Impact of fetal bovine serum on toxicity of mesenchymal stromal cell infusions in humans

by Alexey Bersenev on November 1, 2012 · 3 comments

in cell culture, mesenchymal

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The recent SafeCell study, published in PLoS ONE, analyzed the safety profile of mesenchymal stromal cells (MSC), administered systemically in patients. I blogged about it here. One of the most interesting things was a comparison of infusion-related toxicity between MSC, cultured in different culture conditions, particularly – with fetal bovine serum (FBS) or without. Let’s look at results.

36 randomized controlled and uncontrolled clinical studies were analyzed. 27 of the 36 studies used FBS for MSC cultures, 5 – human serum and 4 – unknown source. As we can see, vast majority (75%) of clinical cell manufacturing protocols still use FBS for culture. So, if FBS has any negative impact on toxicity we would expect acute infusion-related reactions. But, the authors concluded that was no any safety issues with MSC infusions:

No significant relationship between MSC administration and acute infusional toxicity was observed.

The only toxicity reported was a transient fever:

There was a significant association between MSC administration and the development of fever. Fever was transient and not associated with long term sequelae. The mechanisms for fever are not clear but could be related to acute inflammatory reactions by a subset of patients to particular preparations of MSCs, not unlike similar reactions occasionally observed with red blood cell administration.

The use of FBS in cell therapy products manufacturing was highly criticized. But, as this study demonstrates, transition to xeno-free protocols seem to be slow. The authors discussed “serum issue”:

Although the majority of included studies used fetal bovine serum, only one study specifically monitored for potential adverse events associated with its use. Concerns over fetal bovine serum will likely decrease in the future as expansion of MSCs in human blood products becomes more commonplace.

So, despite a big “xeno-free” movement, many clinical sites still use FBS for MSC culture. Although, there is no evidence for increased toxicity after used of FBS in MSC culture, we need studies, which will address this issue specifically.

If you have any experience with use of FBS for clinical MSC culture, please share it in comments. We would like to hear any observations from “serum versus no serum” procedures.

{ 3 comments… read them below or add one }

Lee Buckler November 2, 2012 at 2:51 am

As my friends in industry are fond of noting, the scientific or clinical debate is almost moot because if cell therapy goes commercial at any large scale, there will not be enough cows to produce sufficient FBS. Alternatives must be found to keep cost of goods reasonable at commercial scale production.

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Michael An November 4, 2012 at 8:46 am

Multiple issues need to be addressed with FBS besides short-term infusion effect in this paper. Adventitious agents (not just prion but also the new bovine diarrhea virus), antibody reaction and the reduced efficacy associated with it (see this FDA scientists’ paper http://bloodjournal.hematologylibrary.org/content/110/2/501.full.html), and the supply issue mentioned by Lee. If I were one of those 75% of people still using FBS, I’d lose my sleep.

Serum-free is here.

This comment was moderated

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Sanjay December 31, 2012 at 3:06 am

1. Use of undefined complex like FBS in large-scale expansion of MSCs leads inconsistency in productivity, unexpected growth characteristics, may induce unwanted cells to attach and it is expensive.
2. Every change in FBS lot number needs revalidated prior to use in clinical-scale production, which is a costly and time consuming activity
3. Further, limited availability of validated FBS and induces frequent change in FBS lot number as well as growth characteristics.
4. Moreover, FBS adds high risk of possible contamination of transmission – prion particle, nanobacteria, mycoplasma, fungal, endotoxins and it requires continuous adventitious agent testing.
5. Serum proteins present in FBS may be internalized into stem cells and thus its use carries possible risk of transmitting unknown infectious agents and also involves the risk to initiate xenogeneic immune responses.
6. Final post harvested cells may require additional process steps to reduce bound, loosely attached FBS related components.
7. bovine protein attachment to the cells grown in FBS containing medium has been shown to trigger antigenic response which may affects the viability, safety and efficacy of transplanted MSCs
8. Addition quality testing on residual xenogeneic compounds is required to ensure the purity of MSCs and FBS may triggers MSC heterogeneity.
9. Besides these technical difficulties, it is inhumane to use FBS, as on average of 1 million fetal calves are killed every year for collecting around half a million liters of FBS

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