November 30, 2020

The Niche

Knoepfler lab stem cell blog

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.
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