Failure of autologous cord blood transplant in diabetes

by Alexey Bersenev on October 13, 2013 · 6 comments

in Uncategorized

I’ve written about trials, assessing autologous cord blood transplantation (CBT) in pediatric type 1 diabetes. The results of first such trial, conducted by University of Florida in collaboration with NIH, were disappointing. The results of another trial, conducted in Germany and utilized the same protocol, have been published very recently. And as US trial, this one is also failed! There was no impact on metabolic (C-peptide, insulin requirement) or immunological (auto-antibodies, T-regs, CD4/CD8 ratio) profiles. Negative results of both trials allow us to conclude that autologous CBT does not work in children with type 1 diabetes.

The first thing, I’d like to notice is a slow enrollment rate. In US study, 24 children underwent CBT during 5 years. In German study, only 17 patient were enrolled in 5 years period and only 7 were infused with cord blood. It is very hard to find kids with diabetes, who have their cord blood privately banked. So, we have to wait for many years to get a hint of potential efficacy. The second point is lack of controls. Haller’s study did not have any controls due to “FDA restrictions”. The German’s study, for the first time used so called “natural controls” – children, who fit inclusion criteria, but did not have cord blood banked. More likely, placebo controls can not be implemented in case of autologous CBT.

Failure of both trials tells us that possible differences in cord blood processing, more likely, did not contribute to clinical outcome. Since number of infused total nucleated cells in German’s study was almost 2 times higher than in US study, we can not account it as a possible contributor to outcome. Age of patients seem not to be the factor either (children in German’s study were younger). In regard to CD34+ cell number, they see the positive trend, but not significant impact. However, the authors concluded:

Children who received a richer in stem cells cord blood sample were found to have a better preservation of residual beta-cell function, assessed by AUC C-peptide. The exact mechanism is unclear; however, it may suggest that cord blood therapy could be efficacious if enough CD34+ cells are infused.

As potential future development, the authors discuss possibilities of expansion selective cord blood cell populations, such as regulatory T-cells (T-regs) and hematopoietic progenitors. Unlike German study, Haller’s group observed increase of T-regs frequency up to 6 month post CBT. It was a rationale for development of clinical-grade cord blood T-regs expansion and pursuing a future clinical trial. As Michael Haller told me (via email), University of Florida is on a track of starting T-regs trial in the next 1-2 years. Hematopoietic progenitor cell expansion is another promising direction, but so far nobody tried it in autologous CBT for diabetes. If expansion of selective cell populations will work, it would change a game.

Finally, I’d like to notice, that results of this very important study were not picked up by media and discussed publicly. Well, it is not in favor of massive (regenerative medicine-related) advertisement campaigns by private cord blood banks.

{ 6 comments… read them below or add one }

Frances Verter October 16, 2013 at 3:26 pm

I think it is too harsh to call the Haller study a “failure” because it did not achieve the end point of curing Type 1 Diabetes (T1D), or at least preserving the patients’ C-Peptide. The patients in the study did show significant temporary improvement, which is why there is still motivation among researchers to explore the immune-modulatory impact of cord blood for T1D.

To put this in terms of a personal story: I am friends with the mother of a boy named “S.” who participated in the study. As a result of receiving his own cord blood stem cells, his insulin dependence dropped from 7 injections per day to a single injection. That improvement persisted for almost a year. As measured by quality of life, the study helped S. a lot.

Unfortunately, the improvement was transient. His T1D got worse again after a year, and now his blood sugar is so unstable that he has a service dog to alert the family if his sugar is too high or too low. Hopefully someday we can truly cure patients like S.

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Alexey Bersenev October 18, 2013 at 12:06 am

Frances,
It is harsh judgement, but it is a failure, because the criteria of success are embedded in trial design (didn’t meet primary end points). I see your point, but trial is a trial – it’s not a case studies or cohort studies. In many many cell therapy trials, failed by efficacy, there will be some responders, some non-responders. But overall conclusion could be a failure, because of statistical significance and number of enrolled subjects as designed. For example, even though Phase 3 trial of Prochymal (Osiris) for GVHD officially failed, the company presents a “miracle cases” every meeting. Some kids got GVHD-free (!) only because of Prochymal. Nobody can deny it. But trial is still failed, because of number of patients with good placebo effects and non-responders in Prochymal group overweighted responders. What is very important is ID those responders and conduct a new trial with new enrollment criteria – it will be successful, but will take time.

Trial could be labeled as “failed” simply because: stopped due to funding issues (even though was efficacious!), business reasons (company switch to other programs and sold cell therapy assets), poor design (too slow enrollment, nobody can meet criteria), not safe/ not effective, bad management….
http://celltrials.info/2012/09/17/cell-therapy-clinical-trials-fail/

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Yi October 17, 2013 at 11:40 pm

1\ Can you comment or summary the effect of MSC on diabetes, no matter the source of MSCs and type of diabetes?
2\ whate do you think about the results of encapsulated beta-cells for T1DM, any exciting news from any group for this field?

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Alexey Bersenev October 18, 2013 at 12:59 am

Yi,
1. There are a few reports, you can search. I did not read them, so I can not assess. Some recent, including randomized controlled trial (but in type 2) –
http://www.ingentaconnect.com/content/cog/ct/pre-prints/content-cog_09636897_ct0920bhansali
http://www.ncbi.nlm.nih.gov/pubmed/24121994

2. I don’t see the bright future of allo- and xeno- islet cell transplantation. Immunologic issues (immunosupression could be more harmful for patient than diabetes) is the most important reason. Encapsulation have been around for very long time, but I didn’t see good results of any big controlled randomized trial. I think, will be immune reaction on a capsules too – fibrosis.

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Frances Verter October 24, 2013 at 10:58 am

Another study: Adults with Type 2 diabetes, treated with autologous bone marrow stem cells, said to require less insulin versus a control group.
News article:
http://www.medicalnewstoday.com/articles/262707.php
Publication:
http://europepmc.org/abstract/MED/23561959/reload=0;jsessionid=wwla59XMsxe90PiuxuNk.44

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Amanda January 13, 2014 at 12:12 pm

Greetings,

Can any of you guide me in the right direction in regards to my 7house y/o daughter? She is a Type 1 diabetic, diagnosed 2/14/2010. We have her cord blood banked and I am curious if there is anyone that can fill me in as to the possibility of using her cord blood.

Please email me at the email address above.

Warm Regards

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