The first iPS cell clinical trial insights

by Alexey Bersenev on September 17, 2015 · 0 comments

in cell product, embryonic/iPS

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“For an hour on Friday 12 September, Masayo Takahashi sat alone, calmly reflecting on the decade of research that had led up to this moment”. (David Cyranoski, Nature doi:10.1038/516311a)


A year ago, the first historic transplantation of iPS cell-based product took place in Japan. Recently, the trial was halted due to RIKEN’s decision on changing strategy. Today, I’d to summarize some new info about the first iPS cell trial, based on two recent articles.

Was treatment of the first patient safe and effective?
Safe – YES, as of 6 months post-transplant. One year safety report is coming soon. Some observations of potential efficacy were shared in today’s issue of Cell & Gene Therapy Insights by Hardy Kagimoto (CEO of Healios KK):

She had a series of 18 anti-vascular endothelial growth factor (VEGF) ocular injections for both eyes to cope with the constant recurrence of the disease. The results presented by Dr Takahashi showed that, after the removal of the subretinal fibrotic tissue and implantation of the iPS-cell-derived retinal pigment epithelial (RPE) cell sheet, the patient experienced no recurrence of neovascularization at the 6 month point and was free from frequent anti-VEGF injections. Her visual acuity was stabilized and there have been no safety related concerns so far.

Mutations in the product from the 2nd patient
Some mutations were detected in the iPS cell-derived RPE product, prepared for the second patient. Nobody knows if these mutations were prohibitive for product release, since nobody has a guidance. What we know about these mutations:

… three single-nucleotide variations (SNVs) and three copy-number variants (CNVs) were present that were not detectable in the patient’s original fibroblasts.

The CNVs were all single-gene deletions. With regards to the SNVs, one is listed in a curated database of cancer somatic mutations, but only linked to a single cancer, reports CiRA. “The mutated genes were not driver genes for tumor formation,” wrote Takahashi in an e-mail.

and more from Kagimoto’s piece:

The result of tumorigenicity testing has proven the final RPE cells to be safe. Furthermore, the presence of genetic mutation does not necessarily mean that these RPE cells can be tumorigenic.

Regulatory change
As per trial PI, Masayo Takahashi, the main reason for trial halting was a regulatory change:

Although the mutations were identified before transplanting cells into the second patient, and the mutations may have contributed to RIKEN’s decision not to treat, the main reason not to go ahead with the trial was because of a “regulatory change,” says Takahashi.

New Japanese law on Regenerative Medicine became effective after iPS trial was started and after first product was transplanted. Perhaps, the trial design was not “very suitable” in this new regulatory framework. But still, there is no guidance in new regulation about “allowable” level of mutations and methods of their detection in iPS cell products:

… there is no regulation with which medical professionals are obligated to check gene modification for organ transplantation, mesenchymal stem cell injections or autologous cell therapy.
The fact remains that we do not have clear guidelines today on which the whole community can reach a consensus that “the second” RPE cells are safe enough for implantation .

RIKEN’s decision
It seem to me RIKEN’s decision on halting a trial was wise and very strategic. The first and the most important thing here:

As a pioneer of iPS cell clinical application, Riken took the responsible decision not to rush ahead with the second patient’s RPE cells, which could potentially damage the whole field of regenerative medicine.

The second thing is if there is no “guidance on mutations”, why not develop it now?

Although therefore, the cells were widely thought to be safe to use, after careful consideration, they made the decision that they would not implant another autologous cell sheet until such guidelines could be officially authorized.
They are now coordinating the discussions at the Ministry of Education, Culture, Sports, Science, and Technology, and also at the Ministry of Health, Labor and Welfare to carefully discuss these issues with key opinion leaders in the field including government officials, regulatory experts, scientists and toxicologists.

The third thing is realization that auto- model is not the way go in future:

“As of now, autologous would not be a feasible way of providing wide level clinical therapy,” says CiRA spokesperson Peter Karagiannis. “At the experimental level it’s fine, but if it’s going to be mass produced or industrialized, it has to be allogeneic.”

Moving forward
So, RIKEN is moving forward with allo- iPS cell-derived RPE. Moving together with CiRA. Well characterized partially matched lines with “safety clearance” by rigorous QC testing. However, some concerns about potential immunogenicity were expressed by peers:

But the project is fraught with uncertainty, because HLA-matched cells might still suffer immune rejection. “We’re not going to know until those clinical trials,” says Coffey. CiRA is not typing its cells for minor histocompatibility antigens, which can cause T cell–mediated transplant rejection. “The current effort is going for major [histocompatibility matching],” says Kapil Bharti, a stem cell researcher at the National Eye Institute.

I’m positive about future iPS cell-based trials. I like the approach, which RIKEN is taking. Here some of our expectation for the future (feel free to add to the list):

  • End of 2015 – One year safety follow-up from the first transplant
  • End of 2015 – Update on “discussion with regulators” from RIKEN
  • 2016 – Starting second RIKEN trials with allo- iPS cell lines from CiRA
  • 2016 – CiRA to start collaborations on other iPS cell trials in Japan
  • 2017 – Several other iPS cell trials will be started worldwide
  • 2017 – Tech transfer from RIKEN to Healios and starting industry-sponsored trials
  • 2019 – The first specialized iPS cell trials clinic to be open at Kyoto University Hospital
  • 2019-2020 – Approval of the first commercial iPS cell-based product granted for Healios

PS: Emphases throughout the text are mine.

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