Many years ago I noticed that one of the more prominent companies who was planning to mass manufacture adult stem cells for distribution like a drug made some interesting claims. They reported that they could get 10,000 doses of adult bone marrow stem cells out of a single donor. As someone who has as much clinical experience in the use of cultured stem cells as anyone in the world, I was intrigued. The number seemed way off. This week I learned the reason; most of these companies in FDA clinical trials using these mass manufactured stem cells are likely mass manufacturing cellular junk. Let me explain.
Adult stem cells will grow in culture to bigger numbers. In fact, this forms the basis of our Regenexx-C technology. Bone marrow is plated in a special culture system and exposed (in our case) to the patient’s own concentrated growth factors and this causes the stem cells to multiply to 100-1,000 times more than the starting number. Publicly traded, commercial cell therapy companies are doing the same thing, however, many have decided that it’s more profitable and better fits a Pharma model to take cells from young donors and grow those and then ship those in vials to doctors and hospitals. This is where the number 10,000 starts to become a problem that Wall Street investors seem to have missed. You see, adult stem cells are being used for their great safety profile. One of those added layers of safety is that unlike embryonic stem cells, they won’t grow indefinitely. In fact, they will only grow so long and then generally stop growing. To understand this next part, you’ll need to learn some cell culture terminology.
Each time cells growing in culture are fed, it’s called a “passage”. Once you start the culture process, it takes about 3-7 days for the cells to form colonies. Those cells are then placed into ever bigger flasks and fed (passaged) about every 2-3 days. So cells that have grown only a short time will be known by monikers like P1, P2, or P3 (first, second, or third passage). This is a critical number for the doctor and patient to know. Why? Because regrettably, the longer you grow adult stem cells, the less potent they become. So growing more is a balance between actually getting bigger numbers, but not growing them too long so that the cells aren’t any good. In fact, there are about 100 or more scientific papers in the medical literature that describe how cells grown too long are less effective-losing all sorts of abilities to heal or replace damaged tissue. This is where the commercial cell therapy industry has a huge problem.
Let’s return to our number 10,000. In fact, lets also add the number 100,000. These are the number of doses that most commercial mass manufactured stem cells therapy companies claim that they can grow from a single young donor. I knew this was an issue a few years back, because even on the best day, since these doses require 10-100 million cells each, we could only grow about 50 doses from a very young donor. Maybe, a real outstanding donor might grow 100 doses. However, how are these companies growing 10,000-100,000 doses? You guessed it, they’re growing the snot out of these cells. I learned this week, that most of these mass manufactured stem cells companies are routinely growing these cells to P6-P10! Yikes! This is the cell therapy equivalent of making someone slave in the mines for 22 hours a day! Almost all of the published research would point in the direction that by the time these cells exit the commercial culture process they are much less potent than they would have been if they had been grown to a more appropriate P2 or P3 stage. They are the cell therapy equivalent of using a copy machine to make a copy of a copy of a copy of a copy of a copy. The end result isn’t much like the original.
I’m sure many of these companies will argue that since they use young donors in the prime of their lives, this allows them to grow the heck out of these cells. While there may be a tiny kernel of truth in that argument, it really doesn’t hold water. In fact, a study from a large European University just showed much less clinical efficacy in treating transplant patients with young donor cells that were P3-P4 (grown much less than the commercial cells) versus P1-P2 cells. How big a difference? 75% of the patients who had the P1-P2 cells survived Graft vs. Host Disease (the severe rejection of an organ transplant) whereas only 21% of the patients who got P3-P4 cells lived! In context, these commercial cells are grown twice as long as the bad cells in this study. In addition, the medical literature is rife with studies that show that someone else’s cells are chewed up by the host’s immune system as they begin to differentiate into other cells-a hallmark of adult stem cells. So while you have the advantage of these off the shelf cells coming from a young donor, you have the disadvantage that they will get chewed up by the host patient’s immune system.
What’s interesting about this is that the commercial cell drug industry may have shot themselves in the foot. Because most of these cultured cells don’t have the ability to be protected by strong patents, the industry argued for strict over-regulation to box out competitors. They created a world where common tissues would be hyper-regulated as drugs, instead of being regulated less strictly as simple transplants. This dramatically increased the cost of mass manufacturing cells, as the regulatory cost of producing a cellular drug is much more than processing tissue. For example, stem cells grown using these drug production methods cost several thousand dollars a dose versus pennies a dose for chemical drugs. In addition, drugs need FDA clinical trials, but transplant tissues do not. Hence another several hundred millions dollars of cost was added to getting a “stem cell drug” to the bedside. As a result, the industry has apparently decided to cut corners by growing cells way too long and increasing the number of doses out of each donor. As discussed, while this reduces cost, it also likely seriously reduces efficacy.
The upshot? We’ve seen a rash of clinical trials out of these companies lately where the results have been either good, but not great or barely besting the statistical monkey on their back. Could one reason be less potent stem cells that have been grown way too long for their own good? Could a quest for better looking spreadsheets have overridden good medicine? Time will tell, but this is a very disturbing trend that should concern investors in these companies.