Cell Therapies: What’s in the Tube?

The challenge of generating cell therapies fit for purpose.

Posted Feb 24, 2020

Several times in previous blog posts, I’ve argued strongly against the use of unlicensed cell therapies for the treatment of neurological and psychiatric disorders. Clearly not everyone agrees. Many users trust online chats more than governmental regulators or academic opinion in deciding what works (1). Cell therapy providers themselves are quick to argue that they are being held back by heavy-handed regulation. Why does the manufacture and sale of medicines need to be so regulated? 

The obvious answer is that we want medicines to be safe and effective. Without the data that regulators ask producers to provide, that safety and efficacy cannot be assured. But there is another reason: We need to be sure each dose of the medicine is the same. You take it for granted that every time you visit the pharmacist for another batch of your favourite drug, it will be identical to the last one. You want to be sure that the first tablet in the new pack is the same as the last tablet in the old pack. 

To achieve this consistency, regulators insist on three features: purity, identity, and potency. The first two are obvious. You want to know the medicine you just bought is indeed what it says on the box (identity) and that there is nothing in the tablet that shouldn’t be there (purity). The third parameter, potency, is slightly less obvious. Each tablet needs to be equally effective. 

Seems like this should obviously follow from the first two constraints, purity and identity, and for many medicines, this would generally be the case. But consider some of the more complex medicines now available, particularly biologicals such as monoclonal antibodies. These medicines are not simple chemicals, but rather large complex macromolecules. Lots of changes can happen to such molecules that might not register as either a lack of purity or identity. 

For example, antibody molecules (immunoglobulins) are glycosylated proteins–proteins with extra bits of carbohydrate tacked on. And these carbohydrates affect the properties of the proteins. So a batch of an antibody could be highly pure immunoglobulin, but if the glycosylation has been altered during the manufacturing process for some reason, then that batch of antibody might be less effective, i.e. have lowered potency even though the identity and purity readings remain the same.

Why is this particularly important for cell therapies? In order to measure potency, you need to know how the medicine works. Say you take an anti-psychotic medicine, risperidone for example. This works by binding to particular serotonin receptors in the brain. That’s its "mode-of-action" (MOI). The drug manufacturer can be quite certain that two batches of risperidone have the same potency by showing that they bind the serotonin receptors to the same extent. But what of a cell therapy? In many cases, we simply don’t know how they work (if indeed they do). So how can we measure potency?

Regulators are well aware of this problem, and (contrary to their reputation with some) take a forgiving and progressive approach. When a cell therapy is approaching clinical trials, they understand that the trial sponsor (drug company, biotech, university) might not have identified the MOI completely.  Alright, they say, do your best at this stage, and sort out the definitive MOI as the trials progress. "Doing their best" usually means measuring what seems the most important parameter and assuring themselves that this parameter isn’t varying too much. For a stem cell, this might be its developmental potential or the amount of a particular factor it releases. For neural stem cells (NSCs)—such as those currently in trials for stroke, for example—their capacity to generate new nerve cells seems important, so the sponsors might measure that. For bone marrow stem cells—such as those in trials for multiple sclerosis—it might be a measure of the factors they release. 

But these are just "best guess" potency assays. That’s the forgiving bit. The progressive element is that the regulators would want to see some progress in determining the precise MOI during the course of the trial. Clinical trials often last ten years or more. Plenty of time, you might think, for those drug company anoraks to sort it out before it finds its way into a hospital pharmacy.

Well, that’s turning out not to be the case. Many stem cell clinical trials are now approaching their tenth birthdays, and the MOI still isn’t clear. It isn’t through negligence on the part of the scientists, rather it is for two reasons—one understandable, the other less so.  

The first problem is quite simply that cells probably don’t have a single measurable MOI. We traditionally classify stem cells on their potency: a neural stem cell makes nerve cells; a blood stem cell makes blood; etc. But it turns out that stem cells have empathy. They are enormously sensitive to what is happening around them, and they react appropriately. This means that when injected into damaged tissue, they react to the damage they encounter, and the specifics of that response might be different in different situations and for different individuals. This is a serious problem for the field. How are we to measure how well the cells are working if it keeps changing?

The second problem, however, is more basic and needs to be more seriously addressed. Many purveyors of stem cell therapies cannot control what’s actually in the tube. Far from sorting out the potency question, they haven’t yet sorted out the purity and identity issues. It is one thing to know you have a pure population of identified stem cells but to be unsure of their precise potency. It is another not even to know if the cells are what you say they are. Yet many stem cell preparations fall into precisely this hole.

Why does this situation arise? Partly because manufacturing cell therapies is still in its infancy, and quite simply, biotechnologists haven’t yet worked out how to maintain absolute consistency. Much effort is going on now to overcome this problem. One of the main drivers of the UK Government’s Regenerative Medicines Platform is to achieve precisely this consistency, and other agencies are seeking similar solutions. There are many contributory factors to overcome, but we can lump many of them together as problems of scalability. Cell therapies usually begin life as small laboratory-scale preparations. Scaling such processes up to produce the large batches required for clinical trials and beyond is challenging. Indeed, some processes simply cannot be scaled up, a fact that regulators and industry try to impress on academic labs trying to develop early-stage therapies. You need to think ahead.

But as ever, the big divide is between cell therapies being driven through the regulatory process and those feral therapies, marketed direct-to-consumer, for which no attempt is ever going to be made to bring them up to standard. If you want your therapy to be available finally as a licensed medicine, you know that this will depend on mastering the challenges of manufacture. If, however, you are simply mincing up whatever is recovered from liposuction, sticking a "stem cell" label on the tube, and charging thousands of dollars to squirt the unholy mix into someone’s eyes, brain, or spinal cord, then why bother with consistency. No two patients are ever going to get the same prep twice in any case. What’s the problem?

So, if you are considering offering yourself or a loved one to an unlicensed, direct-to-consumer clinic, here are two pieces of advice. First, don’t do it. Second, if you feel you must at least talk to them, ask how they know what is in the tube. What are their assays for purity, identity, and potency? What cells are in there, and how do they know? What else is in the tube that maybe shouldn’t be there? And, how do they know that preparation works? In relation to the last question, do NOT accept the answer: well, we’ve squirted something similar into many other patients with the same bank balance as you, and they all went away happy.

References

1. Datta S. Emerging dynamics of evidence and trust in online user-to-user engagement: the case of “unproven” stem cell therapies. Critical Public Health. Taylor & Francis; 2018;28:1–11.