For now, stem cells for Covid-19 are mostly a shot in the dark

The uncertainty over how to effectively treat Covid-19 is proving to be an opportunity for people interested in stem cells.

It is such a hot area that there are dozens of clinical trials underway testing different kinds of stem cells and other cells against Covid-19. And many stem cell clinics have started pitching cell therapies for Covid-19 in the past year.

As a stem cell researcher, I don’t think this approach will be a transformative way to treat Covid-19, but I worry that the buzz around it could do harm.

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How did we get into this situation?

In the human body, a skin cell is a skin cell and, when it grows and divides, becomes another skin cell. The same holds for other cell types — except stem cells. One of the amazing things about them is that they can turn into other, specialized cells, some of which have the potential to treat specific diseases. The most powerful stem cells, called pluripotent stem cells, can turn into any kind of cell.

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Adult stem cells, which also have big promise but aren’t quite so flexible, are also often mistakenly thrown under the same broad powerful “stem cell” umbrella.

As a result, many people believe that stem cells in general can turn into any kind of useful cell. So perhaps it isn’t so surprising that the public — and even some scientists — make the mistake of thinking that stem cells can be used to treat any kind of health problem too, as though they are some kind of universal curative salve.

Not so. The sobering reality is that the FDA has approved relatively few cell and gene therapies, and only a tiny subset of these use bona fide stem cells.

Yet the more harmful or lethal the disease, the greater the odds that “stem cells” are being pitched to fix it. It’s an equation for false hope and other problems like wasted research dollars. The use of stem cells for treating disease also poses health risks that need to be evaluated carefully.

This overexuberance and even hype have been going on now for more than a decade.

Enter Covid-19, which has been like a magnet for wishful thinking about stem cells and cellular medicine.

In just about every stem-cell-related Covid-19 clinical trial being conducted, the specific experimental cellular therapy being thrown at the disease had never before been seriously considered for a viral, or even a respiratory, illness. Before the pandemic emerged, these experimental cellular injections were mostly being studied for conditions such as cancer, heart disease, spinal cord injuries, Parkinson’s disease, and many others. The sponsors of many of those clinical trials made a sharp pivot toward Covid-19.

In the U.S., the Food and Drug Administration made this shift not just possible but actively facilitated it by giving clearance to a vast array of trials. Remarkably, the FDA has done this even though many of the trial sponsors had no relevant preclinical data. Most sponsors and the FDA seem to be relying instead on limited preclinical and clinical data from a few other sponsors. It’s a highly unusual situation.

Based on newly published research that my student, Mina Kim, and I have done on trials registered on ClinicalTrials.gov and its counterpart, the Chinese Clinical Trials Registry, there appears to be a similar turn of events with regulators in China.

The FDA has even gone so far as to give the green light to cellular medicine trials for Covid-19 from some sponsors that are unproven stem cell clinics or have some kind of connection with them, including at least one or more that the agency has previously warned about use of unapproved therapies.

At the heart of this matter is the question of rationale. A single common — but in my view, shaky — rationale is being given for most cellular therapies being tested for Covid-19 around the world. It’s this: In some contexts, cells known as mesenchymal or stromal cells (generally going by the acronym MSCs) have anti-inflammatory and immune suppressing functions. So they might attenuate overactive immune responses to Covid-19, such as the cytokine storms that can cause severe damage to the lungs and other tissues.

To my knowledge, only one stem cell company had any directly relevant data from before the pandemic. Athersys had tested its MultiStem product against acute respiratory distress syndrome, which is a component of severe Covid-19. Although the results were a mixed bag, I’d say that Athersys was justified in proceeding to do a Covid-19 trial with MultiStem, even if it was a bit of a long shot. But dozens of other trials then piggybacked off the Athersys’ data and the general idea that stem cells could reduce inflammation.

In addition, the proposed mechanism by which stem cells quell inflammation greatly overlaps with the proven beneficial mode of action of affordable, generally safe steroids, which are now being widely used to treat Covid-19. With steroids as an accepted standard of care here, how can stem cells do better?

They probably can’t.

And to complicate matters, it’s going to be extremely difficult for stem cell clinical trials to tease apart any stem-cell-specific signals in individual patients from steroid-related benefits.

All of this raises questions for me: Why have dozens of sponsors gone down the clinical trial path to treat Covid-19 using mesenchymal stem cells or cells similar to them? Overexuberance to help stem the pandemic? It’ll be good for the bottom line? Why has the FDA flashed the green light for trials so many times? Politics? Pandemic exceptionalism?

Whatever their reasons, Mina and I found more than 79 cellular medicine trials for Covid-19 listed in the trials databases. That seems excessive.

We also found that most of the Covid-19 cellular medicine trials use MSCs or similar cells, but these aren’t equivalent to each other or to Athersys’ MultiStem product. Athersys has even made a point of saying the cells in MultiStem are not MSCs. Further complicating things, our data show that sponsors are using MSCs extracted from a hodgepodge of sources: blood from the umbilical cord, the wall of the umbilical cord itself, bone marrow, adipose (fat) tissue, and dental pulp. These cells are not interchangeable. They each likely have different potential for effectiveness and pose distinct risks. For instance, preparations of MSCs from different tissues made in separate labs likely contain widely different numbers of true stem cells.

More worrisome, our analysis found that the vast majority of cell therapy trials for Covid-19 do not have rigorous design features to form strong conclusions. In most cases, then, the trials are unlikely to prove conclusive. Larger and more powerful follow up trials will be needed. That’s going to be expensive and time-consuming.

In terms of published clinical trial data, they are few and far between. The FDA recommended recently that Mesoblast stop enrolling participants in its Covid-19 trial using mesenchymal stem cells because the data were not encouraging.

Three recent reports of randomized, double-blind, placebo-controlled trials of MSCs for Covid-19 are worth a look, but the results are mostly unclear. In one, a University of Miami team was quite excited about their data, though a closer look revealed that the trial was too small and the groups too unbalanced to make firm conclusions. A subsequent somewhat larger trial from China was also inconclusive. While a third small study out of Indonesia was somewhat more hopeful, it’s unclear if it was balanced or had sufficient power to form any concrete conclusions.

Based on the research Mina and I did, these three published trials were anticipated to be some of the more rigorous Covid-19 stem cell-related trials of the bunch. Even so, because of various features, especially their small size, they still have not provided clear signals. This doesn’t bode well for clarity from the scores of trials that we predicted to be less powerful in design.

Throwing dozens of cell therapy trials against the Covid-19 wall in hopes of seeing what, if anything, sticks is rife with problems and risks.

Resources are limited, so spending tens or hundreds of millions of dollars on mostly unpromising cellular medicine trials is probably going to be wasteful. Further, participants for these trials likely aren’t available to take part in Covid-19 trials with more promising therapies. And there is also the issue of false hope for the participants, their families, and the public more generally.

A more serious, but perhaps less likely, risk is that these approaches could harm people with Covid-19. For example, if the rationale that stem cells might treat Covid-19 by reducing immune system activity has any chance of being correct, then such a treatment could overshoot. Stem cell therapies could reduce immunity too much, leading to greater spread of virus from cell to cell, or cause other harm in unexpected ways.

With so much unfocused activity already underway, at this point we can only wait and see how this experiment in cellular medicine for Covid-19 turns out. So far, more than a year in, there is not much reason for optimism.

Paul Knoepfler is a professor at the University of California Davis School of Medicine whose research focuses on stem cells and cancer. He writes about ethics, policy, and other matters on his blog, The Niche.


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