The value of cord blood (CB) transplantation in hematology is increasing steadily. However, low number of hematopoietic stem/ progenitor cells (HSPC) in one unit of CB is still considered as a major limiting factor for wide spread adoption of CB transplantation in patients (mostly in adults) with hematological and other conditions. CB enhancement technologies are aimed to solve the problem of low cell number and/ or improve hematopoietic engraftment (HSPC performance) from single unit. Because of increased use of CB and regenerative medicine boom, the interest to CB enhancement is huge. In this post I’ll briefly overview current clinical trials, highlight strengths and weaknesses of some techniques and forecast the future trends. I’ll focus only on clinical development and will skip scientific background.
Current status of CB enhancement technologies
I’d summarize the current status of CB enhancement strategies as the following:
- There is no CB enhancement technology approved or/ and adopted in the clinic today with exception of double unit CB transplant;
- Multiple approaches to increase engraftment of CB HSPC are testing in clinical trials (see scheme below);
- Some CB enhancement strategies are entering late stages of clinical development (Phases 2-3 of trials – see below);
- We don’t have evidence for clinical ex vivo expansion of CB hematopoietic stem cells so far. During ex vivo expansion, hematopoietic stem cells rapidly lose stemness and capability for long-term engraftment;
- Results of clinical trials demonstrate, that CB progenitors, rather than stem cells, expanded ex vivo, provide clinical benefit by significant acceleration neutrophil a platelet recovery;
- The number of CD34+ progenitor cells expanded ex vivo directly correlate with clinical benefit;
- Because expanded CB unit can not sustain long-term engraftment, it used, so far, with unmanipulated CB unit in double unit transplant (DUCBT) settings;
- There is no any data on how CB enhancement could be useful for purposes of regenerative medicine.
The graph below summarizes CB enhancement strategies:
As you can see, HSPC expansion ex vivo is a relatively small part of multiple approaches.
Norkin and co-authors highlighted the following requirements to the ideal CB enhancement technique:
- Clinical benefit – shortening time of hematopoietic engraftment, rapid immune reconstitution;
- Safety without specific side effects – no graft failure, no GVHD;
- Elimination the need for second unmanipulated CB unit transplant;
- Durable long-term multilineage engraftment;
- Easy adoption by transplant centers;
There is no technology today, which can fulfill all of these requirements.
Few approaches have been explored in order to manipulate CB ex vivo:
- Long-term expansion in the culture of one unit + one unmanipulated unit in DUCBT settings (Notch ligand-mediated – Fred Hutchinson Cancer Research Center);
- Short-term priming of one unit + one unmanipulated unit in DUCBT settings (ProHema – Fate Therapeutics, C3a complement priming);
- Long-term expansion in culture of part (50%) of single unit (StemEx – Gamida Cell/ Teva);
- Long-term expansion in culture of whole single unit (SF medium + cytokines – University Hospital Bordeaux);
Overview of clinical trials
I’m going to link to trial, indicate who (where) is doing it and mention a technique (mechanism) involved.
There are 8 registered ongoing “expansion” trials (5 academic and 3 commercial):
NCT01221857 – Gamida Cell, nicotinamide (NiCord), Ph 2
NCT00469729 – Gamida Cell / Teva, copper chelation (StemEx), Ph 3
NCT01474681 – Novartis, small molecule HSC835 (LFU835), Ph 1/2
NCT01624701 – Singapore General Hospital – MIT, MSC, Ph 1/2
NCT00498316 – MD Anderson Cancer Center, MSC, Ph 2
NCT01034449 – University Hospital Bordeaux, Ph 2
NCT01235468 – Sheba Medical Center, Ph 1
NCT00343798 – Fred Hutchinson Cancer Center, mobilized Notch-ligand, Ph 2
Enhancement of homing/ migration of HSPC :
NCT01471067 – fucosylation (ASC-101/ Engraftin), MD Anderson Cancer Center/ America Stem Cell, Ph 1
NCT01720264 – CD26 inhibitor Sitagliptin, Indiana University/ NIH, Ph 2
NCT00963872 – complement C3a priming, University of Minnesota, Ph 1/2
Completed/ suspended/ terminated “enhancement” trials:
NCT00654433 and NCT00692926 – ALDH+ cells sorted from part (20%) of CB (ALD-101), Aldagen/ Cytomedix
NCT00393380 – Parathyroid Hormone (PHT) for bone marrow niche manipulation – terminated due to toxicity
Enhancement by accessory cells (mesenchymal stromal cells):
NCT01092026 – Universitair Ziekenhuis Brussel, Ph 1/2
I’m skipping overview of other clinical approaches which aimed to increase engraftment of CB HSPC. These techniques could include, but not limited to:
- Increase number/ yield of HSPC by (i) improving CB collection technique, (ii) processing and cryopreservation techniques; by (iii) combining 2 or more units of CB or other sources of HSPC; by (iiii) placenta perfusion.
- Optimization of unit selection (based on HLA, cell number, HSPC composition, potency assay…) and conditioning regimen.
- New route of cells delivery – intra-bone CB transplant.
Clinical benefit from CB enhancement/ expansion
Early clinical stages of pretty much all clinical trials demonstrated that different approaches to CB enhancement and expansion have good safety profile and result in significant clinical benefit. Particularly, the speed of neutrophil and platelet recovery were significantly accelerated in comparison with historical or unmanipulated DUCBT controls. This is very important clinical end point, because post-transplant neutropenia, caused by slow donor neutrophil engraftment, can lead to fatal infections. Some numbers for neutrophil engraftment below (experimental intervention versus control, in days):
- ProHema: 17.5 days versus 21
- NiCord: 10.5 days
- On mesenchymal stromal cells: 16 versus 26
- Notch ligand: 16 versus 26
- C3a complement: 7 versus 12
As we can see, different multiple enhancement approaches can provide quite similar clinical benefit.
Right now we don’t have evidence that clinical benefit determined by stem cell enhancement. We even don’t know whether enhancement techniques have any influence on stem cells. More likely, the enhancement effects determined by indirect (via T-cells) or direct influence on progenitor cells.
From double unit CB transplant to single enhanced unit
This is very very important issue in CB enhancement. If we can see a great clinical benefit from enhanced single unit, we don’t need DUCBT. One of the most important reasons for such move is a cost. One unit of CB, purchased for transplant via NMDP will cost you about $35,000 USD. For double unit – you pay double! Let’s calculate the approximate price if enhancement technique include 2 units: 70,000 for 2 units + market price for the manufactured product, which includes manufacturing expenses for expansion (I’d estimate 10,000-20,000 for 1-3 weeks) ~ 100k. So, if we will continue to use DUCBT versus enhanced single unit (with condition of similar clinical benefit) we may fail wide spread adoption and availability of this technology.
So far, most clinical protocols involve DUCBT settings, because of failure of ex vivo expanded unit to sustain long-term donor engraftment and chimerism. But, recently, we’ve got some data that clinical benefit could be achieved with single enhanced/ expanded unit. For example, French group reported on ASH 2011, that single expanded CB unit engrafted well in 6 out of 8 patients and sustained full donor chimerism beyond one year after transplant. According to recent press-release, Gamida Cell’s NiCord outcompetes unmanipulated CB unit for engraftment in DUCBT settings. However, they didn’t report engraftment duration beyond 8 months after transplant. I think, most trials, eventually will move to this direction.
Commercial development and competition
Despite the development of multiple enhancement technologies, the market is relatively small and, therefore, the field and getting crowded and competition is getting hot:
One of the challenges facing development of new cord blood manipulation technologies is the sizable number of technologies competing for a limited pool of patients undergoing UCBT, and the numbers of patients undergoing dUCBT (presumably the major target population for such studies) is even smaller.
What technology will win a competition? The one, which with condition of similar clinical benefit, will:
- use only single CB unit (ex: StemEx);
- not involve ex vivo expansion for days-weeks;
- involve short-term (few hours) incubation with priming agent (ex: ProHema) or injection of priming agent after transplant (ex: Angiotensin 1-7);
- use approved drug for ex vivo priming (ex: Sitagliptin);
- be easily reproducible (or widely available on the market), cheap and easily adoptable in the clinic.
To illustrate the importance of market competition between products, I’ll give you one example. If I’d be a hematologist and have 2 approved techniques for ex vivo CB enhancement with similar clinical benefit (let’s say neutrophil recovery time = 14 days), I’d choose the one, which involves short-term (30 min – 2 hours) incubation with priming agent, but not the one, which involves long-term (1-3 weeks) of cell culture. Long-term cell culture is very expansive, time-consuming, labor intensive, introducing additional risks (toxicity, bacterial contamination, genotoxicity), required a bunch of additional tests (raw materials, release criteria). I’d choose single unit versus double unit technique. Double unit = double the cost!
This year we’re expecting the first approval of CB expansion product on the market. According recent press-release, StemEx by Gamida Cell/ Teva have acheived primary end points in Phase 3 clinical trial. As per Gamida web-site:
The market launch of the StemEx stem cell therapy product is planned for 2013.
The big questions, which should be addressed in the next few years:
- Will we able to get significant clinical benefit only from single enhanced CB unit?
- What is long-term engraftment and chimerism from enhanced unit? Does it maintain functional stem cells?
- Will CB enhancement be applicable in regenerative medicine?
- Will it be possible to induce expansion of CB HSPC in vivo and avoid manipulations ex vivo?
- What is the best way to manipulate CB unit ex vivo (starting population, % of unit, expansion protocol)?
- What are the mechanisms of CB enhancement? Is it influencing stem cells directly or via accessory (immune) cells?
- Will CB enhancement techniques be commercially viable?
I didn’t aim to cover all CB enhancenment technologies, but highlighted the major ones in clinical development. There are a lot of good new approaches in experimental stage. I’d like to invite you to discuss these issues with me. I’d especially value opinion of transplant physicians and developers of commercial CB products.
- Cord blood enhancement via expansion on mesenchymal stromal cells
- Some thoughts about clinical-grade cord blood hematopoietic stem cell expansion
- An update for cord blood clinical trials
- Trends in hematopoietic stem cell expansion 2010
- Intra-bone cord blood transplantation – the new clinical route to enhance engraftment