August 11, 2020

The Niche

Knoepfler lab stem cell blog

Are iPS cells being rushed to the clinic or has their time come?

The iPS cell field has run fast and furious over the past 6 years reaching a big milestone surprisingly quickly on Monday with Shinya Yamanaka winning the Nobel Prize.

But is  the field going too fast?

In August I argued that iPS cells are not quite ready for primetime (i.e. clinical trial studies).

Now in October I mostly feel the same way.

But reportedly, some iPS cell researchers are working to start clinical studies wherein iPS cells would be transplanted into human patients as early as next year in Japan.

This is both exciting, but also potentially very risky if not flirting with disaster.

In the Businessweek article on the possible clinical use of iPS cells, Yamanaka is quoted regarding safety:

Scientists first must ensure that the cells are safe, Yamanaka said in a video appearance from Japan yesterday at the San Francisco news conference organized by Gladstone. One concern is that stem cells could grow out of control, leading to cancers.

“We need to double check we don’t see any severe side effects in patients after transfer,” he said. “That’s where we have been spending most of our time. We are getting closer and closer. In some diseases, like macular degeneration, it’s almost ready to go.”

Extensive safety testing must be done in pre-clinical studies prior to the cells ever going into patients.

Is that kind of pre-clinical data already out existent and supportive of starting Phase I clinical trials for safety in patients as early as next year?

I found just one highly relevant article in Pubmed by an author who seems to be the leader of the team that will be part of the iPS cell-based clinical trials, Dr. Masayo Takahashi. This article was not directly a pre-clinical safety study, but rather a study elegantly demonstrating sensitive assays for detecting undifferentiated iPS cells in batches of retinal pigmented epithelial cells (RPEs) made from iPS cells. Very important, but does not a pre-clinical safety or efficacy study.

Alexey Bersenev on his outstanding blog has a piece on safety studies on iPS-derived RPEs here as well. I agree with Alexey that this issue is a big deal.

Alexey cites another published study by a different group, this one at Columbia, that I also believe is relevant and important. The group reported mildly encouraging safety results from transplant studies in mice in which iPS cell-derived RPEs were transplanted into the retina and importantly did not form tumors during the lifetime of the recipient mice. Remarkably, the iPS cells in question were made using lentiviral expression of the standard Yamanaka 4 factors including the powerful oncogene c-Myc, considered one of the relatively less safe approaches from a clinical perspective. Takahashi’s group may be using what seems to be a relatively safer method.

The absence of tumors in this Columbia study is encouraging, but several critical limitations of the work are notable.

Only 1,000 RPEs were used, far below the level of cells needed to be clinically relevant in human patients and less likely to produce side effects such as tumors. BrdU studies for looking for aberrant proliferative cells were not done. It also wasn’t clear if microscopic nests or pre-cancerous lesions could have been present but missed one examination.

How low is 1,000 cells?

Very low.

For example, Advanced Cell Technology (ACT) in their clinical studies is using doses so far of 50,000-100,000 RPEs made from hESC, which are cell levels 50-100 times higher than those used in the Columbia study with iPS-derived RPEs.

More cells = more clinical power but also = greater risk of tumors.

The same Columbia group reported in a previous similar study using ES cells that tumors developed in many of the injected eyes of the mice.

The authors speculate that an extended period of differentiation prior to transplant of the iPS-derived RPEs may have helped reduce tumorigenicity compared to the ES cell-derived RPEs. But the reality is they just don’t know. What if next time an iPS cell study with 1,000 cell injections behaves more like the ES cell one generating many tumors?

Alexey also mentioned in an earlier piece that Takahashi presented pre-clinical data on iPS-derived RPEs at ISSCR 2012. Encouragingly, her group reported no tumors in mice given the treatments. I don’t know the details of those studies such as how many cells were injected and how long the mice were followed.

To my knowledge the work remains unpublished.

I don’t know (but am educating myself) on the rules of the Japanese equivalent of the FDA, called the PMDA, when it comes to pre-clinical data prior to approving clinical trials. Given the FDA historical record on ES cell regulations with ACT and Geron, I would imagine the FDA would require several year’s worth of pre-clinical studies potentially involving thousands of rodents and/or primate data.

Why is it some important for the iPS cell field not to jump the gun and transplant the cells into patients too soon?

The clinical potential of iPS cells is exciting to put it mildly, but if the field moves too fast it may harm patients and set itself back many years. One major concern of course is tumorigenicity, highlighted especially by my lab’s recent paper on the striking similarities of iPS cells and cancer cells on some levels, but there are many other concerns (see here).

It would be tragic if the excitement and creativity exploding from iPS cells became diminished in the future by a rush to the clinic that harmed patients.

So are iPS cells ready to jump to clinical trials? I don’t know if there is a definitive answer. What do you think?

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