More than two years ago, in the first post of “Stem Cell Autopsy” series, I’ve linked to the 1996 Neurology report about the complication of intra-cerebral transplantation of fetal tissues. Recently, the story behind of this bizzare case, was described in the book “When Scientists Go Wrong” by Simon LeVay. You can read the ” neuroscience chapter” for free here. I was really thrilled by the story when was reading this chapter. There were a lot of interesting details. It turns out that It was the first and the only one case of teratoma development in cell tranplantation history. Today I’m sharing more details on this case and quotes from the book.

The author described a development of clinical fetal cell neurotransplantation and interviewed the key people, who was involved in the case of Parkinson’s Disease patient – Max Truex. Neurotransplantation of fetal brain tissue in Parkinson’s Disease was pioneered in 1987 in Sweden.

Then, in November 1988, the first American foetal transplant was performed by a team led by neuroscientist Curt Freed of the University of Colorado. Freed had researched the technique for years, first in rats (like the Swedes) and then in monkeys. This research was funded by federal grants, but when he began the human work Freed had to turn to private funds because the Reagan administration, concerned about the abortion issue, had banned the use of federal grants to support transplantations involving human foetal tissue.
For the first transplant, Freed selected a volunteer by the name of Don Nelson, a 51-year-old Denver man who had been suffering from Parkinson’s disease for 19 years. As with Max Truex, Nelson was deteriorating fast and he was desperate to try some new therapy. Freed obtained foetal tissue from an abortion clinic in the Denver area, dissected out the substantia nigra and (with the collaboration of a neurosurgeon) injected the foetal cells into the striatum on one side of Nelson’s brain.
If the Swedes were publicity-shy almost to the point of secretiveness, Freed was the very opposite: he held a news conference to announce the transplant just two days after the operation, long before he could know whether Nelson would experience any benefit from the procedure.

Years after diagnosis, Max was under observation of their family’s friend – neurosurgeon Paul Iacono (link). Dr. Iacono was brave enough to decide to take him in China and transplant fetal tissues into Max’s brain. It was 1989. The technique was pioneered in 1987. Very few physicians were able to perform this procedure around the world and all of them have rejected Max Truex. China was the only country which agreed to provide them a hospital bed and abundance of aborted fetuses.

In any event, Iacono said that he made great efforts to find a place where Truex could get a foetal transplant. ‘I tried all my friends all over the world – Sweden, Britain, Japan. I tried and tried. And eventually, after two or three years of following Max, I realised I had to do it myself.’

Another surprise had to do with money. According to Kay, the doctors, at the Zhengzhou hospital, or the hospital administrators, demanded a substantial fee – she thought it was in the range of $20,000 to $25,000 – to let the operation go ahead. Don said that Max told him the fee was close to the annual operating budget for the hospital.

Max’s parkinsonism symptoms improved after the transplant and he was fine during almost two years. But in March of 1991, he started to feel something strange and became concerned about his death.

Rebecca Folkerth is a pathologist who performed Truex’s brain autopsy. She was the only available neuropathologist on Sunday at New England Medical Center:

‘I answered my page on the Sunday night and I said, “OK, I’ll come and do this autopsy.” It sounded like Durso was having trouble getting anyone to help him.’

Folkerth reached the hospital around 9pm. ‘Once I got there, I got a call from Dr. Iacono,’ she says. ‘He told me the whole history and said, “Can I ask you to take some of the tissue fresh and freeze it?” I said, “OK, fine.”

Up to now, Folkerth hadn’t noticed anything unusual about Truex’s brain. ‘But as I was cutting it,’ she told me, ‘I made this observation, “Gee, look at this strange stuff in the ventricles, in the third and fourth ventricles, and in the lateral ventricles also.” I thought, “Isn’t that odd?” and I took a bunch of pictures. And I thought, “That looks like cartilage; isn’t that weird!” Even to the naked eye it looked like cartilage, and there were hairs – you could see them, just eyeballing it – the gross pictures are extremely dramatic.’

Brains don’t usually contain cartilage or hair, of course. Nor bone or skin, which she later discovered were also present. ‘You could see the hair shafts,’ she went on. ‘So I knew there was something very strange about this right away. Oh, this was the most strange thing I’d ever seen, and at this point it was the middle of the night. I was the only one there, looking at this case and thinking, “What the hell is this?” It was creepy. So here I am taking these pictures and thinking this is some mistake; this is a tumour – a teratoma.’

Lumps of glistening cartilage lined the floor of one of the ventricles. Part of one of the lateral ventricles was completely filled with a waxy, skin-like tissue. The fourth ventricle, which is located in the brainstem near nerve centres concerned with breathing and other vital functions, was packed full of hair and other tissues, so much so that some of the surrounding brain structures were compressed and discoloured.

There was no doubt that the teratoma originated from transplanted fetal brain tissue.

This whole experience left a big impression on Folkerth, and so over the next few months she devoted a lot of her free time to analysing the tissue samples from Truex’s brain. In the left and right striatum, where Iacono had deposited the tissue from the two 16-week-old foetuses, she found no surviving cells from the transplant, only scar tissue. This was consistent with findings from other research groups, who have reported that tissue from foetuses this old has a very low chance of surviving the transplantation procedure. Folkerth concluded that the reported improvement that Truex had experienced was not due to the presence of any transplanted nerve cells in his brain. Either just the damage caused by the injections had a beneficial effect, which didn’t seem terribly likely, or some other factor, such as the new drug that Truex received, was the reason.
What about all the weird tissues in the ventricles? These presumably arose from the tissue that Iacono had dissected from the very young, five- to six-week-old foetus and had injected into the left lateral ventricle. Folkerth believes that Iacono mistakenly included some tissue that was not from the embryo’s brain at all – tissue from just outside the brain that normally would have developed into the overlying bone, cartilage, skin, and hair.

Later on, Folkerth decided to proceed with publication, but without Iacono:

Iacono had been the initial driving force behind the autopsy, and it would have been natural for him to participate in publishing the findings that emerged from it. In fact, at a scientific meeting three months after Truex’s death, he announced that the results of the autopsy were ‘pending’. But later, Iacono seemed to lose interest in having the results published.

In the publication Folkerth did not mention American physician, who traveled in China with his patient. She also didn’t use a term “teratoma” to describe a cell mass from Max Truex’s brain. The story about publication is quite interesting:

After more than a year’s delay, they sent their manuscript to the New England Journal of Medicine, because that journal had already published several articles about foetal-cell transplantation for Parkinson’s disease. But the manuscript was rejected. ‘That was funny,’ says Folkerth. ‘I thought this was something that was definitely worthy of being in that particular journal.There seemed to be kind of a pro-transplant point of view in the other articles they had published.’
What Folkerth didn’t know was that her manuscript was reviewed by Curt Freed, a major enthusiast for foetal-cell transplantation and an author of one of those ‘pro-transplant’ articles in the NEJM.
The rejection of the manuscript caused another delay, but in 1995 Folkerth and Durso sent the manuscript to another, less prestigious journal,Neurology. It was accepted, and it appeared in 1996, five years after the autopsy it described.

Iacono didn’t respond to the Neurology article, or if he did his response didn’t get published. But the journal did publish a response from a research team that had begun to do foetal-cell transplants at the University of South Florida in 1993. Evidently, this team, like Curt Freed, was worried that Folkerth’s article would throw the field of foetal-cell transplantation into disrepute, and they expressed their feelings about what Iacono had done in unusually strong language. ‘This is a case of extremely poor tissue dissection,’ they wrote. ‘One wonders why this transplant was performed in China,’ they added, ‘outside of State and Federal regulations, Institutional Review Board oversight, and peer review scrutiny.’ ‘We should not be surprised,’ they concluded, ‘that poor science leads to poor outcomes.’

Finally, what Iacono thought about Truex’s death:

Iacono never abandoned his conviction that Truex was greatly helped by his transplants, and he rejected the idea that the tissue in his ventricular system caused his death. ‘There weren’t any signs of increased intracerebral pressure,’ he told me. ‘He wasn’t having urinary incontinence, he wasn’t showing signs of dementia, he wasn’t complaining of headaches. He was acting normally, and his wife said he came in and sat down and died. That just doesn’t sound like [ventricular blockage]. His death was officially signed out as a heart attack.’ (Kay says that Max’s death certificate lists only ‘Parkinson’s disease’ and does not mention any immediate cause for his death.)

So, we have confirmed case of teratoma development after fetal tissue transplantation in human brain. According the patients observation in clinical trials, this case is unique and only the one. Nevertheless, it’s well documented. I was really surprised by the fact that human embryonic tissues (5-6 weeks of gestation) still retain the pluripotency. What do you think?

Download 1996 Neurology report

PS: Special thanks to Doug Sipp for the link to the book chapter!

Related posts:

1. Stem cell autopsy: clinical cases in lupus nephritis and multiple sclerosis
2. Analysis of autopsy material after allogeneic mesencymal stromal cell infusions
3. Stem cell autopsy: Two ALS cases of neurotransplantation in China

More than 200 clinical trials assessing safety and efficacy of mesenchymal stem cells (MSC) are currently ongoing around the world. Now we have many reports about safety of MSC infusions, but we still have no idea what is really going on with cells after infusion. Autopsy material can provide valuable information about cells fate, the mechanism of therapeutic action and long-term complications of cell therapy. Unfortunately, we are lacking reports about pathological finding from autopsies of patients, who underwent MSC-based therapies.

Katarina Le Blanc‘s group from Karolinska Institutet has published a very very important analysis of autopsy material from patients, who underwent MSC infusions. This report is not available in open access, so I’m going to summarize some very important points here.

The authors analyzed 18 patients with hematological malignancies and solid tumors, which underwent HLA-matched allogeneic MSC infusions to treat/ prevent complications of hematopoietic stem cell transplantation (GVHD, hemorrhagic cystitis and some others). All patients died in 3 – 408 days (median 21 days) after the last MSC infusion. Donor’s MSC’s DNA was detected by PCR in multiple tissues. The results of this analysis are the following:

1. No solid tumors (of any origin) or ectopic tissue formation was observed.
Lymphoproliferative disorder was diagnosed in two patients, but no link to infused MSC was found.

2. Tissues from 8 out of 18 patients (44%) were positive for MSC donor DNA. Quantative analysis was done in 6 cases. Only one patient had MSC donor DNA > 1/1000 cells. Positive MSC were found mostly in the lungs, lymph nodes and intestine. MSC donor DNA in bone marrow was detected only in one case.

Histological examination of engrafted MSCs was not possible due to the scarcity of the cells. We can therefore not conclude that the DNA detected represents true MSC engraftment.

3. There were no correlation found between MSC engraftment (donor DNA) and treatment response:

… of the fifteen patients available for PCR analysis, three had shown a complete response to MSC therapy, six a partial response and six were classified as non-responders.

4. Detection of MSC donor DNA was negatively correlated with time after infusion and autopsy/ biopsy.

The bottom line: Intravenous infusion of matched allogeneic MSC does not cause severe complications, such as tumor or ectopic tissue formation due to rapid clearance from the recipient. More likely, allogeneic MSC act as “medicinal cells” shortly after infusion and do not engraft in the tissues. The persistence of donor’s MSC in recipient does not correlate with treatment efficacy:

The function of MSCs appears to be mediated through a “hit and run” mechanism rather than through sustained engraftment in the injured tissues.

Overall, this remarkable study is very unique and well done! Highly recommended to read and cite!

Related posts:

1. Clinical neurotransplantation of fetal tissues – analysis of histological findings
2. Stem cell autopsy: clinical cases in lupus nephritis and multiple sclerosis

Today, I’d like to introduce a guest post by Frances Verter. Dr. Verter is a Founder and a Director of Parent’s Guide to Cord Blood Foundation.

*********************************************

This is a guest post by Frances Verter

This table is an effort to capture a snapshot of all the current clinical trials that are using stem cells from blood or tissues harvested at birth.

The primary research source for this table was searches of ClinicalTrials.gov between Dec. 2011 and Mar. 2012. I have also relied on Lee Buckler’s posts to his Cell Therapy Blog.

Emerging Therapies with Perinatal Tissues and Stem Cells

Table copyright Frances Verter, PhD 2012

Related posts:

1. An update for cord blood clinical trials
2. Clinical neurotransplantation of fetal tissues – analysis of histological findings

Note: There is a print link embedded within this post, please visit this post to print it.
Today everyone is talking about stem cell therapy everywhere. It’s hot, it’s popular, it’s sexy. But nobody ask the very important question: “What is the real stem cell therapy and how can we define it?” I’ll try to answer this question and propose a definition.

Background:
It seems very simple to say “injection of stem cells with therapeutic purpose is a stem cell therapy”. Unfortunately, this current assumption is too far from reality and could mislead the public and professionals. I’ll try to explain why I think so. I’d like to look at 3 parts of this problem – quantity, purity and function of stem cells in therapeutic cell product. I’ll discuss about adult stem cells.

In reality nobody never inject pure stem cells. It’s always a mix of different cell populations. It could be a mix of different stem cells, progenitor cells or mature cell populations from the same or different lineages. In any case – it’s never pure. Even if the percentage of well defined stem cells in heterogeneous cell mix is relatively high (aka enriched stem cells), we still have some accessory cells (let’s call them contaminants), which could possess therapeutic value. Also, we always have to keep in mind that any given tissue contain a tiny population of adult (tissue-derived or resident) stem cells. For example, in blood transfusion we transfer some circulating hematopoietic stem cells, but we never call it “stem cell therapy”.
The bottom line 1: In definition of stem cell therapy we can not rely just on the presence of stem cells in transplanted cell suspension/ tissue.

But what if we start to enrich stem cells? The stem cell enrichment is definitely increasing a probability of their contribution into therapeutic effect (aka potency), because of depletion accessory cell-contaminants. But in many cases enrichment doesn’t play any role. For example, hematopoietic stem cells (HSC) transplantation in hematological malignancies. We can take the whole bone marrow or lineage negative fraction (~ 20x enrichment for HSC number) or CD34+ sorted fraction (~ 40x enrichment) or sort pure Lin-/CD34+/CD38-/CD45RA-/CD49f+/Rho- (~ 400-500x enrichment). If we transplant any of these cells in conditioned patient, we will get the same result – life-long engraftment, multilineage blood chimerism and leukemia eradication. It’s clear “stem cell therapy” and it does not depend on degree of stem cell purification.
The bottom line 2: In definition of stem cell therapy we can not rely purely on degree of stem cell enrichment (purification) in transplanted cell suspension/ tissue.

Now, the most important part. The biological function of stem cell which determines the potency of the transplanted cell suspension should justify our “therapeutic purpose”. In other words – if population of stem cells in any given cell suspension/ tissue underlie the mechanism of anticipated therapeutic action, it’s a “stem cell therapy”. This issue is extremely important in so-called “non-homologous use” of cell therapy. For example, let’s look at bone marrow mononuclear cells (BM MNC) – the most frequently used source for cell therapy. If we use BM MNC for cardiac repair or diabetes, many types of cells could cause therapeutic effects in the heart or pancreas – myeloid hematopoietic progenitors, lymphoid cells, putative endothelial progenitors, HSC or mesenchymal stromal stem cells (MSC). Only if therapeutic effect is exclusively attributed to the latter two (HSC or MSC) populations, we can call it “stem cell therapy”.
The bottom line 3: In definition of stem cell therapy we should solely rely on anticipated mechanism of therapeutic action, which should be exclusively attributed to stem cells, but not to progenitor or mature cells.

Finally, the mechanism of therapeutic action by stem cells should be proven and based on evidence. Few examples:
1. If adipose tissue-derived stromal vascular fraction (SVF) highly enriched for mesenchymal stromal cells (MSC), we would guess that this population cause therapeutic effect in cosmetic applications. But if anticipated mechanism of therapeutic action is a collagen synthesis, it could be attributed to fibroblasts from SVF as well. I don’t think we have any evidence, which indicate that MSC of SVF exclusively do this job.
2. If we use CD34+ purified cells (which is very heterogeneous population) in cardiac cell therapy and expect stimulation of angiogenesis as a mechanism of therapeutic action, we should not call it “stem cell therapy”. At least 3 different cell types within CD34+ population could contribute to this effect – HSC, myeloid hematopoietic progenitors and putative endothelial progenitors. As you all know, stem and progenitor cells are fundamentally different.
In both cases we don’t have evidence for exclusive stem cell effects, therefore, we should not call it “stem cell therapy”.
3. Bone marrow and cord blood transplantation in hematological malignancies is a proven “stem cell therapy”. The evidence is based on long-term observations of life-long persistence of transplanted stem cells which exclusively contribute to multilineage blood formation. Please note that at the beginning (first few months) bone marrow transplant in leukemia could act as a “progenitor cell therapy”, but later stem cells exclusively underlie the life-long blood support and cure.

The definition:
Stem cell therapy is a type of cell therapy in which therapeutic efficacy exclusively attributed to the potency (function) of donor stem cells, presented in any quantity and purity.

Special considerations:

1. This definition is applied to adult or/and neonatal stem cells but not to embryonic stem cells. In case of embryonic stem cells, use of any derivatives could be called “stem cell therapy” or “stem cell-based therapy”.
2. Long-term persistence of stem cells after transplantation is not included in this definition. Stem cells could hang out in the body just for a little while but do the whole anticipated “therapeutic job”.
3. In all unclear cases where we have no evidence, we should use more general term “cell therapy” (by default) instead of “stem cell therapy”. Bear in mind that we frequently have no idea what is the mechanism of therapeutic action of transplanted cells and what cell type actually do the major job.
4. It is a working definition. I’d like to hear your opinion in order to polish it. You can give your examples in comments and we can discuss what is “stem cell therapy” and what is not.

Final remark:
I think it’s a very important issue, because currently professionals and mass media over-use and over-hype adult stem cells and the “stem cell therapy” term. It’s not just a matter of semantics! There is a real danger of uncontrolled branding of stem cells. Widespread use of “stem cell brand”, which distorts reality, can mislead the public and discredit stem cell research field.

No related posts.

Note: There is a print link embedded within this post, please visit this post to print it.
In the last 3 weeks, we have witnessed some interesting moves against so-called “stem cell tourism”. Crackdown on “stem cell treatment” fraud in US, popularization of the problem via “60 Minutes” broadcast and start of reforms in China.

I’ve asked Doug Sipp to comment on some recent events and on the problem in general. Here is my Q & A with him.

Doug Sipp – a Leader of Science Policy and Ethics Studies Unit at the RIKEN Center for Developmental Biology (Japan). He intensively writes on the problem of “stem cell tourism”, regulation and ethics of stem cell research and applications. He is the author of Stem Cell Treatment Monitor blog.

**********************
1. The first question about the current situation in China. The recent news about China’s government order to stop unproved stem cell treatments, made a buzz in mass media. But, what does it really mean? If I understand correctly, the China’s SFDA will stop to accept new applications for clinical trials involved stem cells (as Reuters reported) until a new regulation law. Will government’s order apply to new trials approval only? What will happen with ongoing trials? Why did they decide to start reforms from clinical trials? Trials is the right way to test stem cell treatments. Why halt this?

I have to admit that this recent development took me by surprise. I have not been able to get any behind the scenes details about what led to the new crackdown, but whatever the reason I can say that this is very welcome news! I do not believe that the new ruling applies only to new trials seeking approval, as other local news agencies have reported that “…all unauthorised and unproven stem-cell clinical trials and applications should be suspended immediately, and those approved by the State Food and Drug Administration should follow to the letter the authorities’ instructions, with changes to the trials and profit-seeking banned.” (South China Morning Post)

It is difficult to determine what effect this will have on ongoing legitimate trials and decidedly less legitimate business models– the MOH/SFDA clearly want to put limits on the ability of trial sponsors to tweak or turn a profit on clinical studies that have been approved already, and they specifically state that there should be no charges to patients who enter an approved trial. That said, many medical regulations in China are honored mainly in the breach, and the situation is complicated even further by the fact that hospitals operated by the military, or by organizations charged with promoting development in designated “special economic zones,” operate in effectively separate regulatory domains. In fact, while all such national regulations are established by central government agencies, the enforcement is generally carried out by local authorities (at the level of province, prefecture, or municipality), which results in a highly variable enforcement landscape, despite apparently uniform regulations.

I don’t have access to the reasoning behind this recent decision, so I cannot say with confidence why the MOH and SFDA have taken the extreme measure of putting an across the board hold on clinical trials, but I suspect it was motivated by the widespread abuse of the system by profiteering clinics and individuals, which has harms the reputation of Chinese stem cell basic and clinical research. An enormous number of hospitals, many of them operated by branches of the Chinese military, have made a mockery of legitimate stem cell clinical research, and I think the Ministry is responding directly to this challenge. That said, the ruling does not seem to have had an immediate effect, as a large number of hospitals continue to advertise stem cell treatments for which there is no scientific evidence of safety and/or efficacy in both Chinese and English. Only time will tell whether the new regulations will prove to be more effective than the Advanced Medical Technologies Law passed in 2009.

2. It seem to me that China should start from prohibition of unproven treatments, which are currently offered by commercial clinics and big hospitals without official market authorization. Were commercial stem cell treatments offered as a part of clinical trials or were unregulated at all? What is your take on this?

I agree that it makes sense to prohibit the delivery of untested stem cell products and procedures outside the context of clinical trials. What appears to have happened in China, however, is that there has been such widespread abuse of registered clinical trials involving stem cell applications that the entire system has become corrupted. I believe this is why the authorities made an explicit statement to the effect that “all clinical trials of stem-cell therapies should be free,” meaning that research subjects should not be charged for their participation in medical experiments in which the risks and benefits are, by definition, unknown.

In other countries as well, several clinics and industry-led organizations have attempted to justify “fee-for-service” clinical research and “self-regulatory” oversight schemes. This has led to widespread abuses of patient trust in the interests of profit. The Chinese government is right to be concerned about such abuses, and is justified in taking extreme measures to allow it the time needed to develop its ability to enforce the existing laws on clinical research.

3. Seem like a few noticeable organizations in China, which are conducting clinical trials, have a big impact on stem cell tourism and international reputation. Shenzhen Beike Bio – a company, which is currently conducting at least 5 trials, registered in international databases. Guangzhou Military Command Hospital and General Hospital of Chinese Armed Police Forces are conducting 4 and 5 trials respectively. Almost all of these trials are involving exclusively allogeneic mesenchymal stromal cells derived from umbilical cord. How are they currently regulated and how new ruling will impact their activities? I also wonder why they pay so much attention to the one particular stem cell source?

China has historically been one of the major players in the global “stem cell tourism” industry, as you note. The system under which treatment centers have been able to operate with impunity remains opaque and confusing, even to researchers in China. As I understand it, the problem is not so much with the rules, but with their enforcement, which has been negligible to date. For example, in the 2009 law on advanced medical technologies (which specifically included novel stem cell treatments), the only penalty for violation was a fine with a maximum Yuan amount equivalent to several hundred USD, which is unlikely to dissuade companies that charge tens of thousands of dollars per patient. In any case, it appears that enforcement is carried out in a scattershot fashion, and that many companies have been able to operate in the open with effective immunity from the law. The total picture is one of a dysfunctional system – I think that the MOH/SFDA are now acknowledging this and have, in effect, hit the Reset button.

This sort of action is becoming more and more important as the country’s investments into legitimate scientific research in the field of stem cells is beginning to bear real fruit (I have recently co-authored a paper, published in this month’s issue of Cell Stem Cell, which highlights many of the positive developments in China’s stem cell research). I think the Chinese government realizes that if its real scientific contributions are to be taken seriously by the international scientific community, it needs to weed out the many unscientific groups making loud, but unsupported, claims about the present-day clinical efficacy of stem cells.

Regarding the focus on allogeneic MSCs, I think this a reflection of the large holdings of such cells in government-funded bone marrow and cord blood banks around the country, which appear to have worked with (or at least sold cell resources) to companies that engaged in stem cell tourism. Beike Biotech famously (infamously?) received direct funding from the Chinese government to establish what they claimed was the world’s largest stem cell and processing facility.

4. Can you estimate how much “stem cell tourism” business can make in profit?

Given the secretive and deceptive nature of the business models at work in the vast majority of companies that operate in this industry, it is impossible to make a high-confidence estimate of profits; I am unaware, for example, of any company marketing unproven stem cell treatments that makes its balance sheets public.

I think it is possible, however, to estimate revenues for companies that report average patient costs and numbers of patients treated. As of 2010, for example, Beike Biotechnology claimed to have treated over 9000 patients. The average fee charged to foreign patients was $26,000, while the average for domestic Chinese patients was apparently one-third that (I have this information from someone familiar with the company’s operations). Approximately half of Beike’s patients were foreign, while the other half were from within China (information from the same source). If these numbers are correct – which is impossible to verify, given the secrecy of the company, and the duplicity of its leadership – the revenue on 9000 patients would exceed $150 million. Again, this is a back of the envelope figure at best (based on figures from a questionable company), and in any case, does not reflect costs of cell storage and processing, general overhead, or treatment. It was reported to me that Beike would pay the treating hospital between $10,000 and $12,000, which (if true) would indicate that costs were considerable, but nonetheless part of a business scheme capable of yielding profits in the tens of millions of dollars.

In extreme cases, profits may approach 100% – we have seen from legal actions filed against Frank Morales, and the recent revelation by 60 Minutes of the quality of StemTech’s “stem cells” that products advertised as stem cell therapy are of unreliable quality, at best, suggesting that costs for quality control are minimal, and that in some cases, vials containing only saline or fragments of dead cells are being sold to patients.

It is a mistake to approach companies engaged in stem cell tourism as if they are simply conducting science by alternative means. A growing body of evidence shows that many people who market unproven stem cell treatments directly to patients are simply engaged in fraud, and abuse both the high regard and trust that patients and the general public have for science, and the inherently trusting mechanisms that scientists use to judge each others’ work (in the sense that scientists are expected at a minimum to honestly report their data and exert their best, honest efforts in interpreting them objectively), in the interests of profit. Having studied this industry intensively for several years now, it is my considered opinion that the claims of any company or group that sells or otherwise promotes such putative “stem cell” products or services should be greeted with the deepest possible skepticism.

5. Many commercial clinics and companies use “stem cell” as a brand or marketing tool. How the claim “use of stem cells” close to reality? I wonder if independent expertise of cells which were injected into the patients was ever done.

This is the key question. Clearly, there is an enormous amount of legitimate research into stem cells, both fundamental and clinical, already underway. Given that the results of these cautious, responsible, ethical experiments are not yet conclusive, I think it is irresponsible to speculate publicly on how close we are to seeing expanded use of stem cells beyond their current indications in diseases of the blood and immune system. It is important to point out, however, that the answer to this question for at least some medical conditions for which stem cells are currently under study may be “Never.”

What is clear is that the net effect of the “stem cell tourism” phenomenon has been to be unnecessarily confuse the field and jeopardize it with a combination of unsustainable enthusiasm on the part of some and, increasingly, profound skepticism on the part of others. The scientific method was developed for a reason, which is primarily to minimize the impact of human biases and cognitive fallacies, conscious and unconscious, on the interpretation of experimental results. Introducing unregulated personal and business interests into a nascent scientific field has not produced positive results in the past, and will most certainly not do so in this case either.

Regarding the question of whether independent scientists have ever analyzed cells injected into a patient, there appears to have been very little in the way of such studies. But this is only to be expected, due to the highly variable, uncontrolled and unreliable conditions under which such “treatments” are carried out in the first place. Who would pay for such a post hoc study to be done, and what could we hope to learn from it? In any event, how would the injected cells be identified, particularly in cases in which an unregulated clinic uses autologous cells. There was the famous case of the Israeli boy who was inject with a slurry of unsorted fetal cells for the “treatment” of ataxia telangiectasia, which was only studied after it gave rise to tumors of the nervous system, the cells of which were found to be donor-derived.

This again shows the importance of having a well-developed and adequately enforced system of regulations governing the introduction of novel interventions, such as stem cells, into the clinic. Groups and organizations that operate within the systems already established in places like the US, EU, UK, Canada, Australia, and Japan are required to such follow-up studies themselves in the context of registered trials subject to independent oversight.

Again, I think it is a mistake to treat these fundamentally unscientific, and in many cases anti-scientific, commercial outfits as if they are doing something potentially beneficial. I suppose someone might seek a grant from the NCCAM to fund such a study, but there are enough interesting legitimate research questions to be asked without diverting one’s attention to answering the dubious claims of pseudoscientists and profiteers. Carl Sagan famously said, “Extraordinary claims require extraordinary evidence,” and, crucially, the onus of providing such evidence is on the person making the claim – anyone making such egregiously profit-motivated marketing claims and then asking others subsequently to provide the evidence should be viewed as parasitic at best, and an outright fraud at worst.

6. One of the big downsides of uncontrolled “stem cell tourism” is inability to collect and analyze clinical data properly. Many clinics don’t provide detailed information about cell product or patients. Maybe they don’t inject stem cells at all! We also lack of information about adverse events or complications of unproven stem cell therapy. By some reasons, patients don’t share this information on Internet. How big is the problem of adverse events or “lack of efficacy” in unproven stem cell therapy? How do you think we can track these events and collect the information in order to avoid such things in development of new regulated cell products?

As with the previous questions, it is impossible to know the extent of adverse events and levels (if any) of efficacy, because the organizations operating under this particular business model are inherently unscientific, and design their “experiments” in a way that permit and sometimes exacerbate the long, long list of fallacies, biases and errors that well-controlled studies are designed to minimize.

A particular problem is the notion that “fee-for-service” model of clinical research in which the patient/research subject pays to participate, is capable of generating meaningful results. There are too many fundamental problems with this notion to go into detail here, but the Chinese MOH and SFDA were very wise to explicitly state that, “all clinical trials of stem-cell therapies should be free.”

The problem of badly designed “research” is a longstanding one in the history of medicine, not only in the field of stem cells. The placebo response is perhaps the most famous confounding factor, but selection bias, reporting bias, regression to the mean, justification of effort (or investment), and other forms of systematic error in human cognition, experimental design, and interpretation of data need to be controlled for adequately – efforts to introduce medicines without doing so are extremely likely to yield only false promise (but, unfortunately, massive profits). This is the basis for the success of so-called “alternative” medicine, which are consistently shown to perform no better than placebo in controlled studies, but which nonetheless have vocal advocates who swear by their safety and efficacy. What can we learn from this? Humans are fallible, and clinical research needs be designed properly and subject to independent oversight. But real scientists already know these things, so I am doubtful that rogue companies that engage in unethical business practices mislabeled as research have anything else to offer. It can be useful to think of “stem cell tourism” companies as televangelist preachers who claim to cure with the power of prayer. There are thousands, possibly millions, of people who passionately believe their claims, who will pay money to be “treated” by them, and who swear that such healing is safe and effective, but despite the formidably large number of anecdotes and testimonials, the phenomenon is not likely to serve as a source of useful knowledge for scientists seeking to develop something real. Groups that are sincere in the desire to track outcomes will find an extremely well-developed system for doing so under the auspices of any of the many regulatory agencies around the world that have been set up to facilitate and govern the development and marketing of new forms of medicine.

On a related note, what we do see quite a lot of is irresponsible clinics and promoters of unregulated stem cell medicine taking media reports of interesting preclinical research, or promising results from scientifically designed clinical studies, ad claiming that these somehow justify the immediate, unregulated commercialization of some form of stem cells for some (generally extensive) menu of medical conditions by their particular firm. This is a particularly offensive practice in that it intentionally seeks to profit from the scientific efforts of others in the present day, and will inevitably result in an epidemic of “I told you so” claims in the future if stem cells are shown through actual research to have additional clinical uses.

7. What is your prognosis for the status of stem cell tourism in the next 3-5 years? What trends will be? Will it shrink or proliferate?

That’s a tough one. There has been some positive news in the form of clinic closings, regulatory developments, and arrests of people who abuse the clinical reputation of stem cells to financially exploit patients, but these have only made a modest dent in the industry. Much will ride on the success of the US and Chinese governments in reining in these predatory businesses. One worrisome trend in the US has been the explosive growth of private clinics and companies that market “autologous stem cell” injections (typically using putative “adipose-derived stem cells”), for orthopedic repair, cosmetic surgery or so-called “anti-aging” purposes. There is an active case (USA v Regenerative Sciences) in which one such company is contesting the FDA’s authority to regulate point of care re-injections of autologous cells which, along with the lobbying efforts of various industry groups, appears to have emboldened a number of US physicians impatient with the existing scientific process.

The recent arrests in the Stowe/Morales case, which included one academic scientist accused of processing cells for unapproved clinical use, may be a sign that the US federal government is taking the issue more seriously, and may cause some doctors who previously felt comfortable flouting the law to reconsider. That said, even if China and the United States are both effective in regulating the clinical application of stem cells in those countries, there will always be other, less well-regulated jurisdictions where entrepreneurs can set up clinics and lure international patients with impunity. It is unrealistic to think that the problem will disappear completely – the question is whether for-profit clinical uses of stem cells that have no basis in scientific evidence will be permitted in otherwise well-regulated and scientifically advanced countries, or whether they will be consigned, as they should be, to parts of the world where science-based medicine and the rule of law have not yet taken root.

8. Stem cells could be one of examples of hype cycle in biology and medicine. But did previous hype cycles give such phenomena as “trade on hope” or “medical tourism” or “branding”? For example, I can’t tell that about gene therapy or antibodies. Is it exclusive attribute of stem cells? What do you think?

I agree that neither gene therapy nor monoclonal antibodies have been confronted with the problems facing premature uses of stem cells in the clinic and product marketing, but I don’t think that stem cells are unique in this regard. Tim Caulfield, who has done some excellent studies of the stem cell tourism phenomenon, has frequently pointed out that there were numerous and extremely popular claims of clinical benefit for electricity, magnetism, radium, etc. when these were relatively young discoveries. Marketing moves much faster than science, and this is exactly what we are seeing today.

What I do think is unique about the global commercialization of stem cell pseudomedicine, is that it has taken full advantage of the revolutions in communications (internet) and transportation (international travel) to target the largest possible market at the lowest possible cost, while evading scientific and regulatory oversight. It also appears that many people feel greater familiarity with the concept of cells as fundamental units of the body, which is played upon by companies that suggest cells function as interchangeable “bricks” or “Lego blocks.” There was a pseudomedical fad for “live cell” or “fresh cell” (Frischzellen) injections of material from fetal animals in Europe and the US starting in the 1920s, and it appears to have been based similar claims as we see in stem cell pseudomedicine today. (Unsurprisingly, a “fresh cell” revival is now under way, in which the marketing claims for decades-old rabbit-, sheep- or shark-cell quackery have been updated to suggest that these were stem cells, or stem cell activators, all along.)

9. As I emphasized on my blog, professionals (researchers and physicians) should also do something about unproved stem cell treatment. Obviously, it has a huge negative impact on credibility of stem cell research and reputation of the field in general. What measures, do you think, should be taken by professional community? What our focus should be?

I definitely agree that researchers in the field should be aware of this shadow industry, and at the very least be responsive to inquiries from patients and their families. The International Society for Stem Cell Research (ISSCR) has conducted several public initiatives to set the record straight about the current state of stem cell science and its medical applications, such as through the publication of a Patients Handbook on Stem Cell Therapies (.pdf), and the Closer Look at Stem Cell Treatments website. The International Society for Cell Therapy (ISCT) has also published a position paper on the problem of stem cell tourism (.pdf) and numerous other scientific societies, patient associations, disease advocacy groups, and media organizations have also published critical perspectives and warnings on the issue of stem cell fraud. David Resnick and Zubin Master published an overview of the growing industry of companies marketing scientifically baseless “stem cell” treatments in which they called for greater scientific responsibility, such as closer scrutiny over the distribution and sharing of cellular resources.

At the end of the day, the problem is that scientists are busy with their own work, and must make time for any such outreach activities (which can quickly become extremely time-consuming), whereas many of the companies engaged in selling unproven stem cell treatments to patients invest enormous amounts of time in marketing and spreading disinformation, as this is the foundation of their profit model (in the form of new patients/customers/victims).

I cannot stress strongly enough the fact that stem cell pseudomedicine is fundamentally different from stem cell research. A number of recent cases have highlighted the fact that it has more in common with various forms of criminal fraud, than it does with any form of scientific or medical activity. Scientists can only do so much in setting the record straight – at some point combating this becomes more a matter for law enforcement than for peer review and statements of concern.

Thank you very much for the interview!

Related posts:

1. Mesenchymal stem cell therapy in clinic: current status and problems

In April 2011 I’ve started a new project – Cell Therapy Trials. This is a prototype for tracking of clinical trials and cases in cell therapy field with publicizing it via Twitter. The big part of the project is collection of clinical data via tracking of published literature, conference reports and business press-releases. Today I’d like to share with you some results of this project – tracking of registered clinical trials in 2011.

Data collection criteria
I tracked clinical trials which fall in definition of cell therapy: administration living cells in human with therapeutic purpose. I included tissue engineering and excluded devices for cell processing. I tracked all clinical trials which were registered in 2011 in international databases.

“Registered” doesn’t necessarily mean “new”. Some trials were registered in late phases (2/3 or 3) or listed as completed. Because trials, registered in late stages consist only ~ 3.7%, I include all of them in the analysis. The vast majority of trials (>95%), registered in 2011, were in early stages (1-1/2-2). I called these trials “new”. The status of the most “new” trials was “recruiting” or “not open yet” (just launched). I think, it reflects real situation in cell therapy activity around the world.

I collected data about all cell therapy trials, excluding hematopoietic stem/ progenitor cells for homologous use (hematology – oncology). This approach allows to get a sense about activity in cellular immunotherapy and regenerative medicine.

Data access
I input raw data in spreadsheet. The data include: trial id, hyperlink to trial, country, phase, status, condition, cell type, allogeneic/ autologous, academic/ industry-sponsored. This document is publicly available. Everyone can use and play with these data!

Number of trials: I was able to track 151 trials.

Databases scanned:
US NCT (NIH-FDA)
German DRKS
Japanese JPRN
Indian CTRI
Chinese ChiTCR
Australian/NZ ANZCTR
ISRCTN
Dutch NTR
South Korean CRIS

Worldwide activity:

Monetary support:
I roughly divide all trials on 2 categories – “academic” and “industry”. The term “academic” combined any monetary support (governments, funds…) other than “company-sponsored” (“industry”).

Cell types:
I was able to identify roughly 25 different cell types used in clinical trials. I roughly divide them on “stem” and “non-stem”. “Stem” cell types included: embryonic stem cells, multipotent mesenchymal stromal cells, hematopoietic stem/ progenitor cells, cardiac stem/ progenitor cells, neural stem cells, CD133+ cells.

Abbreviations: ESC – embryonic stem cells, MSC – multipotent mesenchymal stromal cells, HSPC – hematopoietic stem/ progenitor cells, TIL – tumor-infiltrating lymphocytes, DC – dendritic cells, BM – bone marrow, MNC – mononuclear cells, NK – natural killer cells, CIK – cytokine-induced killers, SC – stem cells.

Indications:

Future development:

• trends identification
• analysis of trials outcome via published results
• collaboration and data representation

Source: @CellTrials

How to cite: Bersenev Alexey. Cell therapy clinical trials in 2011. Hematopoiesis blog. January 3, 2011. Available: http://hematopoiesis.info/2012/01/04/cell-therapy-trials-2011

Related posts:

1. Tracking of clinical trials and cases in cell therapy and regenerative medicine
2. Roadblocks for cell therapy clinical trials
3. Cell therapy clinical trials 2009 – part IV

I was not very optimistic about the future of gene therapy 3-4 years ago. Well, I was wrong about it. I was obsessed by cell therapy so much that underestimate the progress in gene therapy. Both fields have matured and so did I. Last two years brought us tremendous development in both fields. I realized how much gene and cell therapy could be bind together. Today I’d like to share some links and opinions on why gene therapy is ready for prime time.

First of all, I’d like to highlight the recent notable advances in gene therapy. Last two years there were many of them. I’d mention a few:

• Long-term survival and recovery of T-cell immunity in children with SCID – UCL study 1/2
• French study on SCID – 10-years follow up, one death out of 8, but disease is corrected
• Results of Phase 2 trial in Parkinson’s Disease
• Results of Phase 1/2 trial study of cell gene therapy for the Wiskott–Aldrich Syndrome
• Few cases of treatment chronic lymphoid leukemia with gene-modified T-cells – reports 1/2
• AVV-mediated gene transfer in hemophilia B – results of Phase 1 trial
• A new gene therapy drug was approved on the market

But not everything went so smoothly this year. There were some setbacks. I’d mention two:

• Gene therapy of critical limb ischemia trial (sponsored by Sanofi-Aventis) failed in Phase 3.
• The EMA rejected Glybera (AMT’s gene product) to market in Europe.

Now, I’d like to share an opinion of two important figures in the field.

Ted Friedmann:

We now passed the stage which we’re trying to prove something to somebody and trying to overcome our history of maybe promising too much and being criticized for that. And now we’re at the point when we can begin to deliver real treatment for real people.

James Wilson:

Gene therapy is ready for prime time and will revolutionize practice of many aspects of medicine and soon to follow will be stem cells.

So, what does gene therapy readiness mean?
In the recent poll of Genetic Engineering News magazine 61.4% of professionals were positive about first FDA or EMA approval of gene product on the market in the next 2 years. There are more than one and half thousand of currently ongoing gene therapy clinical trials. 60 of them on a Phase 3. There are 3 commercially available gene therapy drugs on a market.

Based on all clinical data that gene therapy has accumulated in the last decade, we can say that it works! It could cure a disease or provide better quality of life at some indications. We are ready for expansion and advance of clinical trials. We are ready for marketing approval of few more gene products in the next one-two years. We are ready for post-marketing analysis and commercial manufacturing of the products. So, let field to explode!

Related posts:

1. A new hope for gene therapy of immunodeficiency – how to get out of the bubble?
2. Gene Therapy safety issues arise again and again
3. Gene therapy drug approved on Russian market – Interview with Artur Isaev

Note: There is a print link embedded within this post, please visit this post to print it.
The first gene therapy drug was approved on the Russian market on December 7. Neovasculogen (VEGF) will be used for treatment of peripheral arterial disease (PAD) and its complication critical limb ischemia (CLI). This drug is manufactured by Moscow’s company Human Stem Cell Institute (HSCI). The company’s CEO, Dr. Isaev kindly agreed to answer my questions about this remarkable approval.

**************************
1. Dear Dr. Isaev, first of all let me congratulate you and your company with this notable approval. I think, this is very important for the whole gene therapy community worldwide. Tell us please about when Neovasculogen will be available on the market and where?

The new gene therapy drug will be available on Russian Federation pharmaceutical market in second quarter 2012 after the first batch certification process. HSCI has decided that Novasculgen will be available on ex-USSR pharmaceutical markets, and primarily it will be the market of Ukraine.

2. Can you tell us briefly about the results of clinical efficacy studies? Some other gene products for treatment of CLI have failed in the late phases of clinical trials (for example, Sanofi’s FGF-based gene product). What are your thoughts on that?

We can announce 3rd phase clinical trial results. It was the 6 month comparative trial of unreconstructable peripheral arterial disease patients. Patients received Neovasculgen as a part of conservative therapy. So, the results of our trial showed good therapeutic effect that we observed in April 2011. Neovasculgen led to the development of new collateral blood vessels which was contrasted on angiography. The main endpoint, PFWD (pain free walking distance), detected to increase by 110% that showed statistically significant difference versus the control.
The main and second endpoints have been integrated in combined rates named «success/failure». The score “success” was granted in 94% of clinical observation. The investigators of HSCI used plasmid vector as the most safe. As a result, the adverse events, side effects and complications of Neovasculgen were not recorded.

Fibroblast growth factor type 1 (FGF1) takes part in enhancing of new blood-vessel formation and activates some steps of multilevel therapeutic angiogenesis. Sanofi-Aventis tested safety and efficacy of naked DNA plasmid that includes the gene encoding for human FGF1. The expectations of Sanofi-Aventis investigators did not meet that was announced last year. However, I have to point out that the Sanofi-Aventis drug had original construction with another active gene component and study protocol was primarily addressed to the prevention of major amputation. I believe that feasible and clear end point criteria is the most important issue for the first-in-class drug on its way to the market.

3. What was the regulatory path for this gene drug in Russia? Can you compare the requirements for such products from Russian regulatory bodies with FDA and EMA?

The regulatory path was full of different questions. Neovasculgen is a first-in-class drug. It stimulates a vascular growth (so-called “biological bypass” or “therapeutic angiogenesis”). There are no any drugs with the same action mechanism, but Russian regulators wanted to know, for example, pharmacodynamics of the VEGF expressed from the plasmid. Unfortunately these requirements are not applicable for this sort of a gene therapy drug. In general, the requirements of FDA and EMA for authorization of gene therapy drugs have much in common with Russian requirements – safety and efficacy.

4. What will be the market price for Neovasculogen? Will it be covered by medical insurance? Can foreign citizens get this treatment in Russia or purchase a product?

The price of Neovasculgen will be around 200 thousand of rubles (~ $6600USD) for treatment course. We hope that Ministry of Health and Social Development of the Russian Federation will include this socially significant drug in the medical reimbursement list for special groups of patients. Our company plans to submit an application form in special commission. The Foreign citizens suffering from PAD can get a treatment by Neovasculgen in Russian healthcare hospital or ambulatory.

5. What is the market penetrance for this product? How many patients could benefit from it?

Peripheral Arterial Disease affects an estimated 10% to 20% of all people over the age of 55, with prevalence increasing with age. Prevalence of PAD is also significantly higher, about 30% to 35%, in people with diabetes. Every year 30-35 thousands of amputations are performed in Russian Federation. The symptomatic PAD patient continues to have significant functional disability. HSCI believes that for many patients Neovasculgen may become a real alternative to amputation and can improve a quality of life.

6. What is your projection for Neovasculogen sales in Russia? Are you going to expand your sales outside of Russia and register the product, for example in Europe?

The Company expects the number of patients will be increasing in the course of 5 years up to 20 000 – to start with, in 2012 HSCI plans to initiate Neovasculgen market authorization in Ukraine.

7. What do you think about cell therapy of CLI? Could it compete with gene therapy market?

The experimental and clinical studies show that different cell therapy methods lead to different results of efficiency. The modern understanding of therapeutic angiogenesis mechanism assumes that gene therapy and cell therapy can improve to each other. Nevertheless we must remember that a cell therapy process is locally associated with specialized laboratory or equipment. Neovasculgen is a finished medical product which is convenient and easy for usage in practical public healthcare.

Thank you very much for the interview! I wish you good luck in this business!

Press-release
**************************
Disclosure: I’m on editorial board of Russian scientific journal “Cell Transplantation and Tissue Engineering” published by HSCI. I don’t own HSCI stock and have no plans to initiate any positions within the next 72 hours.

Related posts:

1. Gene Therapy safety issues arise again and again
2. A new hope for gene therapy of immunodeficiency – how to get out of the bubble?
3. US market for stem cell technologies in next 5 years

The cancer stem cell concept is evolving and causing great debate in the scientific and medical world. People are discussing these three most important questions:

1. Do cancer stem cells (CSC) exist and is the concept valid?
2. How can we identify and characterize them?
3. What is the therapeutic relevance (for prognosis and therapeutic targeting)?

In order to estimate prognostic and therapeutic value, CSC should be isolated at a pure level or enriched. Today, almost all protocols for CSC isolation or enrichment rely on surface markers expression. This approach works nicely for normal stem cells, but seem to be seriously flawed for CSC, due to their intrinsic plasticity.

Despite solid experimental evidence, and questionable validity of cancer stem cell (CSC) surface markers, researchers keep publishing tremendous number of papers based on it. As you may know, I’m advocating a functional approach for cancer stem cell identification for some time. Recently, I was happy to find the study from John Dick’s lab, which re-evaluate prognostic value of leukemic stem cells (LSC), based on functional assessment. I think, this study is a breaking point! I hope it will give a start for the new era of accurate cancer stem cell identification and characterization.

… any investigation of CSC properties using phenotypically defined populations is unreliable and requires functional confirmation of CSC activity using well-validated tumor- or leukemia-initiation assays.

Because CSC populations from acute myeloid leukemia (AML) have diverse surface marker profile, the authors validated cancer-initiating population in transplantation assay first. After confirmation of biological properties (leukemia-initiating function), cell populations from the same sample were sorted for following gene expression analysis.

The authors use functional validation for evaluation of clinical prognostic value of CSC gene signatures. For gene expression analysis, they used 25 sorted cell populations enriched for functionally validated CSC (called LSC-R) versus 26 cell populations without detectable CSC. Similar to previous studies, they found that LSC-R or HSC-R (normal hematopoietic stem cell control) gene signatures correlated with poor prognosis in AML. The functional approach makes this study very different technically and advantageous compared with previous published work.

To illustrate the utility of genetic signatures in CSC field I’d quote the commentary:

… quantitative assessment of self-renewal signature via, perhaps, a minimal gene set customized for different cancer subtypes can provide a rapid measure of stem cell activity and a prognostic indicator guiding choice of therapy. A predictive expression signature that bypasses the need for in vivo CSC assay would be very advantageous. However, it will be necessary to first validate the independently predictive value of such assays for different types of cancers…

I hope, in the future, carefully assessed CSC gene expression signatures will allow design of “leukemia prognosis chip” and “leukemia therapeutic chip” and will bring us closer to personalized oncology.

The most intriguing part of this study for me was a comparison of leukemic stem cell gene expression profiles across of all published studies. As we can predict, gene profiles of validated AML stem cells (LSC) did not overlap with “non-validated LSC” studies:

In one latter case the LSC nature of each fraction was not functionally validated and, as we and others have shown, the use of CD34 and CD38 to identify stem cell fractions without concomitant functional analysis can misidentify the stem cell nature of sorted cell fractions.

… we found no correlation with the LSC list generated by Gal et al. based upon phenotypically defined populations (AML CD34+/CD38- vs CD34+/CD38+ cells).

In a second study of LSC to non-LSC AML populations, Ishikawa et al. used a cohort of 4 samples with 2 populations each to identify a small number of genes.
…the LSC-R does not positively correlate with their LSC up-regulated gene set nor does HSC-R negatively correlate with their down-regulated LSC gene set. This suggests that while this study was successful in identifying some LSC-related stem cell genes, it was limited by small sample size and the gene expression variability inherent in cancer samples.

Unfortunately, the authors didn’t perform side by side comparison with recent (“non-validated”) Gentles et al. study. Also, we still don’t know, how gene expression profile of validated CSC would be different at time of diagnosis and at relapse.

Conclusions:

1. I think cancer stem cell researchers should finally accept that using only surface markers for CSC isolation and enrichment is unreliable.
2. Before all “therapeutic studies”, isolated CSC should be validated in functional assays (tumorigenicity in xenotransplant, sphere formation assays…).
3. Findings from previous studies used “not validated” CSC should be questioned and critically re-evaluated.
4. Researchers entering the field should realize and appreciate great complexity (plasticity and heterogeneity) of cancer stem cells.

I’d like to finish by a quote:

… the approach we have taken in AML provides a paradigm for assessing both the identity and clinical relevance of LSCs and CSCs from other leukemias and solid tumors, respectively. A well-validated and sensitive xenograft assay is essential because only functionally validated populations showed clinical relevance, whereas signatures derived from phenotypically defined populations did not.

Related posts:

1. How to train the immune system to kill cancer stem cells?
2. Functional hematopoietic stem cells from human ES cells – significant progress toward?
3. Stem cells, cancer progression and metastasis (part V) – metastatic cascade driven by cancer stem cells

cross-posted on StemCellAssays.com

I wrote a lot about cancer stem cells in the last two years. You can track some of my posts here and here. It is very exciting and evolving field combining stem cell and cancer research. Currently, most professionals from both fields, are convinced in validity of cancer stem cell concept. But still, there are a lot of controversies about biology and clinical significance of cancer stem cells. The biggest unresolved question: “How can we target them therapeutically?” Today, I’d like to ask this question and give you opportunity to express your opinion.

I created a poll – What is the most promising method for targeting cancer stem cells? Please vote and express your opinion in comments. Because I’m asking to pick “the most promising method”, you can choose only one answer. Because some of you would think between two equal approaches, I included “combination of 2 methods” option.

I’d like to ask you to spread the word about this poll and help us to get more votes. Please share this poll via email or post it on your blog, tweeter, LinkedIn and any other social networking sites. I’d love to see your opinion in comments, especially for the last 3 options. Please tell us why do you think so.

poll direct link: http://poll.fm/39tdg
short URL: http://bit.ly/nNyp5s

Related posts:

1. Stem cells, cancer progression and metastasis (part V) – metastatic cascade driven by cancer stem cells
2. How to train the immune system to kill cancer stem cells?
3. Complexity of cancer stem cells