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Potential risk of tumor formation from adult stem cell therapy could be underestimated

A recent case report [1] about a boy who developed tumors after fetal neural tissue transplantation blows up in mass media this week. I have some words to say, but more general.

A few notes about this case report:
1. Cells that caused tumors 4 years after transplantation were derived from brain tissue of aborted fetuses. Were they stem cells, progenitors, mature cell, or a mix of all of them – we don’t know, because the clinic doesn’t provide a signature. But we know that it was brain tissue mash up. So let’s call them fetal neural cells (tissue) or somatic fetal brain cells – any way is correct. I do believe that the fetal brain contains stem cells, but i don’t know their presence in the suspension which that boy got.

2. We don’t know the real situation in the fetal tissue transplantation clinic – % of long-term complications (such as tumors), because there is no data, no statistics. The vast majority of this data is unpublished and unreported. Maybe it’s one case from 1000 (it could be fine then) or maybe % tumors formation is much higher?

3. We can not really extrapolate this case to all cell therapy fields, including embryonic, adult stem cells and cord blood. Because cells are so different, clinical protocols are so different and patient status is so different (some terminally ill, some not). In particular this case was not in “clinical trial settings”, meaning it was not regulated and permitted by government regulatory bodies. Plus patient was immunodeficient.

4. There is at least one earlier indication to potential teratoma-like growth of transplanted fetal neural tissue into the brain of parkinsonian patient. The first report about fatal case in 1996 published in Neurology [2].

A while ago I wrote about embryonic (ESC) vs adult stem cells wars [3]. So, I’ll remind you the main argument of “adult stem cell lovers” (= “ESC haters”) is that ESC gives you cancer! So forget about ESC – they are bad! Well, they do, but in immunodeficient mice. Will you see them in human – we don’t know. If it’s too dangerous to do them in clinic and potential benefits are less than the risk, the regulatory bodies of each particular country have to decide – approve the protocol or not.

Now we have a new evidence for spontaneous transformation of fetal cells (even after more than 20 years claims by “fetal cell therapy clinics” that it’s absolutely safe), without preclinical testing data. So forget about fetal cell therapy – it’s so bad! Now “adult stem cell supporters” will get excited. Now they can claim that “your own stem cells the only one safe source we guarantee”.

Well, I think if in the future we will get the same report about tumor formation after adult stem cell therapy (allogeneic or autologous), it will be not surprising for me. And I can tell you why. I’d like to discuss further about things that you will not hear from the private clinics, selling adult stem cells therapies, because it’s not good for business.

All of stem cell have a potential risk of tumori- or carcinogenesis, much more than mature cell types, it’s their nature to share genetic program with cancer cells. Some more (embryonic), some less (adult), but all of them!

Now I’ll get to the main point – adult stem cells – allogeneic or autologous- after expansion, there is a lot of evidence that shows the potential risk of tumorogenesis.

1. first of all we have a few reports about spontaneous transformation of adult stem cells (including human!) in culture after expansion (mesenchymal stromal and endothelial progenitors, neural stem cells); read references collection [4];
2. adult stem cells (including human MSC) gave tumors after transplantation into experimental animals [5];
3. donor’s hematopoietic stem cells in the clinic can give some kinds of leukemias many years after transplantation for correction of hematological diseases (including non-malignant!); read references collection [6];
4. There are some indications to possible carcinogenesis by donor cells after bone marrow transplantation [7] in the clinic. We don’t know how to interpret that yet (maybe just because most of patients got total body irradiation before the procedure), but it’s a fact.

So, this case report gives more cautions about potential risk of cell therapy when we didn’t expect it. That means we should be extra careful when a clinical protocol is designed and check safety of your cell product when it’s on the way to clinic. For example safety check might include teratoma assays and karyotyping before injections.

I’d like to finish with some citations from commentaries to the case report.

As you might expect, seeing a tumor arise from a cellular therapy, is nightmare outcome for anyone working in this field. As a former regulator at the FDA , I know it is a particular concern for stem or progenitor cells derived therapies, regardless of source; embryonic, fetal or adult.
The bottom line is that if you wish to test stem cells in humans in the U.S., the FDA is going to require robust evidence of efficacy and safety in relevant preclinical animal models, regardless of the source.
Now the FDA has an clear example it can point to, for better or for worse, to justify the extensive preclinical studies it requires.
Darin Weber – Biologics Consulting Group, ex-FDA adviser [8]

I hope it makes people think twice about how cells are isolated and maintained before transplant.
Steven Goldman – chair of neurology at the University of Rochester in New York and an adviser to the US FDA

This paper is actually a really good thing for the field. People who undergo these cell-based therapies have a responsibility to share any adverse events that happen.
Insoo Hyun, a bioethicist at Case Western Reserve University in Cleveland, Ohio

This paper does a very good job of showing that the cells that constituted this tumor did not arise from the patient and were not genetically identical to either of the parents, and clearly came from the donor tissue.
It’s a cautionary tale for studies currently being done in the US and elsewhere.
Since the patient developed the brain tumor four years after the initial injections, researchers may need to monitor patients for a long time after a treatment to evaluate safety.
Arnold Kriegstein – Broad Center of Regenerative Medicine and Stem Cell Research at the University of California, San Francisco

…it’s premature to translate these findings to studies conducted in the US. The researchers who conducted the transplant followed the protocol of a group that has published only one other paper in an international, peer-reviewed journal, and the cells used are a mixture of glial cells, neurons, and progenitors – “a sort of cell mush,” she said. These are “completely uncharacterized populations, populations that would never be accepted in the US or any first-world country.
Aileen Anderson – University of California, Irvine

This is a case report. It has its role in saying it can happen, but we don’t know if it’s common, if it’s uncommon.
Uri Tabori -Hospital for Sick Children in Toronto, Canada

“there are almost no similarities” between the Moscow procedure and our company’s clinical trial.
…one isolated case doesn’t threaten the whole field.
John Sinden, ReNeuron’s scientific co-founder

The outcome in this case reported in PLoS needs to be understood in its proper context. The case involved a diagnosis that has a known increased risk of cancer, and a patient who underwent repeated cell injections eight years ago using multiple donor sources and who had uncertain medical follow-up between transplants.
It would be unfortunate and a disservice to the field of cellular therapy, and those conducting organized research, if results from isolated and uncontrolled transplants were to color people’s perceptions of the prospects of cell transplantation for the treatment of serious neurological disorders.
Stephen Huhn [9]Vice President and Head of the CNS Program at StemCells, Inc.

some citations adapted from:
Monya Baker. Tumours spark stem-cell review [10]. Nature News 17 February 2009 doi:10.1038/457941a [10]
Tia Ghose. Stem cell therapy triggers tumor [11]. the Scientist 18th February 2009
picture credit [12]

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