October 29, 2020

The Niche

Knoepfler lab stem cell blog

Review of Centeno MSC safety paper: without controls, conclusions muted

The number of people around the world being injected with stem cells every day has never been higher and the heterogeneous group of medical providers doing these procedures is also at or near its highest level ever.

The cells used are also highly variable as are the procedures themselves, but most of these cells fall under the umbrella of mesenchymal stromal/stem cells (MSC). The field needs to learn more about these MSC procedures in terms of safety and efficacy. Preliminary, relatively small and most often open label studies have been generally encouraging on safety, but not very definitive. For these reasons, whenever I hear about a new study published by a stem cell business, I am interested to read it and see what it teaches us.

A new published study from Dr. Christopher Centeno reports findings from a number of affiliated clinics that use MSCs for orthopedic procedures.

It is good to see stem cell clinics collecting and publishing their data so that is a plus. I commend them for that. The number of adverse events and in particular stem cell-related, severe adverse events was seemingly relatively very low amongst the population studied, but there’s a catch.

Centeno Table 3
Table 3, Centeno, et al., 2016

The overriding problem with this study is that there are no matched controls, leaving the reader unclear as to relative risk of the stem cell procedures. The data from this paper’s population of stem cell transplant patients who received various kinds of MSCs for a variety of orthopedic conditions is only compared to data from other previous studies reporting rates of adverse events in other populations of patients getting standard of care treatment or to general patient populations.

This lack of controls is unfortunate, but not surprising. For-profit stem cell clinics are in the business after all of making money and most patients are not going to be interested in paying money to the clinics only to have a chance to be a control not getting the stem cells.

Further, clinics in general have not shown interest over the years to themselves pay the additional costs associated with having control subjects. But it could be done. For instance, a clinic could do a study at cost (no profit margin built in) and offer participants the chance to be research subjects at a relatively low cost. Another idea, and this may sound outlandish given where the stem cell arena is today but is perfectly logical and reasonable, is that clinics could even pay patients a small sum to be clinical trial subjects in a controlled study.

Overall, the lack of controls in the current paper greatly limit what we can learn from it. Of the adverse events reported in this new MSC paper some sound concerning such as cancer (termed “neoplasms”; see Table 3 above) in the paper, but again without controls there is no way to be certain if these tumors were stem cell-related. The authors do not believe they were. I can say, “most likely they are right”, but scientifically there’s no way to be sure at this point. It is possible a matched control population would have gotten even more tumors or conversely no tumors at all.

While this study had longer follow up than some past ones, the follow up here still was only around one and a half years on average and it is reasonable to imagine that some adverse treatment-related events could arise much later.

Another concern with the paper is that reading the methods seems to suggest that aspects of the protocols used to administer stem cells to patients varied considerably even within the three individual treatment groups (same day marrow MSCs, marrow and lipid aspirate combo, and culture expanded MSCs). For instance, the number of cells and the amount of co-injected platelet lysate had sizable ranges. An interesting side note to this is that this variability reflects a challenge facing the stem cell clinic industry of every clinic even amongst affiliates doing things somewhat differently.

Update: I also meant to say that I think this paper was largely well written and where appropriate included caveats, limitations, etc.

Finally, I’m not clear on the strength of the methods for assessment of adverse events and assignment of potential adverse events to be related to treatment. Online recruitment of assessors may not be the most reliable approach.

Overall, I’d say this paper is just a bit encouraging on autologous MSC safety for orthopedic use in the short term. It is also a step in the right direction in terms of the more data the better from for-profit stem cell businesses, but without controls it is hard to say much more. For those who say that this kind of study is worthless, consider the hypothetical scenario that the same patients had been given these therapies exactly as reported, but none of this was published. How could that be a better situation than having a publication of the data even without controls? As long as we as a community soberly evaluate such publications, I see how they serve a role.

Finally, I propose a friendly challenge to those doing these experimental stem cell therapies to devote some funds to controlled studies and to do much longer follow up. This would also be a reassuring sign of good faith that the clinics have long term patient best interest as a top priority.

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