Rudy Giuliani has been tweeting all kinds of wild things about the novel coronavirus and is apparently very excited about the idea of “stem cells” for COVID-19 patients.
What could go wrong, right?
Giuliani starts vaguely tweeting about “stem cells”
I wrote a few days ago about how Giuliani had been plugging an upcoming podcast he was doing on “stem cells” for COVID-19. Since then I watched the video so you don’t have to, that is unless you really want to for some reason. In that case, I’ve pasted the YouTube video further down in this post.
At the time Giuliani was still plugging the upcoming podcast but hadn’t posted it, it wasn’t clear what that interview was going to be all about and who it would be with exactly. In fact, it was possible it wasn’t even going to be about real stem cells.
At first before we had such details, I wondered if he was going to be interviewing an unproven stem cell clinic person or someone in that sphere like a clinic supplier. For that reason and because the general idea of stem cells for COVID-19 has caught fire in not entirely positive ways, I was wary of the upcoming podcast.
Now we know Giuliani interviewed Dr. Robert Hariri of the biotech Celularity, which has been focused on placental cell derivatives mostly for cancers like glioblastoma. Celularity originally caught my eye a couple years back because it was generating some buzz in the media and had raised hundreds of millions of dollars. I also was struck by the huge aspirations of the company itself such as trying to extend human life by decades.
The core biomedical idea here
Based on Giuliani’s interview with Hariri, what are Celularity’s COVID-19-related plans? The podcast wasn’t so much focused on a direct stem cell therapy, but on trying to repurpose the firm’s investigational natural killer (NK) cell therapy called CYNK-001 originally developed for cancer for use for COVID-19 instead.
The hypothesis seems to be that many of the patients who get the sickest from the novel coronavirus may have a deficiency in NK cells. This idea is mostly based on one small COVID-19 paper and on past limited data suggesting amongst SARS patients that those who got the sickest sometimes had fewer NK cells.
Remember that in a general sense NK cells are immune cells that have important, unique roles in killing both cancer cells and cells infected with viruses. The populations of NK cells, which are specialized lymphocyte lineage cells, in the placenta may also help protect the fetus from maternal infections, a fundamental concept for Celularity as a company.
The notion of an NK cell treatment for COVID-19 is interesting and worth consideration, but at the same time in my view there’s not much data behind it yet so it’s very early days. There’s much we don’t know. For instance, the Celularity placental allogeneic NK cell product just might not work in this context even if some other NK cells could. The different, but related idea of designer NK cells engineered to home in on SARS-CoV2-infected cells is pretty cool, yet that kind of thing could take a while to make, preliminarily testing, etc. and time is short in a deadly pandemic.
Politics and some eye bulges
To set the stage of the interview, Hariri and Giuliani were sitting across from each other, both with suits adorned by American flag pins. Not that there’s necessarily anything wrong with that, but Hariri had also around that same time been tweeting some rhetoric at POTUS and others that seemed unusual in tone to me. For instance, to me it seemed that his tweets were in part pushing for less regulatory oversight. In addition, he tweeted in a positive way to a stem cell clinic operator, which for me at least wasn’t a positive. Below is one of his tweets toward Trump before the podcast aired.
https://twitter.com/HaririRobert/status/1243912094258528259
In the terms of the podcast itself, I couldn’t help but notice as I was watching the Hariri interview that Rudy has a habit of bulging his eyes outward and interrupting his guest at key moments so that kind of stuff is distracting. For instance, at one point it seemed that Hariri was trying to start to say something like, “We’re fortunate we have a President…”, but he’s then interrupted so it’s hard to be sure if that was going to be a reference to Trump.
Giuliani mentions stem cell clinic-like offerings as context
As the discussion got going more, the former mayor gave some background related to stem cell clinic-like offerings and talks glowingly about it, such as that it was recommended to him by former Yankee pitcher Mariano Rivera and by his own son who’s a pro golfer with “very good results”. There was also some mention of Tiger Woods’ knee. So that wasn’t a reassuring context to start the interview.
The chat mentions in a general sense that there are supposedly minimal adverse effects of cell therapies and there was a claim that generally cellular therapies are “quite safe.” These statements are not things one can just broadly assume. We should keep in mind again too that what Celularity is wanting to test is an NK therapy (I think which is derived from placental stem cells), not actual stem cells.
More details & perspectives on Celularity’s NK COVID-19 plan
From the interview, the plan seems to be that if an IND for this (submitted by Celularity around March 3) is approved, which I think is likely, that they will infuse 50 patients. It was less clear if there will be a 50-patient control group or rather if the 50 mentioned would include 25 controls and 25 infused with NK cells.
Hariri was upbeat about the prospects, saying something along the lines of, “I’m pretty confident the safety is going to be more than acceptable …and we’re going to boost the immune response” in the COVID-19 patients. Based on the limited amount of relevant data available that latter part especially seems like a long shot to me, but I hope he’s right and that I’m wrong to be skeptical. Note that I’m not a physician or immunologist.
There are potential patient risks here too with an NK cell approach such as increased respiratory inflammation due to NK cells potentially attacking massive numbers of patient cells in the respiratory system or elsewhere. While the Celularity NK cells have seemed safe so far in cancer patients, which is encouraging in a general sense, that doesn’t mean they are for sure safe for patients who have had serious coronavirus infections for weeks.
One other thing making me somewhat skeptical about the Celularity plan is the timing. I would have expected endogenous NK cells to have an earlier role in the pathogenesis of COVID-19 so giving an allogeneic NK product late in the course of the disease seems counterintuitive and could pose unique risks.
Then Giuliani brought up the whole Trump-plugged Z pack/hydroxychloroquine thing that has raised concerns in the biomedical community. At that point while watching, I wondered how Dr. Hariri would handle this. Be cautious? Jump right in? He didn’t endorse the Z-pack idea or criticize it, but instead he ended up comparing Celularity’s NK therapy to the Z-pack approach in terms of purported shared big-picture mechanisms.
Looking ahead
Why did Hariri sit down with someone as controversial and politically-charged as Giuliani?
To try to connect with Trump, who might then go on to mention this stuff at a press briefing or on Twitter? To put political pressure on the FDA regarding his IND? Raise funds for his company?
What if Trump ends up vaguely encouraging the world to try “stem cells” for COVID-19 because of Giuliani’s advocacy here? That could do so much harm.
In general, it’s a tough judgment call during a pandemic about what should be tested in the way of investigational therapies in patients and what shouldn’t.
Also, how much evidence should be required before pulling the trigger to go into patients with a new product during an outbreak that is killing tons of people? Note that the FDA just approved the Trump-promoted anti-malarial drugs hydroxychloroquine and chloroquine for COVID-19 based on little evidence.
Going on Giuliani’s podcast was a calculated risk for Hariri. What’s your reaction to it?
In the bigger picture, what do you think of the Celularity NK idea for coronavirus patients?
Paul Knoepfler and Greg Maguire, Ph.D. hate Fox news, POTUS and Rudy Giuliani, this is science? I’ll be voting NO on your 5.5 billion.
Greetings, Dr. Knoepfler, trying to email you for a private communication, but knoepfler@ucdavis.edu. doesn’t work.
Please email me a “hello” or something, so I can “reply”, Thanks, Bruce
That email works. Make sure there is no period “.” at the end of the email address.
Many potential problems exist in using a NK cell therapeutic. Here are just a few potential problems: NK cells can kill non-infected host cells, including immature dendritic cells, activated T cells, and monocytes. For example, NK cells have been found to specifically eliminate activated CD4(+) T cells during chronic mouse cytomegalovirus (MCMV) infection. T cell receptors are generated by somatic genetic recombination thereby enabling T cell recognition and activation, whereas NK cells use a repertoire of germline encoded receptors. Many of the receptors are also expressed by T cells. Further, NK cells also express high levels of NKG2D and CD27 causing high levels of IFN-γ that have been found to be responsible for acute lung immune injury. Not particularly helpful with the severe forms of the disease where the endpoints are primarily pulmonary. And, enhanced NK cell function can decrease an adaptive immune response that facilitates control of virus replication in infection. You won’t find these data in medical school textbooks or in a Fox News report.
A number of epidemiologists are now culling the data, as bad as they may be at this time, to determine whether Covid-19 patients using “checkpoint inhibitors,” that enhance T cell function, have better or worse outcomes.
With more than half of medical procedures not having evidence for their safety and efficacy (McGinnis et al, 2007; Prasad et al, 2013), and an even higher number likely for drugs (Gotzsche, 2019), Pr. Dr. Knoepfler asking about unproven cellular therapies, “What could go wrong?” is right. These problems in medicine are exacerbated in a political climate where science is ignored, and the ideology of deregulation becomes the mantra (Sipp et al, 2017). And remember, “Common Sense” usually equates to Systems 1 Thinking (Kahneman, 2011), and a lack of rational, statistical thought and evidence. PS: Read Kahneman before you react to this – he won the Nobel for this work, and you’ll learn much.
Gotzsche P (2019) Institute for Scientific Freedom. BMJ Evidenced Based Medicine
Kahneman, D. (2011) Thinking, Fast and Slow, Farrar, Straus and Giroux, NY.
McGinnis JM et al, (2007) Learning What Works Best: The Nation’s Need for Evidence on Comparative Effectiveness in Health Care: AN ISSUE OVERVIEW. IOM ROUNDTABLE ON EVIDENCE-BASED MEDICINE.
Prasad V et al (2013) A Decade of Reversal: An Analysis of 146 Contradicted Medical Practices. Mayo Clin Proc. 88(8):790-798,
Sipp Det al (2017) Show drugs work before selling them. Nature, 8 March 2017.
Paul- as you know, I have my own interest in NK cell-based therapies and I am as big a supporter of anyone in this area. That said, I am not clear how allogeneic NK cells will help in treatment of COVID-19. To my knowledge, there is no data that NK cells help in acute viral infections such as cornaviruses, though there is good evidence they help in some other viruses- typically more chronic infection.
One main concern is that severe cases of COVID-19 seems to be due to a cytokine release syndrome (cytokine storm) similar to what is seen in patients treated with CAR-T cells. Therefore, there is a concern that adding NK cells could exacerbate this issue. That said, maybe these NK cells could help, we don’t know. Doing a limited Phase 1 trial might be reasonable with proper FDA review.
However, there are a couple concerns I have based on this piece with the understanding I have no interest to watch the interview: 1) What does Giuilani have to do with any of this? Why use him to promote or hype this type of work. The study and FDA review should be based on strong science, not “friendships” with government insiders. 2) What does any of this proposed study have stem cells? I think this is equally your (Paul’s) point. NK cells are different altogether, and I would hope Dr. Harari is working to make this clear and not confuse these fields.
@Dan,
Thanks for the comment.
I have some of the same concerns.
I think the stem cell angle here is that the NK cells are made from placental HSCs, but I’m not 100% clear on that.
Paul
@Admin ” In addition, he tweeted in a positive way to a stem cell clinic operator, which for me at least wasn’t a positive.” Really? “Thanks Neil. We need to get together.” Is that the so-called “positive” Tweet to which you are referring?
For proper context, Hariri tweeted, “There is a glaring need for regulatory and preparedness reform. If I hear 1 more dilettante dismiss real world clinical experience as anecdotal or unproven I’m going to lose it. When the ship is sinking preventing people from entering lifeboats until you prove they float is nuts.”
Riordan commented, “Right on brother. Well said.”
Hariri replied, “Thanks Neil. We need to get together!”
Apparently, these two have a history: https://singularityhub.com/2017/01/17/stem-cells-are-poised-to-change-health-and-medicine-forever/
In any case, I don’t see how this exchange is germane to the subject at hand other than it was a cheap shot to smear Hariri with guilt by association. Am I missing something?
PS: Why did you delete your Tweet that Hariri replied to,” Paul I have always admired your work. In this case I believe ur dead wrong. Having never treated a dying patient you’re at a disadvantage in recognizing the moral obligation to accept that clinical judgement trumps trial data.BTW half of all approved drugs don’t work in patients.”?
Would you mind sharing it with us? I, for one, would like to see what you said to elicit his response, which apparently prompted you take back what you said.
@Bill
How is any of this a smear?
My tweet response to Bob (that he replied to) that I deleted was simply removed so I could more effectively use basically the same words as a retweet of Bob’s tweet rather than just as a reply to his tweet.
Paul, you’re a scientist. That is why I am totally shocked why you’re putting so much focus on a therapy with limited clinical data just because Rudy is pushing it. Meanwhile, you pay virtually no attention to the most advanced stem cell therapy for acute respiratory distress syndrome that has very promising clinical data in a Phase II placebo-controlled trial. REFOCUS! You have given Rudy’s stem cell therapy way more attention than it deserves and that was his goal.
https://www.foxnews.com/media/cleveland-biotech-company-making-headway-on-possible-covid-19-treatment
Paul, I always appreciate your point of view. I’m struck by a couple of things: You seem to take notice of the fact that I wore an American flag pin almost as if that disqualified me as a surgeon and scientist to labor 7 days a week at finding a treatment for COVID-19; next, and not unexpectedly, you raise skepticism about the general safety of cell therapy. As someone who monitors this, can you please share with me the data across the board on cell therapy. I’ve asked many so called experts who often raise concerns and aside from a few reports of no benefit, no one has real data supporting a frequency of profound serous adverse events when products are made under GMP systems. Lastly, my motivation for joining the Mayor on the show is grounded in my long standing friendship with someone who helped lead my hometown out of 9/11 and the fact that his interest and his audience care about whats happening in this crisis. I believe i was accurate and open in the interview.
Best Regards,
Bob
@Bob – Don’t forget your unforgivable sin of “tweeting in a positive way at a stem cell clinic operator” I found this particular cheap smear to be quite amusing.
It’s not every day that you see the leader of a well-funded biotech company pursuing FDA-compliant pathways tweeting in a cheery way to someone running a stem cell clinic, in this case a clinic outside the U.S. and scope of FDA oversight that, for instance, sells unproven stem cell injections for children. To me, it seemed relevant in the span of a series of tweets about “unproven” (now a bad word?) therapies and FDA oversight, etc.
Thanks for your comment, Bob. As to the flag pin, I just wondered about that in the context of your tweets to POTUS, going on Rudy’s show, tweets that suggested FDA oversight wasn’t working, etc. if you were trying to signal to the Trump sphere you were on “their side” or something. There’s nothing disqualifying about it in terms of science or medicine.
As to safety, there have been adverse events over the years and newer cellular medicines are going to have risks. As to your NK therapy, the GBM safety data are encouraging but it’s hard to say how relevant they are to a patient with a catastrophic viral infection.
If the FDA approves your IND, which seems likely, I hope you are right and the NK therapy significantly helps without any substantial safety issues.
What you write is totally B.S. I refer to
Expanded Umbilical Cord Mesenchymal Stem
Cells (UC-MSCs) as a Therapeutic Strategy In
Managing Critically Ill COVID-19 Patients: The
Case for Compassionate Use
From: 1Tri-State Spine Care
Institute, Cincinnati, OH;
2Pain Management Centers
of America, Paducah, KY;
3Massachusetts General
Hospital and Harvard Medical
School, Boston, MA
Dr. Atluri is Medical
Director, Tri-State Spine
Care Institute, Cincinnati,
OH. Dr. Manchikanti is Co-
Director, Pain Management
Centers of America, Clinical
Professor, Anesthesiology
and Perioperative Medicine,
University of Louisville,
Louisville, KY, and Professor
of Anesthesiology-Research,
Department of Anesthesiology,
School of Medicine, LSU
Health Sciences Center, New
Orleans, LA. Dr. Hirsch is Vice
Chair and Service Line Chief of
Neurointerventional Radiology,
Chief of Neurointerventional
Spine, Massachusetts General
Hospital and Harvard Medical
School, Boston, MA.
Address Correspondence:
Laxmaiah Manchikanti, MD
67 Lakeview Drive
Paducah, Kentucky 42001
E-mail: drlm@thepainmd.com
Disclaimer: There was no
external funding in the
preparation of this manuscript.
Conflict of interest: Dr. Hirsch
is a consultant for Medtronic
and Neiman Health Policy
Institute: Grant recipient.
Manuscript received:
03-13-2020
Revised manuscript received:
03-18-2020
Accepted for publication:
03-20-2020
Free full manuscript:
http://www.painphysicianjournal.com
Sairam Atluri, MD1, Laxmaiah Manchikanti, MD2, and Joshua A. Hirsch, MD3
http://www.painphysicianjournal.com
In addition I quote
Transplantation of ACE2 -Mesenchymal Stem Cells Improves the Outcome of
Patients with COVID-19 Pneumonia
Article in Aging and Disease · April 2020
These people have done more for the treatment of CoViD-19 patients requiring respiratory support than you ever have or ever will. But I guess you feel so much wiser than Harvard folks
You should read the literature
G.S. Kobinia M.D.