May 28, 2020

The Niche

Knoepfler lab stem cell blog

Field throws stem cells for COVID-19 like spaghetti on the wall

The idea of testing stem cells for COVID-19 may be music to the ears of some folks as an opportunity, but to me from the beginning it sounded mostly like a spaghetti on the wall road to trouble.

There is buzz out there that some kind of stem cells or other cells will help with COVID-19. The reality is that that’s probably not going to happen.

Even so, a whole range of people and firms are somewhat exaggerating and in a few cases outright hyping the odds of success. That is harming patients and the cell medicine field.

Stem cells for Covid-19?

An example of the hype in the Cellular Medicine arena regarding COVID-19. A magical mist? This is a definite candidate for my science hype of the year award.

What’s going on?

Cellular Medicine is an exciting, relatively new field that is likely to transform medicine overall, but in my view some of the intended cellular approaches to COVID-19 so far are problematic. Certain efforts in this area are severely underscienced, but are being portrayed as likely to succeed.

The core idea in general behind Cell Medicine is to use cells as a treatment, rather than or in addition to the more traditional pharmaceutical and surgical approaches to medicine. Under this Cell Medicine umbrella we have stem cell-based regenerative medicine as well as other kinds of cell medicine not strictly based on stem cells.

While this general field has enormous potential and I believe it’s going to be a game-changer for some illnesses such as diabetes, certain forms of vision loss, and some blood disorders (just to name three of many likely impacted areas), it also has had some difficult problems at times.

The COVID-19 pandemic of 2020 has amplified the issues and sparked new ones. I’ll collectively call this the ‘stem cells for COVID-19’ problem for the purpose of this post.

Here are examples of the serious issues I see in how some parties in the cell medicine world have approached COVID-19. I also discuss how the problems relate to larger-scale issues in our field that we need to be conscious of and work to avoid.

spaghetti on the wall
Spaghetti on the wall. South Bronx school website pic.

Throwing cellular products at COVID-19 like spaghetti on a wall

One problem that crops up at times in the cell medicine arena is to view one investigational product as a promising treatment or cure for many diverse diseases. The pandemic has made this issue even more pronounced. For example, ‘got a cell medicine product being tested for cancer’, the thinking seems to go, ‘why not try it for COVID!’

Celularity

The biotech Celularity is testing its placental allogeneic NK cell product, originally targeted for cancer, as a possible treatment for COVID-19. The premise for this repurposing is relatively weak in my view, mainly based on the unproven idea that some severely-ill COVID patients may have lower numbers of NK cells.

It’s not impossible that there could be some benefit, but the odds are low and there are definite risks.

Capricor

Moving on to another example, do you have an investigational product in development for heart disease or muscle disorders? Why not try it for the novel coronavirus, right?

Last week the biotech Capricor announced “100% survival” of 6 COVID-19 patients who received its cardiac product CAP-1002 in a somewhat breathless press release. Talk about over the top.

Why would their cardiosphere product potentially help COVID-19 patients? It’s hard to say.

I suppose it could help with some of the cardiac issues that a subset of COVID patients experience. That doesn’t seem to be what the company was suggesting here, which was more related to a proposed immunomodulatory function. Could the product have some other indirect helpful effect? It’s a shot in the dark.

More generally, why do some folks view individual, very specific cell medicine products as having such broad relevance? It might be because stem cells are viewed as so plastic (so able to form many other kinds of cells through differentiation), but that doesn’t mean that one thing works in a vast number of clinical settings.

It is possible, for instance, that pluripotent stem cells may have many applications since they can make nearly any kind of human cells, but once you make a specific product from those stem cells (e.g. retina cells) or if you are using adult stem cells with much more limited potency, one product is extremely unlikely to successfully treat many diverse conditions.

In some of these COVID-19 cases, you might as well claim that neurons or beta cells made from pluripotent stem cells should be tested for activity against the novel coronavirus disease.

FDA lowering the bar quite far for cells for COVID-19

Many cellular medicine biotechs, besides the two mentioned above, have jumped on COVID-19 bandwagon, usually with products never intended to treat viral illnesses let alone COVID-19-related symptoms. Note that in each case the FDA has cleared their small COVID trials to begin so this is definitely not a question of non-compliance.

Still, is what some of them are doing wise? Good for patients and the field?

Part of the problem here at least in the US and probably in many other countries is that regulatory bodies like the FDA have dropped the bar so low for IND clearance (or equivalent abroad) for COVID-19 INDs that it incentivizes various teams to try just about anything for the novel coronavirus. Of course, the stem cell and cellular medicine field isn’t the only one having such a low bar from the FDA for COVID-19, but it’s problematic all around.

The FDA is likely under enormous political pressure to quickly clear INDs for COVID-19 trials, but it should do its best to only clear things that actually have a logical premise and a foundation of solid, even if early data. Note that Celularity was able to get Rudy Giuliani to plug what it was doing and shortly thereafter the FDA cleared their IND.

Unproven Stem Cell & Biologics Clinics

I also worry about the legit field’s behavior in this area inadvertently encouraging stem cell clinics to propose their various injections will help COVID-19 too. The clinics definitely don’t need encouragement.

The clinics and suppliers are now seriously interested in COVID. For example, see this recent FDA letter.

Earlier I also wrote here about unproven exosomes being tested on patients apparently without FDA approval, which lead to an agency letter to a supplier.

Media issues

When we talk about “media” in the stem cell field we often mean the liquid Kool-aid-like concoctions that we use to grow our cells, but here I mean the news media. The news media also sometimes don’t quite know how to handle the cellular medicine approach to COVID-19. I’ve seen many good stories but then some others just take interviewees’ statements at face value or even hype things further.

The above CBS News YouTube video piece was one of the best I’ve seen at keeping it real. The segment was appropriately balanced and realistic, especially the physician from Mt. Sinai who was interviewed, Dr. Keren Osman, MD.

(Note that another great, much more comprehensive resource for media coverage of cell therapy efforts for COVID-19 is on the site Cell Trials Data here. I highly recommend it. The Cell Trial Data team includes Alexey Bersenev, Frances Verter, and Pedro Silva Couto.)

Other cell medicine biotechs

Athersys and Mesoblast are active in this area now. They also have stem cell products they are testing for COVID-19. At least Athersys has some existing ARDS data (although it has been viewed as rather limited by some) when it went down the COVID-19 path so it made some sense for them to move forward. If I was at the helm of Athersys I would definitely have moved forward on COVID-19.

Mesoblast’s product had less data behind it for COVID-19 when it decided to move forward.

Pluristem is also on the COVID-19 path. We have this newspaper headline. Israel’s Pluristem FDA approved for study in treatment of severe COVID-19. It has had just 6 patients and no controls so far. Then it pops up again in this “save a life” kind of story: New York Post: Stem cells from a baby’s placenta may save life of coronavirus victim in NJ. That’s heading into the hype zone.

Could some kind of marrow cells or specific types of MSCs help COVID-19? In theory yes, but it’s just a long shot in my view.

Hype and oversimplification

Some biotech firms’ own portrayals of their odds of success (meaning proven efficacy) and safety are sometimes very problematic. There has been both hype and oversimplification of things.

Part of what spurred me to write this post today was Capricor’s “100% survival” PR. Seriously you’re going to say that publicly with 6 patients and no controls? If you had 1 patient who got your product and didn’t die I suppose you could still say you had “100% survival”, but should you say that? Nope.

From the PR quoting Dr. Linda Marbán, Ph.D., CEO, Capricor (emphasis mine):

“CAP-1002 is an easy-to-deliver intravenous therapy that has been administered successfully to over 150 patients to date. Given its novel mechanism of action, it could be a potential game-changer in helping countless COVID-19 patients.”

At best this comment is premature and over-exuberant. Note that Capricor just got more mixed news today.

When all cells are “game-changers” for COVID

Dr. Camillo Ricordi, stem cells for covid-19
Dr. Camillo Ricordi, Facebook picture.

Then you have the “stem cell mist” cure hype shown in the screenshot at the top of the post. Digging into the Miami Herald article itself, you see that there’s very little “there there” to the biomedical science in that article. One quote, “We’re hopeful,” Dr. Fatima al-Kaabi, head of hematology and oncology at the Sheikh Khalifa Medical City in the UAE, told CNBC…We’ve seen a favorable outcome.” sounds much less substantial than the “cure” headline.

The same Miami Herald article highlighted ongoing work in the US that seems to me to be somewhat hyped:

“The news comes after three critically ill COVID-19 patients in the United States improved after being treated with an experimental stem cell treatment for the first time, the Miami Herald reported.

South Florida doctors used stem cells grown from umbilical cord tissue and inserted them intravenously, according to the outlet. Several days later, two of the patients were discharged from the ICU and the third was recovering.

Umbilical cord stem cells, typically thrown away after birth, “could generate enough stem cells to treat over 10,000 patients,” Dr. Camillo Ricordi, a University of Miami professor and stem cell therapy researcher, told the Herald.

The treatment has not gone through a clinical trial, but the doctors claim it is a “game changer,” the Herald reported.”

It’s already a game-changer? I don’t think so. When I was a kid there was an advertising slogan for fast food that went, “Where’s the beef?” I’d say here in this current cell medicine for COVID-19 area, where’s the data?

Some university researchers have ‘stem cells for COVID-19’ exuberance too?

Some folks at universities are getting ahead of themselves too in my view. For instance, in the Miami Herald we have Ricordi (mentioned in the quote above) in my view again exuberantly talking about stem cells for COVID. He says at one point, “They have amazing potential” and at another point, “It’s practically injecting an army of cells that can fight some of the most severe complications of the virus infection.”

The cells “can” fight the complications?

Not “might be able to” or something more conservative?

The approach that Ricordi is mentioning hasn’t been studied yet. It may do nothing or even make things worse.

Note that back in 2014, an important Nature article by Alison Abbott reported Ricordi’s potential supportive statements regarding the controversial Stamina Foundation in Italy, which had hyped unproven stem cells. From Abbott’s article:

“Other events have further dented Stamina’s credibility. Leading researchers on the scientific advisory boards of two independent stem-cell initiatives headed by clinician Camillo Ricordi have resigned in protest over the apparent public support offered to Stamina by Ricordi. Ricordi, who works on diabetes at the University of Miami in Florida, has in the past called Stamina’s method “safe” and “promising”.

Stamina was never promising in my view and ended up being a train wreck.

Looking ahead

This all kind of brings to mind for me that NPR show A Prairie Home Companion. The show has its Lake Wobegon where “every child is above average.”

Is every cell product above average? All of them, when thrown at COVID-19, are going be game-changers or even above average (meaning better than standard of care) here?

In reality, it’s more likely that the typical cells for COVID-19 trial won’t work. The risks are also not clear at this point and won’t be zero.

What’s wrong with throwing a whole bunch of stem cell therapies at COVID-19 and just hoping something sticks?

If the logic just isn’t there to start with then you are giving people false hope. You’re also setting yourself up to try to squeeze something hopeful out of the data once you get it, which is a road to potential big trouble. Your firm may also find itself hyping things. In addition, you’re wasting resources that could go somewhere else like to another clinical trial that makes more sense. For some other things like grant writing, the throw the spaghetti on the wall approach can be effective.

I hope that some cells will actually help patients with COVID-19 when all the dust settles on the flood cell medicine trials, but I doubt that’ll be what we all see.

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