stromal cells (MSCs) are non-hematopoietic tolerogenic cells present in normal bone marrow (BM), which can be expanded ex vivo to therapeutic doses. Their safety and efficacy have been assessed in inflammatory disorders including GVHD, but heterogeneity in clinical responses has led some to examine MSC manufacturing and administration procedures, which may impact in vivo efficacy. We hypothesized that autologous, early-passage, and culture-recovered (after freeze and thaw) MSCs would be safe and may have superior efficacy. In this phase I single-center trial, we assessed MSC safety and early efficacy of an escalating number of doses (2 × 106/kg doses; dose level 1, single dose; dose level 2, two weekly doses; dose level 3, four weekly doses) in patients aged ≥12 years with treatment-refractory acute or chronic GVHD. Eleven enrolled patients received some or all planned MSC infusions, with a median age at enrollment of 37 years. The most common primary HCT indication was leukemia, and the median time from HCT to first MSC infusion was 2.6 years. MSC infusion was well tolerated, with all severe adverse events expected and determined to be unlikely or definitely not related to the study. Thus, no dose-limiting toxicities occurred in the three dose levels. Three of four patients with acute GVHD (or overlap with acute features) had responses seen at any timepoint, ranging from partial to complete. In those with a chronic GVHD indication (n = 7), an overall response at 3 months was partial in five, stable in one, and progressive in one. No appreciable differences were seen between dose levels in peripheral blood lymphocyte subsets. In conclusion, autologous and culture-recovered MSCs were safe in the setting of refractory GVHD following HCT for hematologic malignancy, and clinical responses were most notable in patients with acute GVHD.

Keywords: Hematologic malignancy; Mesechymal stromal cell; acute graft versus host disease (aGVHD); allogeneic transplant of haematopoietic stem cells; chronic graft versus host disease (GVHD).

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2022 Stenger, Giver, Langston, Kota, Das, Chinnadurai, Galipeau, Waller and Qayed.

Figures

Figure 1

Frequency of AEs following autologous MSC infusion as treatment for refractory GVHD post-HCT for malignant disease. Targeted AEs (A) were captured within 7 days of each MSC infusion. Allergic reaction/hypersensitivity, sinus bradycardia, hypotension, rigors/chills, renal, and hypoxia are not shown, as no events occurred. The most common targeted AE was grade 1 or 2 hypertension, with four events occurring in one patient (16). Sinus tachycardia events were all grade 1, with two events occurring in patient 12 and four events occurring in patient 15. All dyspnea events occurred in two patients (n = 2 in patient 7, n = 4 in patient 16). Only three AEs were attributed to study participation: grade 1 rash possibly related, grade 1 rash possibly related, and grade 2 hypertension (30 min after MSC infusion) probably related. SAEs (B) were captured for 1 year, with the most common SAE being sepsis (n = 4). Death occurred in two patients (patients 5 and 6, due to GVHD and pneumonia and respiratory failure, respectively). All SAEs were expected and were not attributed (unlikely or definitely not related) to study participation. Gr., grade; GVHD, graft-versus-host disease; AEs, adverse events; MSC, mesenchymal stromal cell; HCT, hematopoietic cell transplantation; SAEs, severe AEs.

Figure 2

Chronic GVHD organ-specific responses following autologous MSC infusion. Organ-specific responses were assessed at 3 months (A) and 6 months (B) from first MSC infusion in six patients with primary indication of chronic GVHD regardless of dose level. CR was seen in a subset of patients with GI and lung involvement at both timepoints; otherwise, most patients had PR or SD in all organs. The proportion of patients with PD was highest in the GI system (50% at both 3 and 6 months), with a smaller proportion in joints/fascia, mouth (3 months only), and PS (3 months only) systems. Mo, months; GI, gastrointestinal; PS, performance score; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; GVHD, graft-versus-host disease; MSC, mesenchymal stromal cell.

Figure 3

Longitudinal immune profile following autologous MSC infusion. Flow cytometry was performed to evaluate lymphocyte subsets (CD3+CD4+ and CD3+CD8+; A, B), T-cell activation (CD69+; C, D), and regulatory T cells (E) longitudinally. Data (mean, SD) are shown by dose level, with timing of MSC infusion designated by arrows. The proportion of activated T cells was lowest at day 29 in dose level 3, although T-cell activation was higher at baseline in dose level 1. No significant differences were otherwise seen by dose level in T-cell counts or proportion of regulatory T cells. MSC, mesenchymal stromal cell; SD, standard deviation.