Clinical Research | Is stem cell therapy safe? The Lancet gives an authoritative answer

Professor Thomas C. Sudhof, Nobel Prize winner in Physiology or Medicine, once said, "We can control diseases. Stem cells are a very good treatment method. For problems that cannot be solved by traditional medical treatment, stem cell research will bring new hope."

So, some people will ask: Is stem cell therapy really safe?
01. Clinical trials: safety and effectiveness of stem cells

An article in Eclinical Medicine, a journal published by The Lancet, summarized the randomized clinical trials of mesenchymal stem cells from 2012 to 2019, and the results, as always, confirmed the safety of mesenchymal stem cells.

The authors searched for randomized clinical trial information from sources such as Cochrane Central Register of Controlled Trials, MEDLINE, and EMBASE to explore several possible adverse reactions of mesenchymal stem cells in randomized clinical trials, including:

(1) Acute adverse reactions within 24 hours (2) Infection (3) Thrombosis (4) Long-term events (mortality, malignant tumors)

The authors summarized the clinical adverse reactions of mesenchymal stem cells before this date in 2012, including a total of 8 randomized clinical trials and 369 patients, and determined that fever was the only adverse event related to MSC treatment.

This study also added 47 randomized clinical studies (screened out from 4914 studies), totaling 55 randomized clinical studies, involving 2696 patients, which is an upgraded version of the previous study.

Among the studies are cardiovascular disease, neurological disease, kidney disease, liver disease, respiratory disease, endocrine disease, blood/oncology malignancies, immune deficiency or inflammatory disease states. Cell sources include bone marrow, umbilical cord, fat, etc.

After comprehensive analysis, the risk of fever in the MSC group was significantly higher than that in the control group (but lower than in the 2012 summary), the risk of thrombosis/thromboembolic events in the MSC group was not significantly increased compared with the control group, the risk of death in the MSC group was significantly lower than that in the control group, and there was no significant increase in the risk of malignant tumors or ectopic tissue formation in the MSC group compared with the control group.

In subgroup analysis, the MSC group had an increased risk of acute transfusion toxicity in the neurological and immune/inflammatory populations, when allogeneic bone marrow, umbilical cord or fresh MSCs were transfused, and when the MSC culture medium was non-human (or unclear). The MSC group had a significantly reduced risk of death in three clinical populations (cardiovascular disease, neurological disease and liver disease).

Finally, it is concluded that: There is no association between MSC treatment and non-febrile acute infusion toxicity, infection or development of malignant tumors, and no association between MSC treatment and the development of thrombosis was found. However, MSC treatment is still closely associated with fever. In 19 randomized clinical trials, a total of 880 patients reported fever, and only 6 reported severe illness.

The review findings could provide additional assurance to researchers, clinicians, regulators, patients, and families that MSCs are safe and reliable for use.

(Dynamic image of stem cells under a microscope)

The article also pointed out that with the diversity of mesenchymal stem cell sources (such as embryos or IPS) and new second-generation mesenchymal stem cells, research is still ongoing.

Recent in vitro and clinical data have shown that MSCs can express or increase the expression of proteins related to coagulation (such as tissue factor, thrombin-antithrombin complex) and thrombosis. Depending on the clinical situation, the potential procoagulant effect may lead to beneficial or harmful clinical effects.

In this article, thrombotic events were also included as pre-specified adverse events. The study did not find a significant association. These events are likely to be rare, so researchers are encouraged to actively monitor and report adverse events in the future.

02. 62 clinical studies confirm the safety of mesenchymal stem cells

The latest meta-analysis published in "Stem Cell Research & Therapy" reviewed the clinical trials of mesenchymal stem cells in the past 15 years, identified all treatment-related adverse events related to the administration of mesenchymal stem cells, and explored the safety of mesenchymal stem cells in clinical applications. The conclusion showed: up to 15 years, 3546 patients, and 62 clinical research results confirmed the clinical safety of mesenchymal stem cells!

Only 2 of all the studies were prospective non-randomized trials, while the rest were randomized controlled trials (RCTs), ranging from phase 1/2 to phase 3 clinical trials.

Asia ranks first in terms of the number of clinical trials, with the largest number of studies, followed by North America and Europe.

The mesenchymal stem cells used in these studies were mainly isolated from bone marrow, adipose tissue, and umbilical cord. The injection dose ranged from 4×10^7 to 1.2×10^9 cells. The follow-up time ranged from 6 months to 2 years.

MSC administration was found to have no strong association with major adverse events, such as vascular disease, urticaria/dermatitis, central nervous system disorders, diarrhea, death, or infection.

The analysis showed that MSC treatment may cause patients to have a short-term fever within 48 hours. At the same time, MSC injection may also cause adverse events at the administration site.

Regarding other minor adverse events, mesenchymal stem cells may be associated with insomnia, constipation, and fatigue, but not with anemia, metabolic and nutritional disorders, nausea, seizures, and vomiting.

In summary, several completed clinical studies have confirmed that MSC administration is strongly correlated with transient fever and adverse events at the administration site, but is unrelated to other adverse reactions.

03. Summary

With the continuous advancement of technology, the safety of stem cells has been greatly guaranteed. Studies have shown that under certain conditions, the induced differentiation of stem cells can be effectively controlled, thereby avoiding the risk of tumor formation. At the same time, the immune rejection reaction after stem cell transplantation can be reduced by using methods such as immunosuppressants.

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