Cells Weekly – August 23, 2015

by Alexey Bersenev on August 23, 2015 · 6 comments

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Post updated on 8/26/15 at 5.52 pm EST

Cells Weekly is a digest of the most interesting news and events in stem cell research, cell therapy and regenerative medicine. Cells Weekly is posted every Sunday night!


1. Differential immunogenicity of auto- iPS cell progenitors
New study, published online in Cell Stem Cell this week, described phenomenon of differential immunogenicity of progenitors, derived from autologous iPS cells. The authors used sophisticated humanized mouse model with “human-like” intact immune system and tested two types of mature cells, differentiated from iPS cell:

… we demonstrate that most teratomas formed by autologous integration-free hiPSCs exhibit local infiltration of antigen-specific T cells and associated tissue necrosis, indicating immune rejection of certain hiPSC-derived cells. In this context, autologous hiPSC-derived smooth muscle cells (SMCs) appear to be highly immunogenic, while autologous hiPSC-derived retinal pigment epithelial (RPE) cells are immune tolerated even in non-ocular locations. This differential immunogenicity is due in part to abnormal expression of immunogenic antigens in hiPSC-derived SMCs, but not in hiPSC-derived RPEs.

It is unknown if the same phenomenon applies to human. Also, I’d be curious to see if this differential immunogenicity can be demonstrated by other groups in different humanized models (there are many of them) with different iPS cell-derived progenitors.

2. Big failures in Phase 3 of clinical trials
Israeli-based company Macrocure announced this week preliminary results of their Phase 3 clinical trial, using cell product CureXcell in venous leg ulcers. CureXcell consists of allogeneic leukocytes and get injected directly into the skin wound. PR says that “study is not expected to meet its primary endpoint”, and:

“While we are disappointed with the results of the VLU futility analysis, given the positive clinical outcomes seen in our experience with more than 5,000 patients in Israel, we continue to believe that the technology has clinical merit for patients with chronic and other hard-to-heal wounds,” said Nissim Mashiach, President and Chief Executive Officer of Macrocure.

Company’s stock is crushed (78% down on announcement).

US-based company Vital Therapies announced this week, that their Phase 3 trial fails in primary and secondary end points. The company develops cell-based extracorporeal device for liver failure – ELAD®. Vital will stop two trials and re-analyze the data. Company’s stock dropped nearly 30% on announcement.

3. Results of Tigenix Phase 3 trial in Crohn’s disease fistulas
Belgian cell therapy company Tigenix announced today (.pdf) preliminary results of their Phase 3 trial, assessing efficacy of local injections of allo- adipose stem cells in Crohn’s disease fistulas. The study met primary end points! Not very dramatic, but significant difference with placebo:

In the ITT3 population (n=212), Cx601 achieved statistically significant superiority (p<0.025) with 49.5% combined remission at week 24 compared to 34.3% in the placebo arm. In the mITT4 population (n=204), the combined remission rates at week 24 were 51.5% and 35.6% for Cx601 and placebo, respectively (p<0.025).

Tigenix becomes the first (correction: first allogeneic – see comment) European cell therapy company with successful Phase 3 trial results! Great news for the field! For more details we still have to wait final results and publication.

4. Human brain in vitro – mass media buzz
This week, the Ohio State University released a conference report news about achievement in growing human brain-like structure in vitro. It caused a huge buzz in mass media – read some good coverage in Guardian, Wired and NewScientist. Professional peers reacted to this news with great skepticism. The typical reaction:

Several stem cell researchers WIRED contacted, including one who saw the poster at the meeting, declined to comment on the work. As well they might: The work didn’t say enough to comment on.

That’s right, no data – no comment! More criticism was expressed on social media – see Knoepfler’s post and tweets.
While we are waiting for any piece of data to assess, many would agree that it was bad PR move!

5. Advances in optogenetics
We are continuing to watch the field of optogenetics with great interest. Two new recently published studies The first report came from Stanford University and describes the first implantable wireless optogenetic device. Implantable device is a big step further:

We show how three adaptations of the implant allow for untethered optogenetic control throughout the nervous system (brain, spinal cord and peripheral nerve endings) of behaving mice. This technology opens the door for optogenetic experiments in which animals are able to behave naturally with optogenetic manipulation of both central and peripheral targets.

Seem like the device is so simple and cheap, so you can DIY.

The second study, published in Molecular Therapy, shows utilization of optogenetics for vision restoration in mice:

In this study, we solved a major challenge of optogenetic gene therapy for blindness by introducing a native opsin of the mammalian retina, the light-gated GPCR rhodopsin, as an optogenetic actuator, which we found to provide orders of magnitude of enhancement in light sensitivity over the microbial opsin channelrhodopsin. We delivered rhodopsin to blind mice via intravitreal injection of a viral vector containing a cell-specific promoter and showed efficient, cell-specific expression in ON-BCs.

6. Podcast with pioneers of immunocellular therapy
Novel Targets recorded a great podcast with “titans” of adoptive cell therapy Carl June (UPenn) and Steven Rosenberg (NCI). I found it very very interesting. Rosenberg is not as optimistic about the future of CAR T-cell therapies in solid cancers as June. Rosenberg’s quote:

“I don’t think that CARs are going to have much value beyond the hematological malignancies with very few exceptions.”

Highly recommended!

7. Patient’s on social media updates impact regenerative medicine trial
Boston Globe has very very interesting post on social media activity of patients from spinal injury regenerative medicine trial, sponsored by company InVivo Therapeutics. Patients #1 and #2 updates on social media impacted company’s stock shares and their lives (this is a love story!):

The tweets and the selfies, the uploaded video clips, felt like a natural way for Jesi Stracham to record her halting progress as she fought to recover from a motorcycle accident that had left her paralyzed from the chest down.

She had no idea, as she tapped away at her iPhone from her hospital bed, what her bubbly posts would unleash.

The stock of a Cambridge-based biotech company would rise and fall with her updates.

Jason Napodano, an independent biotech analyst who previously followed the company for Zacks Investment Research, has watched with fascination. “Patients scooping companies on clinical trial data,” he said, “is a new frontier.”

Yes, this is a new frontier and we have to deal with it! We cannot ask patient to stop their social media activity, but investors and companies execs…. common, guys, do not play such stock games! Be wise and base your judgement on solid data, not on social media updates!

Highly recommended to read!

{ 6 comments… read them below or add one }

Alberto Zaragoza Comendador August 24, 2015 at 5:36 am

Are you sure Tigenix is the first? I think Holostem already a successful trial of this kind.


Alexey Bersenev August 25, 2015 at 5:32 pm

Do you mean Holoclar by Chiesi Farmaceutici S.p.A approved in Europe in Feb this year? I covered it here –
Holoclar is totally different thing, since it’s not adipose-derived and it’s not allogeneic. The similarity is that both of them from Europe and both are stem cell-based medicines. So, I was careful in my claims, calling it first allo- adipose-derived in Europe.


Logribel August 26, 2015 at 3:14 am

I do agree with you Alexey, TiGenix’s results are truly a first: autologous stem cell treatments have been around for some time, but TiGenix’s Cx601 is the first allogeneic, commercially viable stem cell product (the closest thing you can get to a “conventional drug”), and it has been thouroughly tested through solid randomised controlled trials. To me, this is a pivotal event for stem cell therapies which could foretell many more successes in the years to come, if only some other biotechs would apply better trial designs and serious management to their own products.

By the way, Cx601 proved to be effective in curing about 50% of highly refractory Crohn’s disease patients with complex fistulas: that is about twice the efficacy of the best medical option available to a similar treatment population (antiTNFalpha drugs such as Remicade which have ~26% efficacy rate) with a stellar safety profile (there were more TAES in the placebo arm than in the treatment arm!): put in context, I would dare to call those “impressive results” even if you think they are not so dramatic…


Lee August 26, 2015 at 11:14 am

Hi Alexey,

To Alberto’s point you did say “Tigenix becomes the first European cell therapy company with successful Phase 3 trial results!”. Holocar data did come before this Cx601 data but don’t worry because you are still right if I’m not mistaken in that TiGenix was the first company with successful phase 3 data many years ago with ChondroCelect.


Alexey Bersenev August 26, 2015 at 5:49 pm

Thanks for correction Lee and Alberto,
I’ll make a note. I’m trying to find PRs or publications about results of Ph3 of Holoclar and ChondroSelect.


Logribel August 27, 2015 at 2:45 am

Well, ChondroCelect was “another” first by TiGenix: it was the first ever officially approved cell therapy in Europe, but it’s not a stem cell therapy. ChondroCelect (CC) is an autologous chondrocyte implantation (ACI) therapy for the repair of knee cartilage lesions. Here are some interesting links about CC:

Phase 3 Trial Results: https://clinicaltrials.gov/ct2/show/results/NCT00414700
Cost-Utility Study: http://www.ncbi.nlm.nih.gov/pubmed/21080737
5-year Follow-up: http://ajs.sagepub.com/content/39/12/2566.full?sid=9ba87338-8ad5-421b-b8bb-11e07e6f3c5a

Still, if we agree to term it “the first allogeneic stem cell treatment success in a Phase 3 RCT” then I am positively sure that TiGenix has indeed become the official title-holder!


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