January 16, 2021

The Niche

Trusted stem cell blog & resources

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.

Review of ACT paper. hESC derived MSCs
Review of ACT paper. Data on hESC derived MSCs.

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.

%d bloggers like this: