Enhancing the Efficacy of Mesenchymal Stromal Cells in COVID-19–related Acute Respiratory Distress Syndrome

Mesenchymal stromal cells (MSCs) have garnered considerable attention as a potential therapeutic option for patients with acute respiratory distress syndrome (ARDS) because of their capacity to modulate inflammation and promote tissue repair (1, 2). In this editorial, we summarize the noteworthy findings of a study published in this issue of the Journal by Gorman and colleagues (pp. 256–269) on patients with coronavirus disease (COVID-19)-related ARDS (3). We discuss the implications of this study for the field and propose a potential strategy to enhance the likelihood of MSCs fulfilling their promise to improve outcomes in patients with ARDS.

The Study by Gorman and Colleagues

Gorman and colleagues conducted a multicenter, randomized, double-blind, placebo-controlled trial to investigate the safety and efficacy of a single dose of 400 × 10⁶ cells (ORBCEL-C), a CD362-enriched, umbilical cord–derived MSC product, in 60 patients with moderate-to-severe COVID-19–related ARDS. The primary outcomes assessed were the incidence of serious adverse events (safety) and the oxygenation index (efficacy) at Day 7. Secondary outcomes included respiratory compliance, driving pressure, Pa_O2/Fi_O2 ratio, and Sequential Organ Failure Assessment score, as well as clinical outcomes such as ventilation duration, length of ICU and hospital stays, mortality, and long-term follow-up measures.

The study yielded encouraging results regarding the safety profile of ORBCEL-C, demonstrating no significant difference in the incidence of serious adverse events compared with placebo. In addition, transcriptomic analysis of peripheral blood samples provided evidence that the ORBCEL-C was active in modulating the peripheral blood transcriptome. However, despite the administration of a very large single dose of MSCs, there were no significant differences in the Day 7 oxygenation index, most secondary outcomes (including surrogate markers of pulmonary dysfunction), and mortality rates at various time points up to 2 years.

Dosing, Sex Disparity, and Subgroup Analysis

A key question is why this study was negative, considering the substantial body of basic science evidence suggesting the efficacy of MSCs in acute lung injury. Several potential explanations exist—aside from the possibility that MSCs simply lack efficacy in COVID-19 ARDS. First, it is possible that the specific dose of ORBCEL-C used, although large, was still insufficient to exert significant therapeutic effects in this patient population. The heterogeneity of the baseline characteristics, biology, physiology, and pathology among patients with ARDS may lead to variability in treatment response, necessitating individualized dosing strategies (4, 5). Second, the effectiveness of MSC therapy may be influenced by factors beyond dosage, including the timing of administration and the local microenvironment within the lungs (6). For example, the function of MSCs can be compromised by unfavorable metabolic conditions, such as acidosis, which are commonly observed in injured lungs (7). Third, the observed sex disparity in COVID-19 outcomes, with higher mortality rates in males, has been observed globally (5). In the study by Gorman and colleagues, 80% of participants in the ORBCEL-C group were male (similar to other studies). Considering the observed heightened inflammatory responses (IL-6, IL-8, MCP-1, GRO, sCD40L, and MIP-1β) in males compared with females, even when matched for COVID-19 severity (8), and preclinical research highlighting the crucial role of the overwhelming inflammatory lung environment in determining outcomes during MSC administration (6), it is possible that sex-specific effects of ORBCEL-C therapy may have been present. Further research with a larger sample size would be required to assess this hypothesis.

Limitations

Although the study by Gorman and colleagues was executed meticulously, incorporating blinding, randomization, biological analyses, and long-term follow-up, it is important to acknowledge several limitations. The study did not report cytokine levels before and after MSC treatment, including the pivotal inflammatory cytokine IL-6 implicated in COVID-19 ARDS. The absence of IL-6 blockade might have influenced the observed outcomes (2, 9). In addition, transcriptomic profiles obtained from peripheral blood samples were not extensively described in this publication, leaving a gap in our understanding of potential biomarkers that could guide MSC therapy. Further analysis of the transcriptomic data, including IL-6, fibronectin, and total antioxidant capacity levels (6), could provide valuable insights into patient-specific responses to MSCs and help identify potential responders.

Future Directions

Based on the results, we suggest the following future directions (Figure 1):

• 1.Pulmonary microenvironment: Understanding the individual patient’s pulmonary microenvironment is likely important to help identify potential responders to MSC therapy in ARDS (6). Factors such as cytokine and growth factor secretion and oxidative stress levels can influence the immunomodulatory effects of MSCs and identify patients likely to respond (6, 9, 10). Modifying the microenvironment, for example, by activating antioxidant enzymes (6) and correcting the acidic conditions in the lungs (7) before administering MSCs may be beneficial in patients in whom the pulmonary microenvironment is considered unfavorable for cell therapy. The use of second-generation bioengineered MSCs incorporating genes targeting specific risk molecules could also confer advantages (6, 10). Detailed transcriptomic analyses, similar to those performed in this study, coupled with statistical tools addressing heterogeneous treatment effects (11), can provide valuable insights into the patients most likely to respond.
• 2.Dose and route of administration: Ascertaining the appropriate dosage of MSCs and the most suitable route of administration (i.e., intravenous infusion, inhalation, or direct lung delivery) based on factors such as target site, safety, and efficacy is vital to achieving optimal responses. Exploring different dosing strategies, including fractionated doses or multiple administrations, and conducting studies involving large patient cohorts, albeit challenging, would be extremely helpful.
• 3.Patient heterogeneity and characteristics: Assessing heterogeneous treatment effects based on clinical variables (e.g., severity, sex) alongside biomarkers would be helpful, including investigating sex hormone levels, immune response markers, and comorbidities. Evaluating whether baseline transcriptomic profiles differ between sexes and influence treatment response would also be pertinent.
• 4.Potential benefits of combining MSC therapy: Investigating combination therapies, such as the concurrent administration of ORBCEL-C with other therapeutic agents or interventions (12), could enhance the efficacy of MSC therapy. Combination therapies targeting multiple aspects of ARDS, encompassing inflammation, immune dysregulation, and tissue repair and regeneration, may yield synergistic effects and improve patient outcomes.

Figure 1.

Suggested future lines of research for MSCs in patients with acute respiratory distress syndrome. MSCs = mesenchymal stromal cells.

In conclusion, the study by Gorman and colleagues provides valuable insights into the safety and efficacy of ORBCEL-C in COVID-19–related ARDS. Although the majority of clinical studies using MSCs thus far have yielded somewhat disappointing results, further research focused on the importance of the lung microenvironment, the identification of potential responders, and the exploration of combination therapies may help fulfill the promise generated by groundbreaking basic studies on MSCs in acute lung injury.