My take on the much-touted ‘SafeCell’ paper on adult stem cell safety: encouraging, but some important reservations

The so-called “SafeCell” paper from the journal PLoS One is one that a number of advocates of deregulation of the stem cell industry often have mentioned to me:

Safety of Cell Therapy with Mesenchymal Stromal Cells (SafeCell): A Systematic Review and Meta-Analysis of Clinical Trials 

I have read this paper and have some thoughts on it.

As with all papers, I try to look for both the strengths and weaknesses in them.

One strength is that it appears that the patients were all part of approved, licensed studies.

A key additional strength of this paper is that it looks at, relatively speaking, a lot of patients compared to the average adult stem cell paper (where often we see N= too few).

However, linked to the strength above is a weakness of the paper in bringing together such a hodge-podge of different studies that do not really fit well together into one meta analysis.

So while a total of 1012 participants (if one includes controls) were included in the paper’s meta analysis, I do not believe they all can so easily be studied together. For example, there was huge variation in what cells were actually used in these studies and how they were manipulated:

“Sixteen studies used autologous MSCs, [11][12][14][15][17][18][23][25][26][28],[30][32][33][38][44][46] eight used third party unmatched MSCs, [13][19][21][35],[36][40][42] five used MSCs from matched donors, [16][22][24][37][45] and seven used both matched and unmatched cells. [20][27][29][31][34][39][43] Twenty-seven of the 36 studies cultured the MSCs in fetal bovine serum, [11][17][19][27][30][31],[33][35][38][40][42][43][46] five in human serum, [28][29][32][37][45] and four did not report the source of serum used. [18][36][41][44] Nine of the 36 studies cryopreserved MSCs prior to administration [13][19][21][22][24][30][32][33][45] and one used both fresh and cryopreserved MSCs, [34] while the remainder of studies used only fresh MSCs. Fifteen investigations reported the viability of prepared MSCs (range 70–99%, median 95%).[11][13][15][17][19][21][28][32][34][41][44][46]

My head hurts just trying to read that.

Lumping together studies of MSCs that are so varied is a problem. Issues such as using matched versus unmatched donor cells, some cells exposed to fetal bovine serum (FBS; a xenogeneic contaminant source), fresh versus frozen, etc are critically important from both safety and efficacy perspectives.

A big additional concern is that only 148 treated patients were in randomized control trials (RCT).

Far more patient data was from non-controlled, non-randomized studies. Such studies are at relatively higher risk of producing biased results.

Indeed, not a single RCT included in the meta study was defined as at a low risk of bias (Table 4). The authors stated: “No RCTs fulfilled all six criteria for low risk of bias”. What does that mean? All the studies included in this meta analysis are at moderate-to-high risk of bias. That’s a problem as bias means the results may not be highly reliable and reproducible by others.

I am also concerned that the researchers themselves may have had their own bias based on their choice of the phrase “SafeCell” as the name for their study and its inclusion in the title of their paper. It seems highly inappropriate for an unbiased assessment of transplanted cell safety. I would call it a huge mistake.

I think the authors’ conclusions (see below) should have included reservations:

Our study provides a systematic examination for adverse events related to the use of MSCs. We did not identify any significant safety signals other than transient fever.Results from our systematic review should provide some assurance to investigators and health regulators that, with the present evidence, this innovative therapy appears safe.

Some bottom line conclusions on adult stem cell safety generally and in relation to this paper:

  • 1. I believe that non-propagated autologous, adult stem cells administered to patients in a controlled clinical trial by trained researchers in a general sense have a very strong safety profile. This is a very hopeful conclusion for the coming results of the hundreds of ongoing adult stem cell clinical trials. In part this safety may arise from the fact that almost all the transplanted cells are killed, die, or are otherwise eliminated from the patient’s body within literally hours or a few days, which presents a clinical challenge since treatments may need to be given repeatedly.
  • 2. It seems to me (correct me if I’m wrong) that all the studies included in this paper were licensed and hence, in my opinion, far more likely to be proven to be safe. In addition, the data are obviously published studies and dubious clinics often do not publish their work. Thus, this paper cannot be reasonably used to support the practices of unlicensed for-profit stem cell clinics that do not play by the same set of rules as the researchers whose data was compiled in this paper.
  • 3. I believe that propagation of adult stem cells increases risks in ways that we do not understand yet. I do not believe that propagated stem cells are the same as endogenous stem cells. This opinion is based on more than twenty years of my growing cells in a lab during my career. I do not believe that from this paper that one can say that ALL propagated adult stem cell treatments are safe for sure, but I would say that the data are mildly encouraging give the rarity of adverse events.
  • 4. I think this paper has its problems as I outlined above, but I am glad they published it even if I disagree with some of their decisions such as the title and presenting their conclusions with no reservations.
  • 5. The enormous variety of MSCs used in the studies put together in this paper illustrate a continuing problem for the adult stem cell field. The huge variability in how cells are isolated, stored, manipulated, and transplanted make it hard to know what kind of safety or efficacy that reasonably may be expected for any given patient at one institution versus another and in one year versus another, etc. In many cases the MSCs used in one case may be so different from another product called “MSCs” that it is really like comparing apples and oranges. Is it possible to have some kind of standardization?
My hope is to see an increasing number of strong clinical trials papers on adult stem cells. I would love to see those therapies become a safe and effective reality for as many patients as possible.

5 thoughts on “My take on the much-touted ‘SafeCell’ paper on adult stem cell safety: encouraging, but some important reservations

  1. Thanks for the great breakdown. I think the authors could have singled out a method or condition. Initially I considered that there may not be much out there but later found a 2001 rapid review on cultured cells and knee cartilege , So all this rhetoric has cycled since before then including discussions on trial methods and this still has produced no real validated objective trials showing efficacy for use.

    I understand if people are out of options they are willing to pay and it is a gamble they are willing to take but why should they have too? Long term social costs include what to do when they run out of money because they have spent it on treatments that don’t work ? It is their business how they divide up the income they have but being able to pay for a housekeeper or aide as a disease progresses is important too as is setting aside resources for young children that will be affected by a parents lost function.

    I am not faulting patients here at all, we all want to live and get better and odds don’t mean much when the back is against the wall and options are vanishing.

    I am calling cell businesses and medics to do the right thing here for society and for individuals. If cells work and it looks good from case studies do the due diligence and run the research so that all can benefit.

    I am also weary of the it costs more if we do research and have a clean lab debate, trials are a small part of the cost.

  2. Paul
    you dissect a meta analysis in order to invalidate its findings so it fits your story line which is that expanded msc are not safe. This is transparent as an attempt to shore up your weak argument that MSC are dangerous.

    The fact is that experts in the field consider MSC safe–ie Caplan at case western. The Safecell meta analysis agrees with that. They don’t cause cancer, teratoma or ectopic tissue.

    While the studies’ variables would never allow them to be lumped together for efficacy, safety is a different matter because it is an a priori event–either people were harmed or they weren’t. Bias is not an issue there like it is with efficacy.

    I agree that clinics are not the same as university research labs and this meta analysis can’t be used as direct support for say a CellTex type of operation in order to say their processes are safe.

    BUT in the same way your finding 9 very elderly people with critical limb ischmia whose health was so poor they stopped the study didn’t tell us anything about CellTex either even though you push the idea it did.

    So when it comes to your arguments you want us to accept far off topic and incomparable items, but when it comes to others arguments you dissect even a valid peer reviewed meta-analysis to say they compared apples to oranges.

    By the way MSC for CLI have been tested many times and found to be helpful. Here’s just two-

    people with CLI are extremely ill people whose limbs are about to be amputated because their circulation is so bad. All circulatory events are at risk in them from strokes to heart attacks…they aren’t science experiments they are people.

    Your dogmatic position on MSC as dangerous cells that must be kept from patients to avoid peril is narrow and leaves out patient needs in a huge type 2 error. Your position would demand a decade of trials on critical limbs with increasingly larger trials to satisfy your skepticism. That would have thousnands of people get amputations instead of stem cells because you refuse to accept the consensus that autologous MSC are safe.

    MSC are safe. What I find amazing is that you insist on trying to control the conversation when your position is weak.

    Feel free to not allow this on the blog–I am talking to you

    • Thanks for the comment, Marie.
      You may not be surprised to find that I disagree with many of your statements.

      I read the paper without any pre-conception of wanting to invalidate it. I pointed out what are, in my opinion, strengths and weaknesses. I do that with any paper. I just taught a grad. class today on stem cells and emphasized over and over how crucial it is that as paper readers they be critical and skeptical. This is even more true when one is talking about clinical applications give that the safety of patients is at stake.

      I believe you are wrong about there being no negative impact on assessments of safety by lumping together disparate studies for meta. I don’t see how that makes sense? It also doesn’t seem logical to me when you write “bias is not an issue there like it is with efficacy”. Can you explain? Certainly safety studies are just as subject to potential biases. Or am I missing something?

      Regarding previous papers I have mentioned on safety concerns, I myself pointed out their limitations and weaknesses when I discussed them.

      You are placing words in my mouth by saying “your dogmatic position on MSC as dangerous cells”, which is something I have never said. In fact, I said I think MSCs that are not laboratory-expanded are in fact most often safe. There is no consensus, however, that laboratory-expanded MSCs are safe, which is an extremely complex issue given how “MSCs” can mean almost anything and they are different depending on the patient, the doctor, the lab, the media, the growth conditions, the day of the week or other seemingly mysterious circumstances.

      Finally, I am not trying to control any conversation, but since this is my blog I certainly can state my opinion. I value it when people challenge me or present their own opinions as you have done. Dialogue connects people and helps the field.

      I respect your viewpoints even if in some areas we do not agree. Thanks again.

      • Thank you for your reply. regarding bias in safety studies, do you propose that the authors of a safety study ignored teratoma and cancer because of bias? couldn’t see it perhaps? didn’t check but then put “safe and well tolerated” in their conclusion because they wanted a “safe outcome”? How do you propose bias as a confounding factor when the outcome they are looking for is patient harm?

        Your position is not credible though certainly you are adhering to the principle that the level of evidence has to meet a checklist of items including blinding to be high level evidence. but the whole point of the trial system is that it moves step wise from a position of knowing nothing to confidence that we “know” something–but the order of progression is safety studies at phase one–unblinded; safety and preliminary efficacy/proof of concept at phase 2; mid sized 2b trials that are blinded or not to see if a large trial is worth doing; and large blinded trials at phase 3 with enough patients and power to make recommendations.

        Pure safety studies are always phase one open studies, though of course more safety data is gathered at later phases. A meta analysis of safety studies is going to include a mix. That is no reason to claim the finding that all 36 studies concluded treatment was safe is somehow tainted by bias because some were phase I.

        Your position seems to be that you’d only take evidence of safety from blinded trials –but blinded trials only come late in the trial system–AFTER safety is established!

        What would the value of a safety meta-analysis be if there were enough large blinded trials that we already knew treatment was safe (as evidenced by the fact there are blinded trials which means there were already safety studies)

        your position makes no common sense.

        But I have to say I can see how careful you are and respect your concern and appreciate your obviously deep interest in this field. I am really pleased that we have people who are thorough doing research on iPS cells–I beleive one day people like me will get neural progenitors straight from a lab like yours and I am really thankful you are passionate enough to work on that.

        But MSC are not your area of study so your constant concern and focus on what the patients who are desperate for treatment want is frustrating.
        Please, look at this:

        She has ample funds–you really think you do her a service to say we need a decade of study before people can get stem cells? She’s not going to get into a study and she won’t be here at the end.. I’m about 7 years behind her.

        Do you understand me now? You can’t possibly see that and ignore it can you? I can’t—I am living it. Your cancer is gone–my problem is a death sentence. Find a way to be helpful–MSC are safe if handled properly-I give you the handling issue

        • Marie,
          I respect your passion about this area, but I would also respectfully suggest that you tone down your language if you want to continue a dialogue. You seem so angry and sometimes downright disrespectful (I’m guessing this is unintentional).

          I have found over the years (often via my own mistakes) that people on different sides can learn from a lot from each other, but it requires a constructive, respectful approach. When you say very extreme, even rude things in your comments to me such as “your position is not credible”, “your position makes no common sense”, “find a way to be helpful” etc it makes it difficult to have a dialogue.

          Also please be careful what you say about prostate cancer and be respectful to people like me with other diseases. MS is a hugely important disease, but there is great suffering from other things too.

          Unfortunately my cancer is not necessarily gone. My docs have clearly told me I am in “long-term remission”, which is not necessarily a cure by any means. My cancer presented as a very aggressive one that has a relatively high risk of recurrence. So for you to say “your cancer is gone” it is (A) flat out incorrect and (B) seems very unkind. I don’t think you meant it that way, but it came across badly.

          Bottom line, if you can have a dialogue in a respectful, constructive way, let’s do it. I’m all for it. Otherwise, I won’t participate.

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