Cord blood enhancement via expansion on mesenchymal stromal cells

by Alexey Bersenev on December 16, 2012 · 0 comments

in Uncategorized

A long-awaited results of MD Anderson clinical trial, assessing cord blood (CB) expansion in hematological malignancies, finally published in NEJM. I wrote about this trial 2 years ago. The results are encouraging! Some physicians even called it a breakthrough:

I like the publication – it’s neat and clear. There is no any word “stem cell” in the article! Do you remember what was 2-5 years ago? It was all about hematopoietic stem cell (HSC) expansion! Any trial for expansion of cord blood cells ex vivo was called “stem cell expansion”. Well, not any more. We’re over it!

31 patients with hematological malignancies received 2 units of matched CB – one was unmanipulated and one was expanded ex vivo. Even though, at this phase, study was not controlled prospectively, the results were compared with historical data – from CIBMTR database. As historical control, outcomes of 80 patients, who received double unit unmanipulated cord blood transplant, were used. Cord blood cells were expanded during 2 weeks in co-culture with allogeneic mesenchymal stromal cells (MSC), derived from family members (haploidentical) or provided by third party (Mesoblast). The authors didn’t see any difference, in terms of cell number, potency, graft composition and clinical outcome between CB expansion with MSC from 2 different sources.

The first month after HSC transplantation in leukemic clinic is critical. Patients have deep neutropenia, low platelet count, highly susceptible to infections and other complications. All we need in this period is rapid neutrophil, platelet and T-cell recovery. These parameters is a major indicator of efficacy in CB enhancing strategies. In this study, the median time of neutrophil recovery was 15 days and platelet recovery – 42 days. The same parameters in CIBMTR historical controls were 24 days and 49 days respectively. Therefore, the outcome of this expansion technique was significantly better. If we compare to another recent CB expansion trial (ongoing in Fred Hutchinson) – the neutrophil recovery time was 16 days (compare to 26 days in control). So, both trials are providing comparable significant acceleration of neutrophil recovery time.

The authors were not able to detect long-term chimerism from expanded unit. Up to one month, approximately half of patients had mixed (from both units) chimeric hematopoiesis (with different predominance), but at time point of one year, was no evidence for hematopoiesis, derived from expanded unit:

At 6 months after transplantation, the expanded cord blood was present in 13% of the patients, although the unmanipulated cord blood predominated. Long-term engraftment (>1 year) was produced primarily by the unit of unmanipulated cord blood in all patients.

The chimerism dynamics look like this:

This picture is quite similar to preliminary result of the “Hutch trial“.

So, there is no evidence for expansion or even persistence of HSC after transplantation. Therefore, the authors conclude:

We attribute the positive engraftment results to the increased numbers of committed myeloid and megakaryocytic progenitors in the expanded cord-blood graft that were capable of rapid engraftment after transplantation.

and:

it must also be acknowledged that the culture process appears to deplete the cells capable of long-term repopulation.

No any single word about “stem cells”! The whole job was done by hematopoitic progenitors.

Two years ago, I criticized the attempts to expand hematopoietic stem cells ex vivo. My skepticism was based solely on the preliminary results of the Hutch study. I called to focus on progenitor cells expansion instead. De Lima’s study, confirms the fact, that we still can not achieve any meaningful clinical expansion of CB HSC ex vivo. Perhaps, we can maintain HSC function ex vivo, at best.

Now, I’d like to discuss some future perspectives of progenitor cell expansion as one of the strategies for “CB enhancement” in clinic. As i’ve mentioned here and here, ex vivo cell expansion is only one of various strategies to “enhance CB”. The ultimate goal of these strategies is to accelerate neutrophil, lymphocyte and platelet recovery. Most of these strategies are currently testing in clinical trials. The obvious disadvantage of “expansion” approach is a complexity and the cost. It is labor-intensive and time consuming. It requires accredited GMP facility and qualified staff. Because it involves 2 units of cord blood, you have to pay for both (double the cost). Plus, you have to buy commercially available third-party MSC. Plus, you have to do additional HLA typing and quality control assays and other tests. My rough estimation of production cost could be around $50k USD. Now, taking in account all of these complexities, how easy, do you think, will it be adopted by clinics around the world, if trial will succeed? The chances are low.

Unlike cell expansion ex vivo, some “CB enhancement” techniques include just simple incubation for couple of hours with a drug. I’m talking about experimental drug ProHema (Fate Therapeutics). According recent ASH report, the median time of neutrophil engraftment was 17.5 days and T-cells 13 days. If such enhancement would be possible just with one unit of CB (current ProHema trial involves double unit CB), the cost of procedure will drop dramatically. It’s not labor intensive and not time consuming. It’s not requiring special facility and highly qualified staff. It’s less costly. Taking in account some comparable results, I think, this kind of approaches will outperform “cell expansion” techniques in the future widespread adoption.

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Disclaimer: I don’t have any financial conflicts of interest and don’t own a stock of the companies mentioned in this post.

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