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

by Alexey Bersenev on February 21, 2009 · 10 comments

in cancer, clinical trials and cases, under discussion

 
A recent case report 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 The vast majority of this data is unpublished and unreported.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.

A while ago I wrote about embryonic (ESC) vs adult stem cells wars. 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;
2. adult stem cells (including human MSC) gave tumors after transplantation into experimental animals;
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;
4. There are some indications to possible carcinogenesis by donor cells after bone marrow transplantation 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

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 HuhnVice President and Head of the CNS Program at StemCells, Inc.

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


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{ 10 comments… read them below or add one }

Darin Weber February 21, 2009 at 11:40 pm

Alex:

Thanks for providing a collection of references to additional publications that touch on this issue with different cell types and clinical indications. It reinforces the concept that regardless of the cell source (adults, embryonic, fetal, iPS, etc..) it will certainly almost always be necessary to assess safety in preclinical models and as part of clinical follow up of recipients.

–Darin

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Sergei February 24, 2009 at 4:30 am

Well, well, well… I don’t think that the whole story is something to discuss. Some guys in Moscow transplabted some (maybe already oncogenic see Methods in the paper “karyotipically normal fetuses” -what it does mean)messy cells (neurospheares or big nucleus?). 2 out of 4 genotypes became or were tumorogenic. Due to patients niche or nobless moscow guys skills? Did we expect it? Yes, we did. What chances? Nobody knows but in general it looks that the less cells are differnetiated more chances of it. One disease or another? What do u prefer SCID or leukemia? It s not even patients’ choice.
But what I really like that this experiment was set up in Russia. It is really fantastic country with unlimited possibilities. Yor remeber this social experiment started nearly century ago, or unique Chernobyls’ experiment. Russia should be in frontiers of stem cell therapy also. I am sure that russian “adult stem cells” people will contribute largely in the field in the nearest future. Experiments are already started let’s wait for the outcome.

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Alex February 24, 2009 at 4:53 am

to Sergei –
I do believe that China could be ahead Russia in those kind of experiments. And “medical tourism” crowd goes to China is more then in any other country. So China actually has incredible experience and we can’t wait to hear about the outcome.
Also in order to prove that China is pioneering in that I linked to the paper back in 1996, published in Neurology – http://www.neurology.org/cgi/content/abstract/46/5/1219

even report didn’t say “tumor formation”, it’s clearly described that autopsy findings indicating to teratomas – tumors containing hair, bones… Proliferation of which basically caused the death.

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Alex February 25, 2009 at 3:00 pm

one more interesting citation:

The Jerusalem Post learned that the researchers’ work, just published in the US Public Library of Science (PLoS) on-line, open-access journal, was initially turned down for publication by the highly prestigious journals Nature and Science.

One of the study’s authors, Dr. Ninette Amariglio, suggested that the journals were apparently “fearful of the multi-billion-dollar stem cell lobby, as the study could hurt its prospects.”

In addition, publishers “prefer optimistic science. Our study is not pessimistic, but it warns that researchers have to be aware of possible complications and dangers,” said Amariglio, who heads the Diagnostic Molecular Hemato-Oncology Laboratory at Sheba Medical Center.

link

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PNewman July 25, 2009 at 1:07 pm

The adult stem cells that come from one’s own body do not have this problem. I know many people who have had much success with autologous stem cells. These are the repair cells that are part of the bodies immune system and do produce safe results.
Do read the information on:
http://www.safestemcellsdotorg for further details.

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PNewman July 25, 2009 at 1:08 pm
Alex July 29, 2009 at 2:20 pm

to PNewman,
I don’t argue that your “adult stem cell” product could be safe, if you use autologous and non-expanded, minimally manipulated, tested in vitro and in vivo for safety tests…approved product. But you have to tell that. Not all of “adult stem cell” products/suspensions injected in patients are similar. Some of them never been tested in vitro and in vivo toxicity and safety assays, especially if we are talking about ex-vivo expanded product (when you expose your own cells by cytokines). Examples that I noticed above shows that.
So when you talk about “our safe cells” you can not extrapolate it to all “adult stem cells”. It could sounds like marketing.

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pNewman July 29, 2009 at 3:32 pm

If you check with a company called Vet Stem -they have successfully (with verified scientific documentation) that they have achieved reversals of arthritis in dogs, and horses by using the animals own ASC’s extracted from fat tissue. They are now advancing to auto-immune diseases treating with adult stem cells from the animals own cells. I am stating that this is already working for animals in the USA, and it seems odd that people cannot have these treatments here-but must go to foreign countries. The USA is missing out -on medicine for the future and instead is concentrating on archaic and outdated, useless drugs to treat symptoms instead of curing diseases. The focus has been on treating the symptoms and causing damage to the bodies immune system rather than working with it.
You must also know that other countries are not under the control of drug companies and therefore will achieve successful cures for diseases.

I would think it is time to put money into find cures rather than prolongation of disease for the sake of drug company profits.

If you wish to reduce health care costs in this country (and who doesn’t) then finding cures should be the objective and goal. I would much rather have stem cells extracted from my own body, to use them to repair damages in my own body and I am the sole owner of those stem cells. It seems the FDA is stifling progress by their recent declaration that my own stem cells be classified as a drug? This purpose of this -is to control my own immune system while I am trying to cure my disease. Take COPD for instance, patients are facing death- would you like to receive sc treatments if it was you- or just die?
Choices-are to go to foreign countries -and this must stop now. Embracing the medicine of the future is the only way to ensure the health of this population, not by delays, and unnecessary research designed to delay these scientific breakthroughs.

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Alex August 1, 2009 at 10:11 pm

to pNewman –
What wrong if americans will go abroad for treatment? If their country can’t provide them the same treatment, because of regulatory bodies, why not? Do you think if FDA will allow autologous cell therapy free of “drug regulation rules”, americans can get better deal? Cheaper? More quality? More safe? Why?
I’m not a proponent of cell therapy abroad, because it’s mostly “low quality work” IMHO, based on money motivation. Just curious about your opinion.

As you know medical tourism was always here for a centuries. Thousands of people from around the globe come to MD Anderson Cancer Center or Mayo Clinic to get the best and unique surgical procedures that they can’t get in their countries, because of absence of technical advances or regulation.

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P Newman August 2, 2009 at 1:51 am

Alex I have no problem with people traveling anywhere to get treatment to save their lives-China or the moon does not matter. It is a shame that dogs can get adult stem cell treatments-and people are being stopped from getting it in the USA. Drug companies want to make sure they get a big slice of the pie-before ASC are ever researched seriously.

If the US government is so stupid -as to allow the drug companies to dictate research then people have no choice. I hope China develops a cure for all diseases including cancer…really fast. They will be the hero’s of the world, the US will lose the race -once again. You can thank the greedy corporations who are making profits off of diseases.

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