Small umbilical cord stem cell COVID-19 trial: sign of efficacy?

A new paper today in Stem Cells Translational Medicine on a small COVID-19 Phase 1/2a trial using an umbilical cord stem cell product reports a surprising degree of possible efficacy. What’s the scoop here and could there be some hype in the media about this new study such as one of the authors describing the cells as “smart bomb technology in the lung”?

Study of umbilical cord stem cell infusions for COVID-19

umbilical-cord-blood, umbilical cord blood stem cells
A unit of umbilical cord blood. Umbilical cord blood stem cell products could have a number of useful properties. Some researchers, including the authors of the study that is the focus of today’s post, harvest stem/stromal stem cells from the cord itself.

The paper comes from the University of Miami and a team led by Camillo Ricordi.

Even as a skeptic of this approach, I’d say that these are somewhat encouraging results and it’s admittedly not what I expected. It seems almost too good to be true to me, but let’s take a step-by-step approach to thinking it through.

See some important caveats toward the bottom of this post that suggest some caution is needed and we shouldn’t overinterpret the results.

But first, here are the key take-homes from the study and paper:

  • This was a double-blind, placebo-controlled phase 1/2a with a primary objective to study safety, but also looking toward potential efficacy.
  • 12 control and 12 treatment group participants.
  • Two infusions of 100 million umbilical cord mesenchymal stem /stromal cells were delivered within three days so a total of 200 million cells. Control subjects just got placebo (vehicle).
  • The cells did not seem to be associated with adverse events.
  • Patient survival at one month was 91% in the stem cell treated group versus 42% in the control group.
  • Faster recovery: More than 80% of the treatment group recovered by day 30, while less than 37% of the control group recovered by then.
  • As to possible mechanism, some cytokines had better profiles in the treatment group versus controls, while other cytokines were not significantly changed.
  • Further study would be needed to determine if what this study suggests is a real effect or somehow due to the study design or small group of participants, but the study unto itself is encouraging.
  • Dozens of other trials are ongoing in this area.

Caveats to the study

A major caveat to the new Ricardi group paper is it is a very small (24 participants total) trial not powered to clearly measure efficacy.

knot in the umbilical cord
Human umbilical cord. Creative Commons image. Photographer Scott Granneman reported that despite the knot, mother and baby were fine.

There are also a few issues with the trial structure itself such as the reported changing of inclusion criteria midstream, the somewhat lower 02 in the control group to begin with, and a major difference in obesity prevalence in the groups, although it was the treatment group (that fared better) that was more obese.

Based on various reports, one might suppose a group with more obesity might have worse COVID-19. However, we can’t just assume that’s true within a group of 24 people and it’s hypothetically possible that somehow obesity was protective in this instance.

We’ll have to see how other trials turn out.

As an update, a reader has pointed out several more things to consider for this study. The treatment group had quite a few more female participants (who tend to fair better with COVID) and other than obesity, this group was healthier to start with as compared to controls related to hypertension, heart disease, diabetes, and cancer (all of which were higher in the control group, and can be associated with worst COVID outcomes.)

Danger of hype here, looking ahead for cells for COVID-19

Dr.-Camillo-Ricordi
Dr. Camillo Ricordi, senior author of the new study.

The recent bad news for Mesoblast on its MSC trial for COVID-19 had cast some gloom over this area, but what should we think about this new cord blood stem cell report and should it spark more optimism?

It’s hard to say until we see more data and from bigger trials so caution would be wise.

Ricordi was quoted in one media report on their new research in a way that seems way over the top to me (emphasis mine):

“It seemed to me that these stem cells could be an ideal treatment option for severe COVID-19,” said Dr. Ricordi, Stacy Joy Goodman Professor of Surgery, Distinguished Professor of Medicine, and professor of biomedical engineering, microbiology and immunology. “It requires only an intravenous (IV) infusion, like a blood transfusion. It’s like smart bomb technology in the lung to restore normal immune response and reverse life-threatening complications.”

Smart bomb tech?

One of the challenges we sometimes see in the stem cell field is the tendency to want to endow certain stem cells with almost superhero-like powers that can be applied to many diverse diseases. To me at least, that doesn’t always add up.

Overall this new small study is the most encouraging results we’ve seen on the cellular medicine for COVID-19 front, but there are good reasons for wanting a lot more data before coming to any conclusions.

A next step for the team is to see if the umbilical cord cell product can stop disease progression in COVID-19 patients.

12 thoughts on “Small umbilical cord stem cell COVID-19 trial: sign of efficacy?”

  1. The negative tone of your comments is disappointing Paul. Sure there are a small number of patients in this study but the results support the discussion by the authors. And like ALL small phase I/IIa trials, they are meant to provide insight into designing larger phase IIb studies.

    And for clarity, the Mesoblast study terminated because the study DMB concluded the study would not achieve the primary endpoint of survival. This was largely due to the change in in treatment of Covid patients with steroids and other therapies. Like most diseases we learn more with time. The challenge for Mesoblast is defining at what stage and which patients can benefit from MSC treatment.

    The Niche you publish would benefit from a less biased approach in your writing. It is clear in a number of your articles you enjoy seeing products fail.

  2. @admin. Did you even bother to read their paper? They didn’t use cord blood.

    “A next step for the team is to see if the umbilical cord blood product can stop disease progression in COVID-19 patients.”

  3. @admin. Are you seriously postulating that obesity is protective for COVID? Your bias is showing once again. Not a good look.

    “and it’s hypothetically possible that somehow obesity was protective in this instance.”

  4. Giacomo Lanzoni and Camillo Ricordi

    Thank you Dr. Knoepfler and colleagues for your comments.

    We believe that these are very encouraging results, and larger clinical trials will provide a clearer estimate of efficacy.

    We are extremely enthusiastic about these results. The study clearly indicates that these MSC decrease the hyper inflammatory response and cytokine storm associated with severe cases of COVID-19. The results as far as patient survival at 1 month (91% for all ages, 100% for age below 85) and faster time to recovery in the UC-MSC treatment group are unprecedented and, to our knowledge, unmatched by any other treatment so far reported in randomized controlled trials. The fact that the results are statistically significant despite the small size of the clinical trial (24 subjects) is remarkable and warrants further investigation. This was designed to be an academic non-profit safety trial with early analyses for signs of efficacy, but the observations are indeed very encouraging! Hence, we have submitted to FDA an IND for a larger multi-site trial that will include 120 subjects with a 2:1 randomization. We will also continue to provide these UC-MSC for compassionate use to centers requesting them, at no charge until allowed by philanthropic or other sources of non-profit funding.

    Our results also support the powerful anti-inflammatory, immunomodulatory effect of UC-MSC. These cells have clearly inhibited the ‘cytokine storm,’ a hallmark of severe COVID-19. 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.

    Concerning the terminology to describe the cells, we don`t have a preference – but Mesenchymal Stem Cells, or Mesenchymal Stromal Cells, or Medicinal Signaling Cells have been used.

    @Paul, in relation to your point on the changing of inclusion criteria midstream, it is important to highlight the fact that the study started in April 2020, and the treatment patterns of COVID-19 ARDS patients changed substantially around June 2020 – with decreased use of invasive mechanical ventilation and increased use of noninvasive mechanical ventilation (e.g., high flow oxygen became broadly used).
    The change in inclusion criteria resulted from the above-mentioned change in standard of care.

    From the manuscript: “The study was initially designed to enroll patients receiving invasive mechanical ventilation. At the time of study inception, there were concerns regarding the potential for high flow oxygen therapy and noninvasive mechanical ventilation to increase aerosolization and infection risk in health care workers. Such concerns led practitioners to avoid these therapies and prompted infection control leadership to restrict them in our study sites. Subsequent studies called these concerns into question (reference 49 on the manuscript) and high flow oxygen became broadly used. At that time, it appeared appropriate to include in our trial patients of similar disease severity but who were being treated with a different modality, and on 22 June 2020, we made a change in our inclusion criteria to reflect this. Subsequent studies have shown that high flow oxygen therapy is associated with a reduction in the proportion of patients who receive invasive mechanical ventilation, but no difference in mortality (reference 12). This supports the idea that the change of inclusion criteria did not necessarily alter the severity of patients enrolled but rather just reflects the secular trends and treatment patterns in the care of patients with a novel disease.”

    It is indeed difficult to avoid small imbalances at baseline between groups of 12 subjects.

    As stated in the manuscript, “This study was not intended as an efficacy trial, but instead as an early phase study to establish safety. We relied on randomization to protect against imbalance in biasing preliminary estimates of efficacy. Stratified, blocked randomization was employed to evenly represent ARDS severity and changing standard of care over time between groups. Even with blocked randomization, confounding may exist because, with small numbers, there is still potential for imbalance” … “The inferences we make from the efficacy results observed in this phase 1/2a trial in 24 subjects, including the outcome of survival, are still subject to limitations of sample size and potential bias because of factors we were not yet aware of. However, results do provide preliminary evidence of a remarkable effect, which substantiates the need for further investigation in a larger, stratified, and adjusted clinical trial.”

    Hence, we are now working on a new larger study to rigorously validate the hypothesis and estimate efficacy.

    Giacomo Lanzoni and Camillo Ricordi

    P.S. The image in the post is not relevant to our publication: we did not use umbilical cord blood, but MSCs derived and expanded from the subepithelial lining of the Umbilical Cord.

    1. Dear Drs. Lanzoni and Ricordi,
      Thank you for your comments and clarifications. I will be curious to see the outcome of the larger study.
      In response to your PS, which is a good point, I have updated the post itself to include a new photo of an actual umbilical cord and noted in the caption for the cord blood image that you used cells from the cord itself. Hopefully this avoids any confusion for readers.
      Paul

  5. Great promising results. But MSCs are not stem cells, better termed as ‘stromal cells’ and exist mostly as pericytes in vivo. MSCs have the ability to ‘rejuvenate’ multiple diseased tissues by providing conducive ‘paracrine support’ to tissue resident stem/progenitor cells that ensure ‘regeneration’. In the present study, MSCs supported regeneration of lungs epithelium damaged by the virus. Since ability to regenerate decreases with age, aged people are more vulnerable to the infection. We have similarly shown VSELs survive chemotherapy in adult mouse testes, increase in numbers to regain homeostasis but are unable to do so as the niche gets compromised by chemotherapy. We published microarray data to support this. Spermatogenesis was restored upon transplantation of bone marrow MSCs or healthy Sertoli cells. GFP positive cells were transplanted and all the sperm were non-green.Similarly VSELs survive in testicular biopsies of adult, azoospermic cancer survivors of childhood cancer. It will be great if someone could study stem cells status in the COVID infected lungs tissue and in peripheral blood of COVID patients. It is crucial to think of stem cells along with their niche for regeneration to occur. Our two articles PMID: 27663915 and PMID: 26553338

  6. @Paul, Although the trial was small, statistically significant p values were hit on various endpoints that can be found in the paper:

    “No serious adverse events (SAEs) were observed related to UC‐MSC infusions. UC‐MSC infusions in COVID‐19 ARDS were found to be safe. Inflammatory cytokines were significantly decreased in UC‐MSC‐treated subjects at day 6. Treatment was associated with significantly improved patient survival (91% vs 42%, P = .015), SAE‐free survival (P = .008), and time to recovery (P = .03). UC‐MSC infusions are safe and could be beneficial in treating subjects with COVID‐19 ARDS.”

    https://stemcellsjournals.onlinelibrary.wiley.com/doi/full/10.1002/sctm.20-0472

    I would say that this is pretty encouraging.

    1. @WST,
      The data they present are surprisingly positive, but we should be cautious because of the small size and other caveats I mentioned, which I’ve now updated to include more.

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