Update on stem cells & cell therapy for COVID trials

From the beginning of the pandemic, I have been mostly skeptical about the idea of cell therapy for COVID including stem cell therapies. However, at the same time, I’ve closely followed the data, especially up until 2022.

Now having just had a nasty bout with COVID myself for the first time this summer, I recently circled back to the idea of cell therapy for COVID again.

Where do things stand now? Are there new convincing data?

cell therapy for COVID
EM of SARS-CoV-2, the virus that causes COVID.

Cell therapy for COVID: background

I’ve tried to keep an open mind, but along the way, there have been good reasons for skepticism.

For one thing, the simpler approach of steroids popped up. Treating certain cases of severe COVID with steroids makes such good common sense. Strong data have repeatedly backed that up as well.

The rationale for most cell therapies like MSCs for COVID is based on a similar proposed mechanism as steroids. Tamping down an over-active immune response that is damaging. Could cell therapy help on top of the simpler approach of steroids? By itself could it be better than steroids? To me both of these seemed unlikely.

Another reason for skepticism was the non-optimal designs of many of the clinical trials for COVID. My student Mina Kim and I analyzed the cell therapy clinical trials for COVID-19 out there at one point. We found that the vast majority were not designed or powered to actually come to rigorous, clear conclusions.

In addition to actual living cells, other kinds of cell therapies have been proposed including exosome therapy or extracellular vesicles.

One called ExoFlo is in Phase III trials for COVID now. New data on ExoFlo from the earlier Phase II trial have recently been published.

Update on cell therapy for COVID: mostly discouraging trials

The trial paper was in the journal Chest, Bone Marrow Mesenchymal Stem Cell Derived Extracellular Vesicle Infusion for the Treatment of Respiratory Failure from COVID-19: A Randomized Placebo Controlled Dosing Clinical Trial.

To me, the results are not very encouraging. Overall, the trial found a non-significant (p-0.134) improvement in mortality for people given the investigational exosome therapy.

In posthoc subgroup analysis, they report a mixed bag of results, some apparently significant:

“For the post-hoc subgroup analyses, 60-day mortality was decreased in ExoFlo-15 compared to Placebo (Relative Risk=0.385; 95% confidence interval [CI]=0.159,0.931; p=0.0340; N=50). In ExoFlo-15 a Relative Risk of 0.423 (CI=0.173,1.032; p=0.0588; N=24) was determined for participants aged 18-65 with moderate to severe ARDS. Ventilation-free days (VFDs) improved in ExoFlo-15 (p=0.0455; N=50) for all participants aged 18-65.

They did not observe adverse events so that’s good. The Phase 2 trial also appears to have been rigorous:

“A prospective phase 2 multicenter, double-blind, randomized, placebo-controlled dosing trial was conducted at five sites across the US with infusions of placebo, 10 mL of ExoFlo, or 15 mL of ExoFlo on Day 1 and 4. Patients (102) with COVID-19 associated moderate-to-severe ARDS were enrolled and randomized.”

I didn’t see any mention of steroid treatment given (or not) to the participants so it’s hard to say if some got both ExoFlo and steroids or not.

For background, I previously had concerns about the Phase I COVID trial on ExoFlo. There is also, in my opinion, evidence that the FDA was politically pressured to clear an IND for ExoFlo. The urgency of the pandemic may have also more generally pushed the FDA to move things forward on more trials for COVID.

I’m very curious to see what the Phase 3 ExoFlo COVID trial finds.

An MSC trial found no efficacy

Other recent papers on cell therapy for COVID also have not clearly shown strong efficacy.

For example, another new paper, Human mesenchymal stem cell therapy in severe COVID-19 patients: 2-year follow-up results of a randomized, double-blind, placebo-controlled trial, found no reason to think MSCs are consistently beneficial.

They concluded, “Long-term safety was observed for the COVID-19 patients who received MSC treatment. However, efficacy of MSC treatment was not significantly sustained through the end of the 2-year follow-up period.”

Other cell therapy approaches

More broadly, many of the cell therapy for COVID trials also used MSCs. I haven’t seen much news on other trials in this space lately.

There are or were many out there. In a current search on Clinicaltrials.gov for stem cells for COVID, I found 65 trials.

There are 15 trial listings of exosomes for COVID-19.

Other types of cell therapy approaches including by the biotech Celularity using natural killer cells are still ongoing in clinical trials as far as I know.

By way of update, a new T cell Phase 1/2 study in Nature Medicine looks very promising. The study, SARS-CoV-2-specific T cell therapy for severe COVID-19: a randomized phase 1/2 trial, found signs of strong benefit:

“Overall, in hospitalized patients with severe COVID-19, adoptive immunotherapy with CoV-2-STs was feasible and safe. Larger trials are needed to strengthen the preliminary evidence of clinical benefit in severe COVID-19.”

Looking ahead

At this point, with the pandemic waning, is it worth continuing to pursue cell therapies for COVID? What do you think?

Perhaps there could be specific situations where a cell-based approach is uniquely helpful. However, by the time we see more conclusive late-phase data, will there be any need for a cell therapy for COVID-19?

Right now there are still too many people in hospitals and even dying from COVID so it’s far from over and new approaches are needed. Another possibility is a new cell therapy could help ARDS more generally, which can have other causes besides COVID.

An interesting side note is that many cell therapy biotechs experienced major COVID bumps in their stock prices (sometimes doubling or tripling in PPS) during the first couple of years of the pandemic, but most stocks in this area are way down for the past few years now.

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