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Following the Body’s Own Prescription

Mon, 04/01/2013 - 10:22am
Cynthia Fox

Umbilical cord of a new born baby (Source: iStockphoto)An intuitive approach, which co-opts the body’s own molecular machinery, has led to massive expansions of umbilical cord blood cells. It and other new approaches “will revolutionize all transplantation,” says University of Minnesota Blood and Marrow Transplantation Director John Wagner.

“There are multiple ways to do this, and all are occurring now.”

“The next five years should be exciting ones indeed for our field!” wrote Massachusetts General Hospital hematologists Karen Ballen and Corey Cutler in a recent Blood Reviews.1

Adult blood stem cell transplants have rescued many leukemia, lymphoma, and chemotherapy-ravaged patients. When transplants are immunologically matched, they can help revive immune systems—and even cure. The problem: more than 50% of patients lack matched sibling, or matched unrelated, donors.

It has long been thought umbilical cord blood (UCB) cells may provide an answer. UCB cells are taken from the cord right after birth. They are multi-potent, able to mature into all kinds of blood and immune cells. They are immature, robust, and comparatively mutation-free.

Additionally, recent trials have led to a key insight: UCB cells are so immunologically naïve, they can avoid some of the lethal graft vs. host disease occurring in adult blood stem cell transplants. Even when UCB cells are not perfect immunological matches, they can sidle comparatively easily into bone marrow of patients, not yet fully “trained” to see them as foreign.

This has been a major development.

But there has been a major problem. UCB stem cells, like adult blood stem cells, are hard to expand (replicate) in the Petri dish. And since UCB doses are necessarily small—able to produce only 1/10th to 1/20th of the cells in normal adult stem cell grafts—for a while UCB transplants only worked in children. In adults, small UCB transplants resulted in “significant delay in engraftment and immune reconstitution, as well as an increased risk of graft failure and early transplant-related mortality.”2

Two (“double”) cord blood grafts helped. They “significantly” improved UCB transplants. But even double UCB transplants did not prompt the rapid immune reconstitution needed to avoid “increased risk of graft failure.” The low stem-cell dose in UCB grafts remained “the biggest hurdle.”2

But in a recent New England Journal of Medicine, investigators from MD Anderson Cancer Center described a Phase 1 and 2 combined clinical trial in which they expanded all cells 12-fold—and stem cells 40 fold—in a double UCB transplant. A far faster engraftment occurred in 31 cancer patients receiving expanded grafts than in 80 control patients.3 Translation: patients recovered much faster.

The group, led by Elizabeth Shpall, accomplished this with an ingeniously simple approach. The group first cultured the normally recalcitrant UCB cells in an environment that mimics the bone marrow, the niche where replication of blood stem cells normally occurs. That is, they cultured the UCB cells on a bed of bone marrow cells called mesenchymal stromal precursors.

It worked. The cells flourished in vitro.

The mesenchymal cells were provided by Mesoblast Limited. MD Anderson had earlier used mesenchymal cells from bone marrow of patients’ relatives, to dodge immune problems. But it took over a month to prepare each patient’s cells.

Mesoblast had off-the-shelf cells that were ready to go—if foreign to the UCB cells. But when MD Anderson switched to Mesoblast cells, culturing moved swiftly, without immune problems. (This may be because mesenchymal precursors mature into cells that mediate immune reactions.)

The NEJM paper has the “potential” to give an immense boost to transplantation, says study coauthor Marcos de Lima. But it does needs verification by a larger trial—now being conducted.

De Lima, Wagner, and others note many groups have been closing in on the refinement of UCB cell transplants. MD Anderson is the second group in history to achieve rapid bone marrow engraftment of ex vivo expanded stem cells in patients. In 2010, Irwin Bernstein and Colleen Delaney of the Fred Hutchinson Cancer Center were the first to report this, by culturing UCB cells with Notch ligand, which switches on a key stem cell gene.4

Another technique, now in a Phase 3 clinical trial, uses a copper chelator to expand UCB cells. And Shpall “is exploring a technology called fucosylation, in which sugar molecules are added to the cells before they are infused in the patient,” says de Lima.“It is hoped that this process will expedite engraftment, by improving ‘homing’ to the marrow.”

Researchers say combining two of the above techniques may provide a finishing touch. Both MD Anderson and Fred Hutchinson’s approaches were historic: clinical “successes,” as Delaney notes. But both did need to throw some unmanipulated UCB cells into the mix, at the end, to create a crucial coterie of longer-lasting blood cells. It might be tidier if one combined treatment did the trick.

But technically, if the above approaches are verified by larger trials, we will have finally achieved our decades-long goal of mimicking our bodies’ effortless ability to make—and remake—our blood cells.

 

References

1. Cutler, C. et al. “Improving outcomes in umbilical cord transplantation: State of the art,” Blood Reviews, Vol 26 Iss 6, November 2012: p241-246.

2. Delaney, et al. “Cord Blood Graft Engineering,” Biology of Blood and Marrow Transplantation, Vol 19 (1 Suppl), January 2013: pS74-78.

3. de Lima, M., et al. “Cord-Blood Engraftment with Ex Vivo Mesenchymal-Cell Coculture,” The New England Journal of Medicine, Vol 367 Iss 24, December 13, 2012: p2305-2315.

4. Delaney, C., et al. “Notch-mediated expansion of human cord blood progenitor cells capable of rapid myeloid reconstitution,” Nature Medicine, Vol 16 Iss 2, February 2010: p232-236. 

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