Cell-Based Therapy Under Evaluation for the Treatment of COVID-19

Mesenchymal Stem Cells

Mesenchymal stem cells are investigational products that have been studied extensively for broad clinical applications in regenerative medicine¹ and for their immunomodulatory properties.² It is hypothesized that mesenchymal stem cells could reduce the acute lung injury and inhibit the cell-mediated inflammatory response induced by SARS-CoV-2.

Recommendation

• The COVID-19 Treatment Guidelines Panel recommends against the use of mesenchymal stem cells for the treatment of COVID-19, except in a clinical trial (AIIb).

Rationale for Recommendation

No mesenchymal stem cells products are approved by the Food and Drug Administration (FDA) for the treatment of COVID-19. There are limited data to date to assess the role of mesenchymal stem cells for the treatment of COVID-19.

The FDA has recently issued several warnings about patients being vulnerable to stem cell treatments that are illegal and potentially harmful.³ Several umbilical cord blood-derived products are currently licensed by the FDA for indications such as the treatment of cancer (e.g., stem cell transplant) or rare genetic diseases, and as scaffolding for cartilage defects and wound beds. None of these products are approved for the treatment of COVID-19 or any other viral disease.⁴ In the United States, mesenchymal stem cells should not be used for the treatment of COVID-19 outside of an FDA-approved clinical trial, expanded access program, or an Emergency Investigational New Drug application (AIIb).

Rationale for Use in COVID-19

Mesenchymal stem cells are multipotent adult stem cells that are present in most human tissues, including the umbilical cord. Mesenchymal stem cells can self-renew by dividing and can differentiate into multiple types of tissues (including osteoblasts, chondroblasts, adipocytes, hepatocytes, and others), which has led to a robust clinical research agenda in regenerative medicine. It is hypothesized that mesenchymal stem cells could reduce the acute lung injury and inhibit the cell-mediated inflammatory response induced by SARS-CoV-2. Furthermore, because they lack the angiotensin-converting enzyme 2 (ACE2) receptor that SARS-CoV-2 uses for viral entry into cells, mesenchymal stem cells are resistant to infection.^5,6

Clinical Data

Data supporting the use of mesenchymal stem cells in patients who have viral infections, including SARS-CoV-2 infection, are limited to case reports and small, open-label studies.

Clinical Data for COVID-19

A pilot study of intravenous mesenchymal stem cell transplantation in China enrolled 10 patients with confirmed COVID-19 categorized according to the National Health Commission of China criteria as critical, severe, or common type. Seven patients (one with critical illness, four with severe illness, and two with common-type illness) received mesenchymal stem cells; three patients with severe illness received placebo. All seven patients who received mesenchymal stem cells recovered. Among the three severely ill placebo-treated patients, one died, one developed acute respiratory distress syndrome (ARDS), and one remained stable with severe disease.⁷

A small clinical trial evaluated human umbilical cord mesenchymal stem cell (hUC-MSC) infusion in patients with severe COVID-19 who had not responded to standard of care therapies after 7 to 10 days of treatment. The standard of care therapies included supplemental oxygen, umifenovir/oseltamivir, antibiotics if indicated, and glucocorticoids. The study was intended as a randomized controlled trial; however, due to the lack of sufficient hUC-MSCs, it was not possible to randomize the participants as originally planned. Among the 41 patients eligible to participate in the study, 12 received hUC-MSC infusion and 29 received standard of care therapies only. The study arms were well balanced with regard to demographic characteristics, laboratory test results, and disease severity. All 12 participants who received hUC-MSC infusion recovered without requiring mechanical ventilation and were discharged to home. Four patients who received only standard of care therapies progressed to critical illness requiring mechanical ventilation; three of these patients died. These results are not statistically significant, and interpretation of the findings is limited by the study’s lack of randomization and small sample size.⁸

A double-blind randomized controlled trial investigated the safety and efficacy of hUC-MSC infusions in patients with COVID-19 ARDS. Twenty-four patients were randomized to receive either two infusions of hUC-MSC (prepared at a single site) or placebo on Day 0 and Day 3. The primary endpoints were occurrence of prespecified infusion-associated adverse events within 6 hours of each hUC-MSC infusion; cardiac arrest or death within 24 hours after an infusion; and the incidence of adverse events. Secondary endpoints included survival at 31 days after hUC-MSC infusion and time to recovery.⁹

There were no differences between the arms in the primary safety analysis; however, more deaths occurred in the placebo arm (7 deaths) than in the hUC-MSC arm (2 deaths) by Day 31. Data for one participant in the hUC-MSC arm who died due to a failed intubation was censored from the analysis. Time to recovery was shorter in the hUC-MSC arm than in the placebo arm (HR 0.29; 95% CI, 0.09–0.95). Interpretation of these results is limited by the small sample size and a change in an eligibility criterion from enrolling only individuals on invasive mechanical ventilation to including those receiving high-flow oxygen or on noninvasive ventilation.

Clinical Data for Other Viral Infections

In an open-label study of mesenchymal stem cells for the treatment of H7N9 influenza in China, 17 patients received mesenchymal stem cell treatment plus standard of care, and 44 patients received standard of care only. Three patients (17.6%) in the mesenchymal stem cell arm died versus 24 patients (54.5%) in the standard of care arm. The 5-year follow-up was limited to five patients in the mesenchymal stem cell arm. No safety concerns were identified.¹⁰

Clinical Trials

See ClinicalTrials.gov for a list of clinical trials evaluating mesenchymal stem cells for the treatment of COVID-19, COVID-19-related ARDS, and COVID-19-associated multisystem inflammatory syndrome in children (MIS-C).

Adverse Effects

Risks associated with mesenchymal stem cell transfusion appear to be uncommon. The potential risks include the potential for mesenchymal stem cells to multiply or change into inappropriate cell types, product contamination, growth of tumors, infections, thrombus formation, and administration site reactions.¹¹

Considerations in Pregnancy

There are insufficient data to assess the risk of using mesenchymal stem cell therapy during pregnancy.

Considerations in Children

There are insufficient data to assess the efficacy and safety of using mesenchymal stem cell therapy in children.