Blogging today’s FDA stem cell meeting: Part 2 Clinics, Policy & Ethics

The FDA is holding its first 2016 stem cell meeting today and you can read about some impressions of the morning session of this meeting here.

In this post, I’m focusing on the afternoon session, which has been mostly on policy and ethics, including on stem cell clinics.jonathan-kimmelman-fda

Jonathan Kimmelman from McGill University got the afternoon going with his excellent talk “Ethics, Evidence, and Regulatory Approval for Cell-Based Interventions“. Jonathan started his talk addressing the stem cell clinic situation in the U.S. and asking more broadly how regulatory authorities should establishment a benchmark for making experimental interventions such as stem cells available to patients.

He asked if there is a zero sum game between innovation and oversight? He argues there isn’t. They can actually work together. With oversight you maximize the amount of data per patient put at risk.

He used gene therapy taking decades (and still no approved therapy) as an example of the timeline for experimental stem cell therapies.

What about the idea of patients vs. bureaucracy? Is that a genuine dynamic? Are the most vocal patients democratic representatives of patients more generally?

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jonathan-kimmelman-stem-cell-clinical-translation-talk slide

In talking about the idea of safety vs. efficacy, he discussed risks of cell therapies.

He asked, “How do we as a society want to distribute the costs and burdens of medical uncertainties?”

How does this all tie in with the new 2016 ISSCR guidelines on stem cell clinical translation?

Key issues include the primacy of patient welfare and social justice. There should not be exposure of patients to unproven therapies outside of true clinical trials or in other unique circumstances (I’m thinking expanded access).

Jonathan also talked about concerns with pay-to-participate trials for stem cells.

Above is a summary slide from Jonathan’s talk.

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stamina-stem-cell-protocol-problems

Massimo Dominici, MD next gave his talk “Dissecting Unproven Cellular Therapies: The International Society for Cellular Therapy (ISCT) Position.”

Dr. Dominici talked about global stem cell clinic locations, the costs, and the global challenge here. He showed data from the important John Rasko Cell Stem Cell paper on global stem cell clinics. He also cited the example of the Stamina problem in Italy and the “weird” protocols involved there in that treatment. One patient died. See his slide above on Stamina, where UCT means unproven cell therapy. To sum up he indicated that a problem is confusion between unethical versus innovative cell-based approaches.

Peter Rubin, MD wrapped up the session on  “Clinical Adipose-Based Therapies.” Dr. Rubin is a plastic surgeon who studies adipose (fat) stem cells. He talked about autologous fat transfer versus adipose stem cell treatment. As to the former, he discussed the strong safety profile and good results with fat transfer outcomes (for instance with facial deformities from wartime injuries). There’s about 63% retention of volume induced with fat transfer in their experience. He reported that the # of cells in the fat tissue correlates with better outcomes. Tissue remodeling (not just volume) occurs. He did also mention how fat stem cells might be able to promote cancer recurrence or progression.

What about adipose stem cell treatments? Rubin called the basis for this as being “bioactive” cells from fat or the stromal vascular fraction, which someone from Wisconsin he says apparently calls colloquially “sushi”. I’m not sure I get that. Rubin uses an automated machine to make SVF. Lots of heterogeneity in SVF cell types. He talked about IFATs (a federation for fat tissue/cells). These cells make growth factors. They are using these cells in pre-clinical studies now (e.g. in rodents). Their clinical strategy under an IDE is to mix the SVF with the fat graft for traumatic amputation. He advocated for taking a responsible, evidence-based approach.

Overall, I found these talks to be really fascinating together linking together real-world experiences with stem cells in clinical use (responsible or not or even in the middle gray zone in some cases depending on one’s perspective) along with ethical and policy considerations as well as guidelines.

5 big picture stem cell trends at #ISSCR2016

Now that the ISSCR annual meeting is over, some overall stem cell trends are evident from the meeting in terms of the direction of the stem cell field. This was one of my favorite ISSCR meetings.

Translation expectation and upbeat tone. The overall vibe at the meeting was a sense of excitement and optimism about the field and where it stands in terms of advancing knowledge and translating stem cells to the clinic. There are challenges and debates over the different possible paths forward, but the general buzz at the meeting was positive and optimistic. It was also great to see quite an impact from patient advocates at the meeting including from several who were speakers.

There was also much more discussion of stem cell regulations and clinical translation even amongst more basic scientists than in past years. I expect the debate over stem cell clinical regulations will continue to be a major focus for the field in the coming year.

ISSCR 2016 packed house

Differentiation differentiates itself. From the talks I attended, the most striking change from past ISSCR meetings was the relatively large focus on differentiation. While there was still lots of discussion of potency of stem cells and inherent stem cell properties, there was much more emphasis on mechanisms of commitment and differentiation. How do cells properly exit the stem cell state to become the correct kind of progenitors and then terminally differentiated cells? At ISSCR 2016 one of the key stem cell trends was the big emphasis placed on answering this question. More focus on differentiation is valuable.

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ISSCR President Sean Morrison on challenges and future of stem cell field

Sean Morrison M.D.I recently chatted with Sean Morrison, current President of ISSCR, on his goals for the Society, where the stem cell field stands today, top challenges, and the future.

What are your goals for your tenure as President of ISSCR?

SM: ISSCR is the international voice for research in the scientific community. There’s been less effort though amongst policy makers and the general public. I want to expand the reach beyond just the scientists. ISSCR will be building its capacity to participate in stem cell policy issues worldwide and also it’s capacity to communicate with the public.

What’s the plan to make this happen?

SM: A range of things. Beefing up ISSCR communications programs. Blogging, twitter and other efforts.

What are the main challenges & opportunities that ISSCR faces now?

SM: ISSCR has had steady and remarkable growth. It has grown and its scope has grown too. Managing the growth is a challenge. Prioritizing future opportunities. How can we have the most impact for the membership? How can we grow that impact? The annual meeting continues to grow. International ISSCR symposia have grown. Publishing activities have expanded including with Cell Stem Cell and now Stem Cell Reports. We continue to expand those kinds of activities. There is a set of opportunities related to going beyond the science. Our mission is to improve human health through stem cells. We can’t do that solely by meetings and publishing. Those are critical core activities, but there’s more that we can do such as in industry. Reaching out to those stakeholders. Expanding the activities of the Global Advisory Council (philanthropists, Susan Lim, and Deepak), stem cell policy, and communication.

How can ISSCR bring in more industry people?

SM: I do think more involvement of industry is important. How best can we do that? I attended the Industry Committee meeting at ISSCR meeting in Stockholm, where we had that conversation. I really do hope that we can increase the attractiveness and value provided by the annual meeting to people in industry. We want people talking about exciting unpublished data. One difficulty comes up though in this regard: who from industry is willing to talk about unpublished data? Some people have shown up in the past and are not willing to talk about data. The program committee needs to address that.

What’s your view on the evolution of the IPSC subfield?

SM: I’m excited about stem cells generally. We need all kinds of stem cell research to move forward. Historically we’ve not been very good at predicting which cell type will work. I’m very excited about somatic stem cell research and pluripotent stem cells, both embryonic and IPSC. Look at the things going on at Shinya’s institute. They’ve been bold at diverse ways that they can have impact. With each year that goes by, the more plausible scenarios arise for possible therapies using pluripotent stem cells.

The pioneering IPSC trial in Japan was put on hold. How serious is that?

SM: If you’ve been culturing cells, some of the time there’s going to be mutations. The fact that they found the mutations says that the process that they have in place worked. It’s not uncommon in clinical trials for things to go on hold. It’s not unique to stem cell trials or IPSCs. I have every expectation that they’ll get that back on track. 

What are you most excited about with your own research?

SM: We’re doing a lot of work to characterize the HSC niche. We’ve now identified the cells that are sources of the key factors for stem cell maintenance. In many ways the hematopoietic system is a paradigm. This will allow us to understand at a single cell level how the niche works and look for novel growth factors. Each time we identify one of those it has the potential to provide new tools.

What do you see as the most important and exciting stem cell development or trend of 2015 so far?

SM: We’re at an inflection point in terms of stem cell therapies moving into high-quality clinical trials. In 2008 when we were fighting the public policy battles about where the line should be drawn on ESC research. Also there were people making claims about difficult problems. I was skeptical at the time. I felt that a lot of the problems could be too biologically complicated for cell therapies to work. Yet the science has surged forward much more quickly. There’s really exciting preclinical data and actual clinical trials that are about to start or have started. Spinal cord. Macular degeneration. And others. Some people have spent 10-20 years trying to understand the biology. Parkinson’s with Lorenz Studer. Cell therapy for heart disease with Chuck Murry. It’s important for the general public to understand the timeframe and that some will fail. In the past some were just squirting cells into tissues…sort of like buying a lottery ticket. People now understand the biology better. Now we have a rational chance of success.

The debate that is shaping up for CIRM is also very important now. Stem cell research is already delivering and there’s opportunity looking ahead. More funding for CIRM makes sense and it would be a major setback to not do that, especially with declining federal funding. One thing that will distinguish the winning states from the losing states is who has the vision to keep the biomedical research enterprise going at the state level. The conversation changed with CIRM’s birth. It became, “How do we keep up with California?”

The spread of stem cell clinics selling non-FDA approved offerings in the US has accelerated. What should ISSCR and individual stem cell scientists be doing to address this growing problem?

SM: There’s a lot that you’ve done and we appreciate that. There’s also a lot that ISSCR has done. We have our A Closer Look website. ISSCR has spoken out more on this topic than any other topic relevant to the general public. Although stem cell research has enormous promise—and this is the most exciting time that we’ve ever had—unfortunately most people in the general public don’t understand how long it takes to go from the idea or proof of principle in a mouse to do it in humans. Sadly there are fraudulent people out there that are preying on patients. These are at best unproven and in many cases not even plausible therapies.

Where do you see the stem cell field in 5-10 years?

SM:  We should be excited, but I’m always wary of these kinds of predictions. If we look over the last 10 years there’s been a lot of twists in the plot. There’s been both good news and bad news. Some things have surged forward more quickly and some things that we are most excited about now weren’t on our radar screens then. We don’t really know where we’re going to be. But I’m very optimistic. The thing that we have to remember that we always forget, even when we identify an idea that works, it takes a lot of years to get that to a patient. Look how long it took for bone marrow transplant to develop. We now talk about bone marrow transplant as an example but it took 14 years. We should bear in mind that even if some of the things now in clinical trials are correct, it could take years to develop them in a safe and efficient way.

Monday morning musings: stem cell stocks, ISSCR, grants, CRISPR, New Book, & more

Wake up, it's Monday

What’s on your mind on this Monday morning? Are you caffeinated enough yet? Depending on where you live it may even be time for dinner, bed, or already early Tuesday.

Here’s some musings…

To get safe and effective stem cell treatments to patients in a responsible, compliant manner you need commercial efforts and that in almost all cases means biotechs.

Doing this blog for 5+ years has made it really sink in just how crucial the commercial side is to all of our shared goals. This means that things like stocks, patents, etc. are really important for us all to think about including academics, patients, students, and more. Of course stocks are very important more directly to investors too.

I’m not a big investor overall and my only stock in the stem cell biotech world now is Ocata ($OCAT) in which I have a very small holding (consider this a disclosure). I like the company’s scientific leadership and its technology. Throw in some promising clinical trials for an area of huge need like macular degeneration and it’s hard not to get excited about Ocata. However, even as Ocata rang the bell at NASDAQ last week, the OCAT stock price has been getting its bell rung this year and in particular more recently it has dropped off a (small) cliff. I don’t claim to understand the subtleties of stock investing super well, but one gets a sense that the company is at a sensitive moment in its history right now. The above issues as well as some rumors and intangibles give a feeling of change in the air.

Of course Ocata is not alone. The stem cell  sector is super volatile and the stock prices of other stem cell companies routinely take beatings. For instance, StemCells, Inc. has had a pretty awful time of it lately on the stock front and things seem pretty dicey right now for them. I hope it can turn around. By the way, this post is clearly not financial advice.

More broadly in this area I suppose we can just hope for the best in terms of trial results and financials holding up during tough periods of time. This has been a tougher year than I had imagined on this front for the field. Stay tuned for more posts on stem cell stocks soon. Still it was good to see many stem cell biotechs at ISSCR making presentations of largely encouraging data.

Speaking of ISSCR, I wasn’t there myself, but the sense I got from some attendees is that it was fairly upbeat. Again, seeing more biotechs presenting talks than in the past is very encouraging. I believe that the more diverse that ISSCR can become the better. Stay tuned also for one or two more posts on ISSCR Stockholm including possibly more from Heather Main (see her posts here). It’s looking like Heather may become a more regular contributor to this blog, which I think would be awesome.

Grants are on everyone’s minds even more now than in historical times in science (i.e. meaning a few decades ago). In my 2+ decades in science in various positions I’ve never seen it quite this bad. These days it seems like I’m always working on at least one grant and sometimes several simultaneously. It eats up a lot of time, focus, and energy, but that seems to just be the new reality.

I consider myself lucky to have gotten one foundation grant funded recently. Even so we’ve all got constant worries on grants. I also recently participated again in another NIH study section, which is always a lot of hard work, but a huge learning experience.

CRISPR science has moved at warp speed, but there is also rapidly growing focus in the life sciences on policy issues related to CRISPR-Cas9 technology, particularly in 2015. The next 6-12 months are likely to prove crucial in determining the path forward including possible action by Congress, the NAS, and more.

In addition to participating in the dialogue, I am also currently finishing a new book on human genetic modification that will probably come out late this year or in early 2016. I hope that it educates and sparks more dialogue without getting me in too much hot water. Stay tuned for some previews/teasers on this book in the next month or two.

There’s been a lot of talk lately about the “postdoc crisis” of there being too few academic positions for postdocs, postdoc training periods being too long, etc. This problem has been growing over the years, sometimes the same possible solutions get trotted out, and people wring their hands, but nothing substantive changes. I don’t have some kind of miracle solution, but it is something we should all be thinking about. What might be some creative solutions?

Review of Biotech/Translational Talks #ISSCR2015: StemCells Inc, Semma, ViaCyte, & Le Blanc

By Heather Main

The path to the clinic is a slow and arduous activity, frustrating not only to the researcher and patient, but investors. Successful clinical translation of technologies requires a balance of science, streamlined translation and funding. To develop fantastic science and then realise the most important components cannot be adapted to the clinical environment is as disastrous as having a great product but no cash to get it past the post. The fruitful interaction of researchers, companies and clinics will save a lot of pain in streamlining technologies to patients. Thus, it was nice to see an ISSCR 2015 plenary session on stem cell therapies including companies StemCells, Inc. and ViaCyte, Inc. The topics were a good spread of autologous and allogeneic cell sources as well as therapies directed at inflammation and immune reactions versus integrative cell replacement technologies.stemcellsinc-logo

StemCells, Inc. presented progress in clinical trials with allogeneic neural stem cells in brain, spinal cord and eye disorders. As is the reality for companies giving talks some data and beautiful pictures is not disclosed. Though there were no revolutionary data sets on efficacy, what was clear was that grafts could persist 1.5 years post removal of immunosuppression (this was determined with HLA-mismatch begging the development of a Shinya Yamanaka style allogeneic HLA cell bank). It should not be a surprise that there were no amazing efficacy leaps in these first trials. There would be a lot of luck in getting the right cell, the right dose and the right transplantation method in the first go. Even the development of reliable measures of graft behaviour and efficacy will take time to develop and standardise.

Semma TherapeuticsDoug Melton was clear to state that they “haven’t (just) done an academic study”. That while they are not yet in the clinic and even though they present a more classical academic study, showing a complex defined differentiation and detailed functional analyses, that they recognise the importance of not just talking the talk but walking the walk. Doug presented their in-vitro beta-cell body technology that show functional characteristics equivalent to, if not better than, cadaveric islets. They were able to upscale this technology and are now on the prowl for encapsulation technologies to move into the clinical space, which will happen through their new start-up Semma Therapeutics.

ViaCyte New LogoIt’s always nice to hear an Aussie accent ;), giving additional benefits to listening to Alan Robins present the progress of ViaCyte in clinical trials of their pancreatic progenitor and encapsulation technologies. Following on from Doug, Alan made a couple of comments to assure the audience that there was a lot of vigorous science behind their technology, the curse of not being able to disclose and thus somewhat unfairly being seen as less careful. The ViaCyte technology is based on the major phase of expansion in pluripotent cells followed by mass differentiation and subsequent encapsulation. Interestingly in their pre-clinical animals studies the grafts were able to regulate insulin levels at the standard human blood concentrations, indicating not only functionality but also species specific functionality.

Katarina Le BlancKatarina Le Blanc presented her work on MSCs for GVHD, diabetes and vocal cord scarring. Somewhat disappointingly I heard the comments of someone leaving this talk with the all too common disregard that MSC technologies are inferior to pluripotent technologies rather than recognising them as complementary technologies. Katarina showed epithelial cell death and inflammatory markers were reduced with maximal effect at 3 weeks after IV injection for GVHD, even though they also prove that IV infused cells have mostly disappeared already at 3 days post infusion. She also showed that while coagulation and complement cascades are activated in response to IV infusion of MSCs blood clotting is not a common occurrence. The risk of clotting was cell number, dose and passage number dependent, which is a little scary when many autologous therapy clinics do not standardise the cell number they IV inject.

It’s great to see both academics and companies being recognised as the drivers of cellular therapies. Working in a stem cell company myself, I was surprised 2 years in a row to see talks from academics about skeletal muscle differentiation protocols that do not come close to our technology. It’s somewhat understandable that when it is not possible to disclose a lot of details of your research, the companies are often not taken seriously and are relegated to paid presentations during the lunch break. It is fantastic however, to see positive movement in reputable exposure for the companies attempting to drive research to patients.