Advanced Cell Technology (ACT; $ACTC) has a new paper out on using human embryonic stem cells (hESC) to make MSCs with potentially powerful therapeutic potential.
The paper, entitled Mesenchymal stem cell population derived from human pluripotent stem cells displays potent immunomodulatory and therapeutic properties, was published in the journal Stem Cells and Development.
What’s the scoop on this paper and this area of adult stem cell preclinical/clinical research?
It’s an interesting, notable paper. At the same time there are some areas in the paper that could have been stronger and the path to an approved, commercially viable hESC-MSC product could be long and challenging with fierce competition.
What’s this arena like for background?
One of the best things about adult stem cells is that we all already have them in our bodies.
For example, there are relatively abundant populations of mesenchymal stem cells–now more becoming more commonly referred to as mesenchymal stromal cells (MSCs)–in both adipose tissue and bone marrow in adults as well as in umbilical cord blood.
Another beneficial aspect to adult stem cells such as these is that they have a relatively very low (although not absent) tumorigenic capability.
These factors make adult stem cells a readily accessible source of material for cellular medicine therapies. Thousands of clinical trials all around the world are already underway using adult stem cells including hundreds that are MSC-based.
When I first heard generally about the line of research that ended up in this Kimbrel, et al. ACT paper on hESC-derived MSCs last year I have to admit my first reaction was to be a bit puzzled and can be summed up as follows as a question:
why use hESC to make MSCs for potential allogeneic use if we can just relatively easily harvest endogenous MSCs from patients for autologous use?
This question was still on my mind as I read the actual paper.
The authors make several arguments as to why hESC-MSCs are needed, but sum up the case this way:
“Our data suggest that this novel and therapeutically active population of MSCs could overcome many of the obstacles that plague the use of MSCs in regenerative medicine and serve as a scalable alternative to current MSC sources.”
What more specifically are their arguments for hESC-MSCs?
- More is better. The team can make nearly an unlimited supply of hESC-MSCs, whereas endogenous MSCs have limited proliferative capacity in culture.
- Higher consistency. The authors argue that hESC-MSCs are more homogeneous and consistent in nature than purified endogenous MSCs or MSCs amplified in culture.
- Younger is superior. They also assert that hESC-MSCs may for many older/sick patients essentially be younger, healthier cellular versions of their own endogenous MSCs.
As the authors point out, they are not the first to make hESC-MSCs, but they seem to have done it arguably in a simpler, more scalable, and more clinically relevant manner plus investigated the hESC-MSC properties more thoroughly than others have in the past. For example, there is some intriguing data here on the immunomodulatory properties of hESC-MSCs in rodent disease models.
There are also some gaps in the paper.
For instance, while they report that their data indicates that hESC-MSCs have a 30,000-fold greater expansion capability compared to endogenous MSCs (see Figure 2A below), this is a double-edged sword on the safety front.
Endogenous cultured MSCs have a very lower spontaneous immortalization rate, which is a great thing, but it is not zero. Immortalization is the first step toward becoming a cancer cell. When MSCs are grown beyond about 15-20 passages or about 4-5 weeks, there have been enough population doublings and sufficient time that has passed that the relative risk of immortalization and mutations goes way up.
What this means is that while being able to grow hESC-MSCs to and even beyond 30 passages gives a team the ability to make a heckuva lot of potential therapeutic doses of MSCs (which is great), there could well be a direct inverse tradeoff with decreasing safety occurring at the same time.
See how the green and purple curves are beginning to level off after 1 month? That’s the normal lifespan of MSCs in vitro and is protective against tumorigenesis. The relatively straight blue and red more sharply sloped lines means the hESC mesenchymal stem cells are continuing to grow like gangbusters, but again that growth could come with a safety tradeoff. Or maybe not. Without more data we just don’t know.
More broadly the area of safety of hESC mesenchymal stem cells was one major area in which I thought the paper could have been much more thorough and needed more depth. In fact, words such as “teratoma”, “immortalization”, “safety”, “tumorigenesis”, and “karyotype” are not used even once in the paper that I could find.
Perhaps the team of authors knows these cells to be safe in a preclinical rodent setting, but it would have been great if that data were included. Perhaps in a 2nd paper?
A second key issue is immunogenicity. The authors assert rather absolutely that hESC mesenchymal stem cells could be used in an allogeneic manner in human patients without immunosuppression and without negative consequences. I’m not so sure that we know that to be so clearly the case. While hESC mesenchymal stem cells may have some level of immunoprivilege, immunosuppression could well prove necessary when used in an allogeneic manner. Again this is an issue where at this point we just don’t know. In contrast, even lab-expanded endogenous mesenchymal stem cells when used autologously would not require immunosuppression.
For more helpful background see an excellent recent review in Nature Biotechnology by Jeffrey Karp’s team: Mescenchymal stem cells: immune evasive, not immune privileged. It discusses in a very clear and insightful way the key challenges facing autologous and allogeneic mesenchymal stem cells therapies and makes the argument that MSCs are not immunoprivileged. It concludes this way:
“To maximize patient benefit and minimize patient risk, next-generation MSC therapies should be built on a foundation of thorough characterization and fine-tuning of MSC immunogenicity, survival, potency and disease-specific mechanisms of action.”
A third significant issue for the hESC-MSCs is regulatory in nature. Endogenous MSCs, if less than minimally manipulated, are not regulated as biological drugs, while hESC-MSCs are certainly biological drugs and hence subject to far more lengthy and expensive FDA vetting. Of course even endogenous MSCs are often grown in culture as well (and therefore are in that form biological drugs too) and stem cell clinic operators have told me privately that they believe that amplification of MSCs is needed to make an effective product. Even so, I predict that the FDA would view hESC-MSCs as relatively of greater safety risk to patients than amplified endogenous MSCs.
The bottom line is that this ACT hESC-MSC paper is solid and interesting, but just the beginning of the story on ACT hESC-MSCs. There’s a lot more we need to know to judge their clinical potential as well as their relative utility compared to endogenous MSCs, and foremost on my mind is safety. Data on the karyotypes, immortalization rate, and tumorigenicity of the hESC mesenchymal stem cells grown for months in culture would go a long way toward clearing things up.
Any hESC-MSC-based commercial product would face stiff competition from the numerous commercial entities already years ahead and collectively conducting about 350 clinical trials using either allogeneic or autologous mesenchymal stem cells therapies. This doesn’t mean that ACT shouldn’t continue this work, but there are numerous challenges.
Disclosure: I do not currently own stock in ACTC or any competing company.
there is paper in 2010 disclosed this idea long term ago. their idea even cannot file for patent
http://www.cell.com/cell-stem-cell/abstract/S1934-5909(10)00633-8
What about all the ethical debates about procurement of hESC for this purpose?
I’m not sure I understand what this commenter means. Could you please elaborate?
the method they are using is not a good method for derive MSC. they need make hemangioblast first, which is very expensive and time consuming. that method is original used to generate HSC, the msc they got is a byproduct of HSCs. There are many paper published to get MSC directly from hESC with simple small chemicals a few years ago, this is not a method has any advantages. While they claim their cells can grow many fold, they didn’t tell you what’s function of later passage hES-MSC. People know when MSC will lost function when over-passaged.
As with everyone in the industry, safety is of paramount importance – not just for the trial patients but for the successful development of the sector and ultimately the entire patient population that is waiting.
My sense of this issue is that ACTC’s hESC technology has so far been proven a safe cell derivation process in actual human subjects. This has been achieved in part by using a Purity Assay, which the FDA has reviewed and authorized the resulting cell batches for clinical use. If I recall this was the most important aspect of the FDA IND review process given the very issue you raise and ACTC passed that extensive test 3 years ago and have improved the process since…. it will be repeated of course for all INDs but there history here already to instill confidence IMO.
The Technology states up to 1: 1,000,000,000 Billion in Purity – with batch expansion….
Take a look at the below link as it may reassure on the question of hESC tumor risk for ACTC’s hESC programs – including eMSCs.
http://patentscope.wipo.int/search/en/detail.jsf?docId=WO2012012803&recNum=1&maxRec=1&office=&prevFilter=&sortOption=&queryString=ALLNUM%3A%28WO2012012803%29&tab=PCTDescription
Cheers
Thanks, msemporda. Good reference and info.
Paul
“A second key issue is immunogenicity. The authors assert rather absolutely that hESC-MSCs could be used in an allogeneic manner in human patients without immunosuppression and without negative consequences.”
I am baffled where Dr. Knoepfler found the above assertion by the authors. I read their whole paper and their PR and could not pin point such assertion.
Dr. Knoepfler’s comment about high proliferation rate vs cancer risk is a very good point though which needs to be addressed.
Hi Ymc. You have a good point. As I said in reply to another commenter, “assert rather absolutely” was probably not the best choice of words by me and maybe I should have said instead something like they “say rather matter-of-factly”.
I wholeheartedly agree with Paul’s assessment of safety concerns. Having said that, I read the paper with hES-MSC efficacy and proof of principal in mind.
I’m not exactly sure how he came to the below conclusion as it was part of an introduction citing previous studies?(Leblanc et al 2003) I am under the assumption that there are no studies to the contrary. I especially disagree that the authors would test safety without considering immunosuppression or other safety precautions in human subjects. (I’d assume Paul would agree with that, perhaps it just wasn’t clear to me)
“The authors assert rather absolutely that hESC-MSCs could be used in an allogeneic manner in human patients without immunosuppression and without negative consequences.
vs
” Unlike other types of cellular therapies, MSCs can be used in allogeneic settings without immunosuppressive therapy due to their ability to evade immune detection……may contribute to their immunoprivileged status, although the exact mechanism is not entirely clear.”
Through their patent filings, you will see that the lead author suggests several methods to account for the possibility of adverse events in future therapeutic applications/clinical trials (e.g. mitotically inactivated MSCs) In human patients.
for me, this paper boils down to observed differences in expression of CD10, CD24, and Sto-1.
CD10 expression seemed to vary with media used in BM-MSCs, one of which seemed to match the expression rate of hES-MSCs
Sto-1 levels were very low in hES-MSCs but the authors point out that this is also seen in adipose derived. They concluded Sto-1 to be important for BM proliferation but not for hES-MSC.
finally, the authors identified CD24 expression differences between adult derived MSCs and hES.
They went on to say:
CD24 is an alternative ligand for p-selectin, is mutated in several autoimmune disorders, and has pleiotropic roles depending on the cell type in which it is expressed [76] Liu Y and P Zheng. (2007)
CD24 expression was only found in 1-2% of BM-MSCs vs 18% in hES-MSCs. In conclusion, the lupus model group treated with 2 injections of hES-MSCs had a 100% survival rate.
From here, my guess is that the authors will continue to research the mechanism behind the hES-MSC so that perhaps they can possibly offer an acellular product or hES-MSCs with an enhanced safety profile. I don’t think it would make sense to compromise preliminary results which seem to be much greater than previous studies using BM-MSCs when the safety concerns are thought to be manageable.
I guess I should contradict myself in that ACT has harped on the immunoprivileged aspects of MSCs for a long time, also asserting that immunosuppression isn’t necessary. I’m just not ready to believe that they would conduct first-in-man studies without doing so.
It appears that in their current animal trials, they are in fact using a powerful immunosuppressant (cyclosporine A) if Im not mistaken. However, some of their trials have exclusion criteria for dogs that get any immunosuppression or steroids after receiving a systemic injection of MSCs.
“dogs will not be able to receive corticosteroids or immunosuppressive agents for the first 42 days after injection of MSCs.”
Meanwhile, in even more of their current studies, they will have multi-arms where some dogs will get MSCs while others will get steroids
“This is a double arm, randomized controlled open-label study of adjunct effects of hES-MSCs added to standard of care. Dogs (n=3/group) will be randomized to receive either (1) high dose corticosteroids (tapered over 8 wks) and intravenous hES-MSCs or (2) high dose corticosteroids (tapered over 8 wks) and procarbazine for 8 weeks followed by a single intravenous injection of hES-MSCs.”
Alright, sorry to hijack the comments section but thought I would just add a little background if I could. Thanks for the review, Paul.
This is helpful context. Thanks, Alan.
Thanks, Alan, for that great comment. Yes, “assert rather absolutely” was probably not the best choice of words by me. Maybe my sentiment would be more accurately reflected by they “say rather matter-of-factly”.
Thank you so much for this analysis. It’s very difficult for people who are not extensively trained in the hard sciences to try to sort through this type of information.
I agree with you that this seems fascinating and promising, too. But from a practical POV, ACT has a much greater chance of getting the AMD drugs out earlier. Nobody has made it as far as they have in that field; everyone else working on the same issue is either years behind or in a position where there are many clues that their studies aren’t working out nearly as well, IMHO (Stemcells Inc being a good example.) So– that’s my take on it, anyway.
Thanks, Anise. I think AMD is going to be the key for ACT.
ACT Interim CEO Ted Myles presented yesterday at the Alliance for Regenerative Medicine meeting in New York. He said that the company is looking to partner their MSC program, presumably the paper reviewed here by Paul is part of that outreach.
Interesting paper but not convinced one needs to go through all of the effort and expense of generating MSC when generally one can obtain almost unlimited amounts of MSC from adipose tissue. Adipose-derived MSC can generally be harvested at rates of about 1 million per cc of fat, and have a doubling time of 30-40hours. We have been able to expand a few million of these MSC to greater than 1 billion MSC in culture without any difficulty.
That reality is a big challenge for ACT in the MSC arena.