Back in April, during the onset of pandemic in the United States, TrialSite reported that the U.S. Food and Drug Administration (FDA) has granted immediate authorization for a mesenchymal stem cell-based study led by Dr. Camillo Ricordi with University of Miami Miller School of Medicine, Jackson Health System and a group known as the Cure Alliance. The 24 participant study involved the testing of the safety and exploratory efficacy of umbilical cord-derived mesenchymal stem cells (UC-MSCs) to block the life-threatening lung inflammation that can accompany severe cases of COVID-19. This same regenerative therapy has been shown to reduce the risk of death and accelerate time to recovery for the severest COVID-19 patients. The study, published in the journal Stem Cells Translational Medicine Review this month. The study results, although preliminary due to study limitations, including size, and prospect of bias, evidence a remarkable impact pointing to the rationale for larger studies. The completion of this study was funded by the North American Building Trades Unions.
The Investigational Product
The study involved the use of umbilical cord-derived mesenchymal stem cells (UC-MSCs). A form of regenerative therapy, these are adult stem cells derived from umbilical cord, that can transform into other types of cells, including bone, cartilage, muscle, neural, skin, and corneal cells. The medical community has known of the existence of these MSCs for a long time, however only since recent advancements have researchers been able to activate and supplement these cells to treat a variety of conditions.
For a long time, researchers believed these MSCs only existed within bone marrow. However, recently they have discovered a number of sources for these stem cells exist, including umbilical cord tissue, body fat, molar teeth and amniotic fluid. MSCs have demonstrated the ability to avoid a negative response from a person’s immune system, allowing the cells to be transplanted in a wide range of patients without rejection. Hence, they are under investigation to treat a wide range of therapeutic issues, including COVID-19. They may not provide a technical cure but rather augment the body to heal and mitigate symptoms for an extended period of time.
As Dr. Ricordi recently declared in the EurekAlert! press release, “The umbilical cord contains progenitor stem cells, or mesenchymal stem cells, that can be expanded and provide therapeutic doses for over 10,000 patients from a single umbilical cord. It’s a unique resource of cells that are under investigation for their possible use in cell therapy applications, anytime you have to modulate immune response or inflammatory response.” He said, “We’ve been studying them with our collaborators in China for more than 10 years in Type 1 Diabetes, and there are currently over 260 clinical trials listed in clinicaltrials.gov for treatment of other autoimmune diseases.”
This Phase 1/2 study (NCT04355728) involved the investigation into the safety and efficacy of human umbilical cord derived mesenchymal stem cells (UC-MSC) for the treatment of COVID-19 patients with severe complications of acute lung injury/Acute Respiratory Distress Syndrome (ALI/ARDS). Involving 24 patients the study stated late April 2020 and ran till October 31, 2020.
The study’s experimental group included umbilical cord Mesenchymal Stem Cells plus Heparin along with best supportive care. The UC-MSC was administered at 100X10^6 cells/infusion administered intravenously in addition to the standard of care treatment while the placebo group involved Heparin along with the best supportive care. This study was led by Dr. Ricordi with the Diabetes Research Institute (DRI) and Cell Transplant Center at the University of Miami Miller School of Medicine.
According to the recent published research, the patients with COVID-19 hospitalized at University of Miami Tower or Jackson Memorial Hospital and who had developed severe acute respiratory distress syndrome received two infusions given days apart of either the mesenchymal stem cells or placebo.
The double-blind study meant that the study team wasn’t aware which patient received the investigational product versus the placebo, reported Dr. Ricordi. He shared that, “Two infusions of 100 million stem cells were delivered within three days, for a total of 200 million cells in each subject in the treatment group.”
Patient survival at one month was 91% in the stem cell treated group versus 42% in the control group. Among those patients under 85 years of age, 100% of them treated with the regenerative therapy survived for one month. Moreover time to recovery was faster among the treatment arm over the placebo arm of the study. For example, over half of the patients treated with the mesenchymal stem cell infusions recovered and went home from the hospital within two weeks after their last treatment. Over 80% of the treatment group (again group infused with the mesenchymal stem cells) recovered by day 30, versus less than 37% in the control group.
The study team disclosed that there were two (2) serious adverse events (SAEs) observed in the UC-MSC group and 16 SAEs in the control group. Moreover, the authors point out that the results from this study (and others) suggest exploration of “synergistic combination strategies” such as the use of dexamethasone and convalescent plasma.
Additional Benefits of MSCs
Another author and professor at the Diabetes Research Institute, Dr. Giacomo Lanzoni, PhD, reported “Our results confirm the powerful anti-inflammatory, immunomodulatory effect of UC-MSC. These cells have clearly inhibited the ‘cytokine storm’, a hallmark of severe COVID-19,” said Giacomo Lanzoni, Ph.D, lead author of the paper and assistant research professor at the Diabetes Research Institute. “The results are critically important not only for COVID-19 but also for other diseases characterized by aberrant and hyperinflammatory immune responses, such as autoimmune Type 1 diabetes.
Apparently, when given intravenously MSCs migrate naturally to the lungs. That happens to be where therapy is needed in COVID-19 patients with acute respiratory distress syndrome, the dangerous complication associated with intense inflammation and fluid build up in the lungs.
The Cure Alliance offered the funding necessary for the launch of the trial while a $3 million grant from the North American Building Trades Unions (NABTU) allowed. Dr. Ricordi and colleagues to complete the clinical trial and expand research with mesenchymal stem cells.
Apparently, this union has supported the Diabetes Research Institute since 1984 when they initiated a campaign to fund and build a state-of-the-art research and treatment facility. Other groups involved with support included the Barilla Group and Family, The Fondazione Silvio Tronchetti Provera, the Simkins Family Foundation and the Diabetes Research Institute. The National Center for Advancing Translational Sciences also supported the study.
The next step is to study use of the stem cells in COVID-19 patients who have not yet become severely ill but are at risk of having to be intubated, to determine if the infusions prevent disease progression.
Other Research Opportunity
Dr. Ricordi suggests other areas ripe for research include hyper-immune with hyper-inflammatory responses in autoimmune diseases might share a common thread with why some COVID-19 patients transition to severe forms of the disease and others don’t.
This study had a small sample size, hence further studies with more power will be necessary. Moreover, potential bias exists due to factors researchers are not aware of as of yet.
Giacomo Lanzoni, Ph.D, lead author of the paper and assistant research professor at the Diabetes Research Institute
A number of other authors were involved and can be viewed at the source.
Call to Action: TrialSite will continue to follow the work of Dr. Ricordi as well as other relevant MSC-based trials.