Safety of systemic cell therapy with human mesenchymal stromal cells – results of SafeCell analysis

by Alexey Bersenev on October 29, 2012 · 1 comment

in complications/ safety

The results of SafeCell study – a systematic review and meta-analysis of safety mesenchymal stromal cell (MSC) therapy, have been published online in PLoS ONE. This is the first and unique analysis of clinical trials, assessing systemic administration of MSC in different indications.

The authors did a great job in retrieving data from databases and filtering the information. 36 clinical studies were included in analysis – 8 randomized controlled (n = 369 patients), 10 non-randomized controlled (n = 466) and 18 uncontrolled (n = 252). Some limitations of the study:

First, despite our comprehensive search strategy, there are a number of completed but unpublished industry sponsored studies and studies published in abstract form only that may alter the safety profile of MSCs. Second, we pooled adverse events across heterogeneous disease states. Given the limited number of clinical MSC studies, and the small sample sizes of each, it was important to pool data across trials to determine if any potential signals of harm existed.
Third, the majority of RCTs included in our analysis would be considered a high risk of bias.

The main outcome measure of the SafeCell study was statistical analysis of adverse events. The authors tracked acute (infusional) reactions as well as long-term events, such as death and tumor formation. Adverse events were also grouped by organ systems (cardiovascular, gastrointestinal…). The analysis didn’t identify any significant adverse events:

Our analysis was unable to detect associations between MSC treatment and the development of acute infusional toxicity, organ system complications, infection, death, or malignancy. There was, however, a significant association between MSC administration and transient fever.

Infusional reactions, such as fever or chills are very common in cell therapy. It could be associated with dead cells/ debris in the cell suspension, cryoprotectant and patient’s immunological status. More importantly, the frequency of long-term adverse events was not sugnificant.

Interestingly, the authors dissect the studies by MSC characteristics, such as immunocompatibility, cell viability and culture in xeno+ or xeno-free conditions. 44.4% of studies use autologous MSC, 22.2% – unmatched cells, 13.9% – matched, and 19.4% – both matched and unmatched. 75% of studies cultured MSCs in fetal bovine serum. Less than half (41.7%) of studies reported cell viability.

… concerns for immunogenicity may be unfounded as 13 studies used unmatched allogeneic MSCs with no reports of acute infusional toxicity.
Although the majority of included studies used fetal bovine serum, only one study specifically monitored for potential adverse events associated with its use.

In the discussion, the authors commented on potential reporting bias:

The reporting of adverse events was highly variable among the included studies. This may be related to editorial constraints of journals. Since use of MSCs may be associated with neoplastic growth long term, it is difficult to understand why approximately 50% of studies did not report follow up duration for adverse events. For highly experimental interventions with unestablished safety profiles, we contend that it is important to summarize the adverse reporting plan in the methods section of manuscripts and report short term and longer term events.

For the folks, who tightly follow the filed, these results were expected. MSC administration demonstrates remarkable safety profile in pretty much all clinical trials in the last 10 years. I’m in favor of the theory that systemic administration of MSC leads to their rapid clearance from the body. This theory could explain remarkable safety profile. Please note, that none of the studies addressed MSC persistence after infusion. We still don’t have evidence for the link between efficacy and cell engraftment. The recent Le Blanc study, which was done on autopsy material, demonstrated that very very few allogeneic matched MSC engrafted after infusion and were detected in 44% of patients in various tissues. In case of systemic infusion, more likely, we’re dealing with medicinal effects of MSC. I’d speculate, that long-term persistence of MSC in various (non-targeted) tissues is unwanted event and could be potentially linked to some complications.

I’d highly recommend to read this study to every cell therapy professional!

{ 1 comment… read it below or add one }

Raymond Mouzannar October 31, 2012 at 12:07 pm

Great article but it is very important to emphasize that allogeneic biologicals are expected to elicit an immune response. Matching is very important if one desires engraftment of the cells infused. This has been emphasized lately by a study presented at ISSCR in Yokohama earlier this year.
No doubt that MSCs have an immune suppression effect on their own, are capable of differentiating into cartilage, bone and adipose tissue cells, have the capacity to migrate to inflammatory centers and even enhance cancer growth. However, all these functions are dependent on environmental and genetic factors like the MHC type of the cell, age and the immune system state of the host. That is what I think clinicians are failing to take into consideration when assessing the safety and therapeutic effect of MSCs.

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