Since the first report of mouse iPS cells in 2006 by Yamanaka, many of us have been excited about the prospect of iPS cell therapies. A report on production of human iPS cells came just a year later in 2007. Now, almost 20 years later, we don’t have any formally approved stem cell therapies based on these powerful, reprogrammed cells.
However, I would argue there’s never been more promise from iPS cells than now. It’s an exciting time. One challenge is deciding when there are enough data to approve any particular cell therapy. A key panel in Japan just green-lighted two iPS cell therapies for the first time.
In my view, this was premature. Let’s go through the therapies and their potential risks.
The 2 investigational iPS cell therapies
Here is one of the news stories on this development: Japan panel OKs medical products using iPS cells.
What are these products that seem destined for conditional approval soon?
Cuorips developed an iPS cell-based cardiomyocyte sheet product for ischemic cardiomyopathy called ReHeart. Sumitomo Pharma has Amchepry, an iPS cell-based cell therapy for Parkinson’s disease. Both are allogeneic therapies, meaning based on someone else’s iPS cells.
If the cell therapies are beneficial and safe, this could be a great development. However, let’s go through why I have some concerns about marketing these new approaches so soon. Note that I’ve had long-standing concerns about Japan’s conditional approval system for regenerative medicine. See Japan stem cell oversight system too lax?
Why it's too early in my view
It’s great to see the iPS cell field advance in general. I see a variety of early clinical work based on iPS cells, including on the two products viewed favorably by the panel, as potentially encouraging.
However, in my view it’s too early for commercialization for any of the iPS cell-based therapies under investigation around the world including these two products in Japan. For reference, these specific products have gone through the equivalent of tiny, uncontrolled Phase 1 clinical trials with from 6-8 patients. Both had signs of solid safety and gave hints of some efficacy, but with so few patients and no controls, it’s hard to be sure of much here so far.
Obtaining data from trials with much larger, better controlled groups including blinding, randomization, and placebo controls prior to commercialization is the way to go forward in my view.
Risks associated with conditional approval of iPS cell therapies based on little data
I respect that patients with such serious illnesses face pressing needs and I understand that regenerative medicine biotechs can benefit from early commercialization, but with limited data from open-label studies on just a few patients, the major risk is relatively high that many of those receiving these still investigational therapies after the expected conditional approval will have little or even no benefit. New adverse events may also emerge. With pluripotent stem cell-based therapies, we tend to worry most about tumors like teratoma, but other issues could arise like immune system problems.
Since the cells in these products are not from the subsequent recipients, the trial participants (and future patients getting these after conditional approval) will have to receive immunosuppression, which also comes with risks.
Allogeneic versus autologous iPS cell therapies
This also raises the larger consideration for the iPS cell field of pursuing allogeneic versus autologous cell therapies.
Years ago, Japan decided to mainly focus on allogeneic iPS cell therapies. Around the world more generally, there are a mix of allogeneic and autologous iPS cell therapies ongoing, including for Parkinson’s disease. For instance, Aspen Neuroscience has an investigational autologous iPS cell-based therapy in trials that has some encouraging data. At the same time, hESC-based allogeneic therapies for Parkinson’s also look promising.
To me, the idea of getting a customized cell therapy based on your own iPS cells still seems the most exciting, but if allogeneic cell therapies work and immunosuppression is well-tolerated, that becomes another option that could be more widely available, ready much more quickly, and less costly. So what’s better? There is no one answer. (note: see Promising signs for stem cell-based therapies for Parkinson’s in two new studies)
For such questions, much will depend on the data from trials with large numbers of patients. Marketing too early runs one final additional risk of broad negative impact on the field if serious adverse events occur from conditional approval and marketing.
Notes
Other researchers and I are also quoted on our concerns on the panel’s decision in a new Nature news piece: First-of-a-kind stem cell therapies set for approval in Japan Regenerative medicines are headed for people with Parkinson’s disease or severe heart failure — but researchers are concerned about minimal clinical-trial data.
Since my opinions are often quoted, I want to add another opinion. I do not believe that a randomized placebo trial design is appropriate for iPSC-derived cell therapies that involve surgery. A “sham surgery”, in which the patient is in the operating room for many hours and receives only a superficial operation, a hole drilled in the skull for the Parkinson’s disease therapies or (and I know less about this), an incision that makes the patient think that they received a patch on their heart. It’s worse for allogeneic therapies, in which the patients are immunosuppressed for a year for more. To be a truly revealing trial, the sham surgery patients would also have to receive immunosuppression, to control for the effects of being immunosuppressed. I think the sham surgery concept is unethical as well as being scientifically flawed. Patients can easily “unblind” themselves by simply having an MRI, that would show whether the heart or the brain has been accessed to put in the cells.
Paul, as you know, there are efforts to provide a “kill switch” that can be activated if a cancer is detected, killing off the transplanted cells. But it doesn’t solve the problem of detecting cancerous growth when it happens – a possible solution would be a blood test that specifically identifies DNA made by that specific cancer type, like Grail’s cancer screening blood test. And, the kill switch technology relies on inducible transgenes, which are almost always leaky…that is, in the absence of induction, the cells would make the killer gene at a low level, perhaps a level sufficient to kill them prematurely. This gets complicated…perhaps more complicated than just using autologous iPSC-derived cells for transplantation.
John, not so simple. Gene editing introduces mutations in the genome that increase the risk of transplanted cells becoming cancerous; hypoimmunity requires modification of multiple genes and there are reports of multiple genomic abnormalities resulting from this editing. To make matters worse, the cells are invisible to the surveillance by our immune system that kills off cancerous cells before they become dangerous. The transplanted cells could form a tumor and never be detected.
Gene editing will allow allo without immunosuppressants. See CRSP and Lineage Cell
@John, Yes, in the future that’s an interesting option that could be helpful. The thing with that kind of approach is that since the introduced cells fly under the immune system radar, they could pose unique risks. Trials will help clarify whether this potential concern with hypo-immune allo cells is something to worry about.