Cautionary Tale: Tumors Caused by Neural Stem Cells

I usually avoid commenting on current events occurring in the field of regenerative medicine, primarily because I can’t keep up!  In this case,  I believe the recent publication by Amariglio et al, has FDA regulatory implications for the clinical development of therapies based on stem cells.  The under-lined portion of the title of the publication says it all:

Donor-Derived Brain Tumor Following Neural Stem Cell Transplantation in an Ataxia Telangiectasia Patient”


If you haven’t read the journal article, I would strongly encourage you to do so.  As has been widely reported in the press (examples  here and here) tumors developed in the spinal cord and brain of a recipient after receiving a series of  three fetal cell transplants over several years.   The authors appear to have some very nice work to clearly demonstrate the cells present in the tumors that were surgically removed came from one or more of the fetal tissue transplants the recipient received over a period of several years.

In the case reported by Amariglio et al, it appears the fetal cells were administered at a clinic in Moscow.  I quickly looked at the stem cell preparation protocol included as supplementary information and did not see any mention that the fetal cells were characterized to determine if the desired cell types were present in the preparation given to the recipient.  However, it does appear the stem cell preparation has been previously published.  Though in the abstract of that paper the authors clearly point out

“Samples from embryos of even the same gestation differ dramatically regarding neural cell development, their phenotype and viability”

This obviously raises the issue of what exactly was transplanted into the recipient? An equally important question is given the recipient’s disease state, should he have been considered a suitable candidate for this type of therapy?  I don’t know anything about the clinic where the cells were administered, but presumably the parents of the recipient were led to believe fetal neural cells might help their child.  Presumably, money changed hands in order for the cells to be administered.  Hopefully, now that the ISSCR has issued its Guidelines for the Clinical Translation of Stem Cells and companion appendix Patient Handbook on Stem Cell Therapies Parents or anyone  considering if a stem cell transplant, of whatever source, should be considered for a loved one, will be better prepared to ask some tough questions of those who offer the hope of a cure of at least some improvement.

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.  The good news is that many developers of stem cell derived therapies, including Geron, have in fact been able to generate the preclinical efficacy and safety data needed to enter human clinical studies.  Now let’s hope these therapies deliver on the promise to address the unmet medical needs of so many patients, while at the same time being safe.

Let me know in the comments how you think this unfortunate case will impact the field of regenerative medicine, including stem cell therapies.

–Darin

5 comments ↓

#1 Lee Buckler on 02.20.09 at 5:14 pm

Darin,

Great post. Thanks for putting this out there. It is important that people in the industry put out balanced analysis on the issue.

Stem Cells Inc also released today what I thought was a well-considered “commentary” on the report.

http://www.businesswire.com/portal/site/google/?ndmViewId=news_view&newsId=20090220005092&newsLang=en

I’ll add my take on the topic in this week’s issue of Cell Therapy Industry HiLites which will be posted later today and will certainly link my readers back here for your analysis.

Keep it up.

–Lee
http://www.celltherapyblog.com

#2 Lee Buckler on 02.20.09 at 5:33 pm

Darin,

Do you think this will have any implications on how insistent (or not) the FDA might be on the need for cell tracking studies (using image-able cell labels) as part of the pre-clinical and/or phase I package?

–Lee

#3 Darin on 02.21.09 at 12:50 am

Lee:

Great question. I don’t think this specific incident will be cited by the FDA regarding the importance of performing biodistribution studies for cellular therapies, since it seems the cells did engraft in the CNS, where they were supposed. It is of course their ‘behavior’ in terms of forming aberrant tissue (i.e., tumors) that was unexpected, which is why the FDA typically requires tumorgenicity studies in which cells are delivered to severely immunocompromised rodents at the intended site/route as planned for human studies.

However, your point is very important since everyone wants to know where the cells go. Some groups genetically modify the cells with markers such as green fluorescent protein (GFP), oblivious to the fact that the FDA almost always rejects the results from preclinical safety studies, since GFP modified cells are not clinical product intended for use in humans and FDA is concerned that the modified cells may not reflect the behavior of the cells to be administered to humans. The net result is they have to repeat the studies using non-genetically modified cells. As a result, there is tremendous interest in identifying ways to label cells with materials that do not significantly modify the cells. Some examples under development include “quantum dots,” iron-dextran beads and perfluorocarbon derivatives. I am sure there are others I am forgetting. I believe there is a real opportunity for someone to develop an imaging agent for cells that could be used both in preclinical research and following clinical transplantation of cells.

–Darin

#4 Thomas Ichim on 02.21.09 at 11:31 pm

Working for a company that has recently filed an IND on a new cellular product (Endometrial Regenerative Cells), I can sincerely state that my interactions with everyone in the Agency have been very positive.

The issue of potential tumor formation has always been in the minds of both regulators and industry. HOWEVER it will be a great error to overemphasize the importance of this unfortunate incident.

The complex differences between embryonic, fetal, and various types of adult stem cells, and also depending on culture conditions can not be argued in one publication or brought down to the level of a public “opinion” forum.

Our position has always been that with any new cellular therapy, as much data as possible must be published so that other scientists and regulators can comment and take the science to the next step. People like Darin have published their opinions in various peer reviewed settings. Unfortunately when i speak with my CEO colleagues I do hear a somewhat reluctance to publish…”if you want to publish Tom, you should have stayed in Academia” they tell me.

This unfortunately incident tells us how important it is to publish and share our information so as to be able to have a scientific debate about what should and shoudl not be allowed.

Personally, I feel that there is too much momentum in the field for this to have a major impact. With Osiris anticipated BLA in 2010, the demarcation between adult and fetal stem cells will become very clear.

Tom

#5 Darin on 02.22.09 at 12:19 am

Tom:

Thanks for your insightful comments on this case report. I absolutely agree that more publications of this type are welcome, so that the entire field can ‘learn’. Congratulations on filing an IND!

–Darin

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