- Masayo Takahashi, the trial leader, on the medical potential of iPS cells (Image: Nippon News/Alamy)
Last summer, the New Scientist gave us a cancer scare. Specifically, there were claims that a stem cell trial was suspended because of potentially cancerous mutations found in the iPS cells used (that is, cells that can give rise to any type of body cell).
Should we be scared?
The short answer is no. The media just blew it out of proportion, but as usual… there’s more to the story.
As a brief background, we’re talking about the first phase 1 human clinical trial using iPS cell therapy, conducted at the RIKEN Centre in Japan. The aim was to test the safety of iPS cell therapy, and to stop the worsening of age-related macular degeneration, the leading cause of blindness affecting 25% of over 60s. The procedure was autologous, involving skin fibroblast cells being taken from a woman in her 70s being reprogrammed into iPS cells, and differentiated into retinal-pigmented epithelial (RPE) cells that were then transplanted back into her eyes in September 2014. One year on, her vision reportedly stopped getting worse and there were no safety concerns such as teratoma (tumor) formation, even without immunosuppressants.
A while later, a second patient had the same procedure but didn’t receive a transplant, and the trial with the first patient was halted in March 2015. But why?
It turned out that the second patient’s iPS cells had 6 mutations that weren’t present in the original fibroblast cell population. One of these mutations is associated with a remote risk of cancer, and that’s why people got scared. There were also speculations that the mutations were caused by a faulty reprogramming process used to turn the somatic fibroblast cells into iPS cells.
Dr Takahashi, the trial leader, assured us that the mutations were much more likely to have arisen de novo during cell culture or differentiation, as could also happen with embryonic stem cells. Importantly, she claimed, “the mutated genes were not driver genes for tumor formation”. In fact, tumorigenicity testing showed the cells were safe, which was pretty much assured anyway as RPE cells are unique and never form tumors even if there are mutations present. This is due to them making PEDF, an anti-tumor factor.
As largely ignored by the media, the trial was actually suspended mainly because the Japanese law was revised in November 2014, with the PMD Act stating that a regenerative medicine product, provided that it is safe, can be conditionally approved on the market, with 7 years in which to prove its efficacy. But isn’t this a dangerous policy?
Regardless, the revised law facilitated RIKEN’s decision to switch from testing autologous (self) to allogenic (non-self) transplants, using banked iPS cells. This may seem counterintuitive, since the biggest promise of iPS cells was making patient-specific specialized cells that wouldn’t be immune rejected.
But since this is so costly, slow, and hard to quality control, especially on an industrial level, many scientists think that establishing iPS cell banks is more commercially and economically viable. You can make huge batches and thoroughly test them before use, without the long wait to turn your own cells into iPS cells.
The iPS cell bank in Japan is being established with government funding, screening many potential donors to find matches for the major human leukocyte antigens (HLAs) of 90% of the Japanese population (HLAs are cell-surface receptors that if mismatched, are the primary cause of immune rejection). It is predicted that iPS cell lines from 140 individuals will be needed for this, and they should be characterized by 2023. This theoretically leaves just 10% of Japan needing expensive immunosuppression, ~$14,000 per person per year, for life! Definitely beats using embryonic stem cells, which can’t be HLA-type preselected.
Allogeneic transplantation would allow us to treat more people in the same time period than autologous transplantation, and Takahashi did animal experiments giving evidence that there is little to no immune response if HLA matching is carried out. Though, there will always be some uncertainty since we’re not focusing on matching “minor antigens” as well.
Making HLA-matched cells for the whole population is a lot more challenging in the US and UK because of the huge ethnic diversity, so iPS cell banks would likewise need to be huge, meaning higher costs. I think that the obvious solution would be to share iPS cell lines globally, but this means we need a clinical grade iPS cell bank that fits within global regulatory networks. Luckily, the Cell Therapy Catapult in the UK has already established such a source, banked according to good manufacturing practice (GMP, addressing safety and quality of cells) with the aid of the MHRA, who provided expert advice and guidance.
In the US, Lozna, a global leader in cell therapy and manufacturing, recently published a protocol in the journal Stem Cell Reports that describes the generation of clinical grade GMP-compliant iPS cell lines. This would provide solutions to advancing iPS cell commercial manufacturing, since the protocols are freely available to the global stem cell community.
We’ve already come a long way in increasing the safety and eventual efficacy of iPS cell therapy (more detailed paper here). We don’t use potential oncogenic factors like c-Myc in the reprogramming protocol anymore, and we’ve found small-molecule replacements of transcription factors to chemically make iPS cells instead, improving safety and quality. We’ve also replaced viruses with non-integrating viral vectors so transgenes won’t integrate into the genome. We have ways of separating differentiated cells from tumorigenic undifferentiated iPS cells, and we can directly target and kill oncogenic cells via new technologies.
There’s another iPS cell trial in Japan, this time for Parkinson’s disease, and the UK will undoubtedly conduct it’s own trials soon, bringing us closer to reaping the benefits of Yamanaka’s exciting 2006 iPS cell discovery. It’s about time.
MBBlog 