Sorry to break this up into 3 posts, its just easier to manage my thoughts whilst looking through my notes. There's much more detail but I'm summarizing the points which I feel are particularly relevant and important to StemLife.
On the 2nd day of the conference, the discussion moved onto expansion (increase in numbers) of umbilical cord blood stem cells. One of the major challenges in cord blood banking is having sufficient cell numbers to support larger adult patients. Prof. EJ Shpall joked that in Texas (where she works), the average weight of a typical patient ranges from 80- 100 Kg, almost one and a half times of what the average weight is in Asia. Thus, a transplant based on cell count and patient weight would "weigh" in at a disadvantage for those on the heavier side of the scale. Everyone agreed that if this challenge could be overcome, umbilical cord blood stem cell transplants for adults would be on prime time.
The 2 ways of improving engraftment from a cord blood stem cell unit:
A) Increase cell number by amplification of the necessary cells
B) Improve immunosuppression methods and achieve engraftment through better understanding of myeoablation and marrow interaction.
(A) was covered in extensive detail by Viacell's Dr. Michael Choi, Prof. Ian McNiece and Prof. EJ Shpall. (B) was described in some detail by Dr. Ping Law but much research is still in progress. In this entry, I will focus on (A).
Dr. Choi described the isolation and attempt at expansion of a rare stem cell known as the Unrestricted Somatic Stem Cell (USSC). These stem cells he said were found in extremely small numbers in cord blood and had multipotential capability of forming other tissue types. In addition, USSC's are also thought to require less immunosuppression and thus may be suitable for use in other individuals. Viacell plans to make this form of cellular medicine available to its 65,000 strong client base and others needing the service.
Prof. McNiece dug deep into the scientific detail of his experiments explaining the different cocktails of growth factors and stimulants he used to encourage the stem cells to grow. First of all, he starts off with 2 cord blood stem cell units. Let's name them UCB1 and UCB2. The outline of the experiment was to thaw UCB1, pass the cells through an automated machine (Clinimacs) which selects of a specific type of stem cell that he want to investigate, grow the stem cells in culture between 7x to 18x which may take a few weeks. When the cells have reached the desired numbers, UCB2 is thawed and both the expanded culture plus the uncultured unit are co-infused into the patient. To ensure that the patient's immune system recovers, GCSF is administered post transplant.
Essentially, stem cells take about a week to get to confluency (uniform growth to layer the entire surface of one flask, but several flasks are needed to get adequate cell numbers) and the McNeice method describes using only 10% of the cord blood unit as a seed culture.
In another experiment, 3 stem cell units were involved. Bone marrow, UCB1 and UCB2. Bone marrow was harvested and combined with a thawed UCB1. This combination was then selected for stem cells, expanded ex-vivo for 14 days which yielded between 7x-24x expansion. The patient was given the necessary high dose chemotherapy prior to the transplant and the cultured cells was infused together with a thawed UCB2. Additionally, the patient was given GCSF to ensure no lack of immune cells and to ensure the cultured cell survival in the body.
What are the problems with the existing method?
(1) Expansion numbers still cannot be well controlled or predicted- the range is very variable between 2x, 5x to 18x depending on the type of cells you're after.
(2) Cord blood units contain a type of stem cell known as CD34+. Upon thawing, the cells can be found in the unit. However, after a selection procedure, the total count can DECREASE by 400x! This may be very problematic for transplants as patients need the supporting cells as well.
(3) Thus far, all expanded products have used serum derived from animal sources (provides the nutrition for the cells to grow) and there is a concern about applying animal products in human use. However, a medium derived from human sources has yet to be developed which can provide the same growth support in the lab.
Prof. EJ Shpall's talk discussed the clinical aspects of transplanting ex-vivo expanded cord blood stem cells in the "University of Colarado Cord Expansion Trial" where they were trying to improve time to engraftment and to reduce the graft failure rate in patients. The study recruited 40 hematologic malignancies (blood cancers) and 3 breast cancer patients. The key difference from the studies mentioned before is that in this study, the CD34+ cells were selected out from the UCB unit, expanded in culture and then re-infused to the patient with the remainder of the UCB unit. This means that its the same as a UCB transplant except that specifically selected stem cells would be greater in number. The conclusion from the study was that it is feasible and suitable for adults.
Prof. Shpall's team also collaborates with Prof. McNiece's team (they have been doing so for a decade) and now both parties are also collaborating with Viacell to do the research in Singapore on expanded cord blood stem cell units for transplantation.
What's the final take on stem cell expansion? It's possible, but not yet well defined in protocol, cell yield or patient recovery. Many patients didn't make it through the procedure well (but in early stages of medical development, this is expected). And, no one has dared to breathe a price tag on it, because the culture methods are expensive and customized to each patient (Clinimacs selection sorters are also very pricey). More work needs to be done before this technology can be effectively commercialised for supporting stem cell transplants worldwide.
Until then, every cord blood stem cell unit collected must be maximised for numbers. The first step of collection is still fundamentally important, and if cell expansion succeeds, the benefit to patients will be even greater.
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