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Banking on cord blood stem cells

Banking on cord blood stem cells
lion cells, whereas the lower threshold for public banking is 1–1.5 billion. Only 8–12% of banked units have enough cel s to transplant New research will shed light on claims from commercial banks that an average ( 80 kg) size adult.
cord blood–derived stem cells can be used in diseases beyond One strategy to get around this limit is to combine two cord blood units, a procedure hematological disorders. Sarah Webb investigates.
introduced by a team led by John Wagner at the University of Minnesota in 1999 (ref. 1). "Although that strategy appears to work, no In April, University of Minnesota researchers North Carolina. The cells are less mature than one understands how or why," according to conducted the first cord blood transplant to those from an adult donor and less likely to Kurtzberg. Typically, only one unit engrafts, cure a pediatric patient of leukemia and HIV/ trigger an immune response.
she adds, and it's not necessarily the bigger AIDS, only the second patient and the first In addition, collecting cord blood is non- unit or the better matched unit. "There is a lot child to receive such therapy. (The first patient invasive, and it makes use of tissue that of research going on trying to understand that, received bone marrow from a CCR5 variant in hospitals would otherwise discard as medi- but no one has figured it out," she says.
2007, and ostensibly has been cured of HIV/ cal waste. Much of the motivation for and Research presented at the American AIDS.) Also eagerly anticipated are the results governmental support of cord blood bank- Society of Hematology meeting in December, of two phase 2, placebo controlled trials for ing has come from the opportunity to break in Atlanta, offered conflicting results about cerebral palsy using autologous cord blood. down treatment barriers for underserved the double-unit strategy. A retrospective If successful, any of these trials could provide populations, says Shelley Grant, chief of study by Eliane Gluckman's group, in the a watershed moment for cord blood–derived the blood stem cell transplantation branch Hôpital Saint-Louis in Paris, showed that stem cells, which, up to now, have been used of the US Health Resources and Services there were fewer relapses among adults mainly for treating hematological and selected Administration of the US Department of with acute leukemia who had received two Health and Human Services (HRSA). Public units compared to those who had received However, the hype surrounding these cells cord blood banks focus considerable effort single-unit transplants2. However, these has outpaced the research into their clinical on collecting units from diverse popula- results conflict with those of a study by the All rights reserved.
benefit. Against a rising tide of marketing tions, with the goal of increasing the likeli- Blood and Marrow Transplant Clinical Trial from private cord cell banks that often prey on hood that patients of all ethnic backgrounds Network, presented at the same meeting3, parental fears, a skeptical medical community will find suitable matches. With cord blood, which suggested that in acute leukemia in chil- is encouraging parents of newborns to donate four matches out of six markers is accept- dren, an adequate single cord blood unit with cord blood to public banks, rather than paying able, whereas matching bone marrow from a particular drug regimen to prevent graft- America, Inc.
for collection and storage in private ones for an unrelated adult requires seven or eight out versus-host disease (called conditioning), is their own use. But should new research legiti- of eight markers to match. The goal, however, as effective as a double transplant.
mize the effectiveness of cord blood in cerebral is to find the best unit for the patient in terms This might mean that how conditioning is palsy or in other areas of regenerative medi- of both HLA match and cell quantity, says done is more important than whether a second cine, private banking might complement public Mary Halet, recruitment director for the unit is used, says Juliet Barker of the Memorial 2013 Nature
efforts that increasingly face a funding shortfal central region for Be The Match, part of the Sloan-Kettering Cancer Center in New York and more stringent regulatory environment.
National Marrow Donor Program.
and a member of the University of Minnesota team that pioneered this procedure. She notes A ready source of hematopoietic stem cells
Giving umbilical cord blood a boost
that around the time double-cord transplants For over 40 years, clinicians have used hema- The number of cells recovered from most were introduced, some changes were made to topoietic stem cells derived from bone mar- umbilical cords is small, averaging 500 mil- the drugs given to patients both before and row or peripheral blood, provided by human leukocyte antigen (HLA)-matched family members or unrelated donors, as a lifesav- ing treatment for severe anemia and hema- tological cancers (Fig. 1). Seventy percent of
patients will not find a matching donor within their families and must go to one of the pub- lic donor registries; patients from minority groups or with diverse ethnic backgrounds often have difficulty finding a suitable match within the adult donor registries, accord- Number of transplants 1,500 ing to the National Marrow Donor Program (NMDP), based in Minneapolis. Cord blood transplants have been found to be useful in these situations, as the requirements for HLA matching are not as rigorous for these cells, says Joanne Kurtzberg, professor of pediatrics Peripheral blood stem cells and pathology at Duke University and director Figure 1 Increasing use of cord blood in regenerative medicine. (Source: National Marrow Donor
of the Carolinas Cord Blood Bank in Durham, Program) nature biotechnology volume 31 NumBeR 7 JulY 2013
bers of CD34+ cells by culturing them with an Table 1 Selected companies with products to assist with cord blood transplants
immobilized engineered Notch ligand for 16 Level of testing
days. The technique produces high yields of Cellerant therapeutics CLt-008, made from adult myeloid Phase 1 for hematologic progenitor cells cells, Delaney says, up to 200 cells for every (San Carlos, California) CD34+ cell they started with. In a recent fate therapeutics ProHema, made from modified Phase 2, hematologic malignancies hematopoietic stem cells from cord Nature Medicine paper6, they describe a phase 1 study during which they carried out double- Stemex, cord blood with cells Phase 3 for hematological unit transplants using one unmanipulated unit expanded using a copper chelator malignancies and a second expanded unit. As with the study and infused with unexpanded from MD Anderson, the cells engrafted more quickly in these patients. The modified unit NiCord, Cord blood expanded using Phase 2 for hematological nicotinamide (NaM) malignancies, sickle cell and MDS engrafts at first in these patients, but after sev- Perkinelmer (ViaCord) Human umbilical cord perivascular In development eral months, the unmodified unit takes over and provides long-term engraftment. With the extension of the Hutchinson Center trial to patients at other centers, Delaney says, the after the transplant (antithymocyte globulin, A variety of ex vivo expansion strategies also engraftment times have dropped further to a an anti-rejection agent and anti-inflammatory look promising to help speed engraftment and median of 11 days, which she attributes to bet- corticosteroids were eliminated, and the even boost the cell dose. Unlike a typical cord ter selection of the units for expansion.
purine analog Fludara (fludarabine) and blood transplant where the units are used It's unclear what types of CD34+ cells are immunosuppressant Cell Cept (mycopheno- after minimal handling, in ex vivo expansion, responding to these ex vivo factors, Delaney late mofetil) were added). But the conflicting researchers treat the cells with various chemi- says. Both stem cells and the more differen- results between the studies might also suggest cals and/or protein factors or culture them in tiated progenitor cells express CD34 on their fundamental differences between diseases supportive cellular environments to boost the surfaces. In the work from both MD Anderson of children and adults and how each patient numbers of specific cell types. Researchers led and the Hutchinson Center, the cells from group responds to cord blood transplantation. by Elizabeth Shpall at Houston's MD Anderson the modified unit engraft initially, but the All rights reserved.
Cancer Center tried to spur expansion in unmodified cord blood unit ultimately takes cord blood by exposing cells to a cocktail of over. That may occur because the cells from Even with the success of double cord trans- growth factors: stem cell factor, granulocyte the manipulated unit are farther along the dif- plants, the cost of the procedure raises con- colony-stimulating factor and thrombopoi- ferentiation pathways at the time of transplant, cerns. In the US, the cost for just a unit of cord etin, says Chitra Hosing, who worked on the Hosing suggests, and can provide that initial America, Inc.
blood for transplant hovers around $40,000. clinical trials and is associate director of the support.
Hospital costs can be higher as engraftment MD Anderson Cord Blood Bank. Though they That potential for expanded cord blood with cord blood takes longer (21–35 days) increased cell dose, it didn't lead to a clinical cells to serve as an immune system support than engraftment with cells from an adult benefit for patients, she says.
for patients has led Delaney and her col eagues donor (20 days). In addition, cost calculations Since then, the team has moved to using to pursue the development of off-the-shelf 2013 Nature
that look only at the cost of the cord blood monolayers of mesenchymal stromal cells expansion products that don't require HLA units and hospital stay ignore the overall (MSCs), which produce molecular cues that matching. The need to expand cord blood long-term survival of a patient, and whether stimulate expansion in cord blood cells. At from a matched donor adds time, money and a patient treated with a less-expensive proce- first, they used MSCs produced from the bone complexity to the procedure, so they're test- dure relapses within a year. "If the patient does marrow of haplo-identical donors for indi- ing whether they can develop expanded cells better long term, that cost is absolutely war- vidual patients. But as it can take up to three that don't include immune cells from fresh ranted," says Barker.
weeks to produce those cells from donors, cord blood units that could then be frozen But researchers are looking for ways to Hosing and her colleagues moved to treating and given with unmodified cord blood units both improve patient outcomes and lower the unit for expansion with off-the-shelf MSCs to speed engraftment. They're currently test- some of these costs. Researchers in Spain produced by Mesoblast, a company based in ing this idea in the clinic both for transplants have pioneered a procedure that transplants Melbourne, Australia. After an expansion and as a supportive therapy for acute myeloid a unit of cord blood from an unrelated donor process of 18–19 days, the expanded unit was leukemia patients treated with chemotherapy.
and peripheral blood cells from a partially transplanted into patients along with a sec- Another ex vivo expansion strategy may matched donor (known as a haplo-identical ond unmanipulated unit of cord blood. In an overcome both the engraftment delay and the donor), typically a parent, sibling or child of initial study of 31 patients, the median time cell-dose limitations in cord blood transplants. the patient4. The peripheral blood cells serve to engraftment was 15 days compared with Gamida Cell in Jerusalem has developed a as immune support, reducing the duration a median of 24 days observed in the control product that uses nicotinamide (vitamin B3) of neutropenia in these patients. The Weill group5.
to expand CD133+ hematopoietic stem cells Cornell Medical College in New York is cur- Researchers led by Colleen Delaney and within a unit of cord blood over a period of 21 rently enrolling patients in a phase 2 study that Irwin Bernstein at the Fred Hutchinson days. In a recent phase 1/2 study, 11 patients will compare so-called haplo-cord transplants Cancer Research Center in Seattle are also with hematological cancers received these with double-unit transplants. Companies are looking at ex vivo expansion by taking advan- manipulated cells, called NiCord, along with also testing various off-the-shelf products that tage of the expression of Notch receptors on a second unmanipulated unit of cord blood. could serve as a bridge until the cord blood the critical CD34+ stem and progenitor cel s in Engraftment occurred in a median of just over cells engraft in a patient (Table 1).
cord blood. The procedure expands the num- ten days. Unlike the other expansion tech- volume 31 NumBeR 7 JulY 2013 nature biotechnology
niques, the manipulated unit supported long- Box 1 Going private
term engraftment in eight of these patients. In June, Gamida Cell will begin a fol ow-up clini- the commercial side of the cord blood banking business is growing; market research cal study of a single expanded NiCord unit in company Bioinformant worldwide of roseville, Minnesota, reports double-digit growth these patients, without the added unmodified in the past year both in the uS and abroad in the number of companies offering banking unit. "If you can develop a drug which is com- services, which outpaces the growth of the economy during the same period. Morey Kraus posed of only one cord blood unit rather than of Perkinelmer's ViaCord of Cambridge, Massachusetts, feels the rapid growth experienced two, then you will obviously save $40,000 in in the last decade is attributable to increased knowledge and expanding treatments costs," says Yael Margolin, president and CEO regarding cord blood, although he points out that there is a low bar for entry into the field.
of Gamida Cel . Gamida Cell has also initiated the number of cord blood units stored in private banking is outpacing that in the public a trial on sickle cell anemia; Duke's Kurtzberg banks. the National Marrow Donor Program reports 185,000 cord blood units currently is co-principal investigator on this study as available for transplant in the uS, whereas individual private banks report more than that well as the one on hematological malignancies.
in their own collections, a testament to their marketing skill. ViaCord, for example, has over 300,000 units (up from only a few thousand units in 2000), Cord Blood registry of Economic and regulatory challenges
San Bruno, California, 400,000. the discrepancy stems from the fact that public banks Public cord blood banking in the US is sup- will store only units of a certain size. Hence, much of the donated cord blood—some say ported through a combination of government as much as 70%—is discarded. In contrast, private banks store all-comers, and annual grants, private donations and fees received for storage fees help defray the processing costs. "without annual storage fees it would be cord blood units as they are distributed for difficult to justify the business bases on current charges for processing cord blood units," transplant. HRSA provides contracts to sev- eral organizations that coordinate bone mar- the impact on clinical medicine is in the eye of the beholder. Success rates of row and cord blood donations. The National transplants hover around 90% from commercial banks (one year survival) whereas the Marrow Donor Program coordinates the cord National Marrow Donor Program reports one year survival in the 70% range, (though for blood registry that allows physicians to find non-malignant indications only). However, the commercial banks provide services to suitable cord blood units for patients from families, where, given the high probability of having a match, engraftment rates are better.
public banks in the US or in other countries. tension between commercial and public banking is only going to intensify if the All rights reserved.
HRSA also supports 13 public banks in the US treatable conditions expand into more common childhood diseases. Banks, public and as part of the National Cord Blood Inventory.
private, list upwards of 80 diseases as being treatable, many of them quite rare. with that in mind, all the professional societies advise against private banking, based on the The funding was set up through the 2005 small probability that a transplant would be needed, unless the family has a medical Stem Cell Therapeutic and Research Act condition that could be treated with a transplant. estimates of lifetime use vary somewhat and its 2010 reauthorization. "Roughly 40% depending on how it is calculated, but a generally accepted value for the likelihood of America, Inc.
of what was authorized was appropriated so having a transplant by age 70, based on actual usage data collected from 2000 to 2003, far," says Kurtzberg. With so many continu- is 1 in 217 (ref. 8), although at age 20 it's considerably lower, 1 in 1,666. However, with ing resolutions in the federal budget in recent more common diseases like cerebral palsy (1/500 births) or autism (1/88 births), both of years, she says, the preprogrammed funding which are under study, the calculus will clearly change for private versus public banking, increases that were part of the initial legisla- favoring private storage.
2013 Nature
tion have not been put in place. In 2012, $11.9 andrew Pecora, chief medical officer of New York-based NeoStem says, "the real issue mil ion from HRSA went to the National Cord is what happens tomorrow. [the potential for umbilical cord banking in emerging diseases] Blood Inventory; the law authorizes $23 mil- isn't discussed enough. Discouraging people with means from private banking is equally lion per year to be appropriated for the collec- bad as promoting it. In five years, it will be too late." tion and maintenance of cord blood in fiscal years 2011 through 2014.
The cord blood banking process is expen- That led to the initial investigational new drug requirements remain available for transplant sive, which contributes to the high cost of applications for banking cord blood units.
under an IND during this transitional period.
each transplant unit. Donor mothers com- But in 2009, FDA gave public banks two A by-product of this will be to standardize plete a questionnaire about their medical years to apply for a biological license appli- industry, says Karen Taylor, medical director at history, with the idea of eliminating the risk cation to distribute minimally manipulated StemCyte in Covina, California, which banks of infectious disease, such as hepatitis, and cord blood for established uses, Rubinstein both public and private cord blood units. The avoiding genetic risks that might be manifest says. (Products that are manipulated or being new regulations may help with quality control, in the recipient. For example, Halet says, if tested in experimental therapies require an but they are also putting a financial squeeze on both parents have had cancer, a public bank investigational new drug application (IND)). the public banks. It's not clear that all of them won't collect the unit. Units are also screened Those new procedures include more detailed will be able to afford the new FDA licensing for conditions such as sickle cell anemia and questionnaires for the mothers who donate procedures. "[The process of obtaining licen- thalassemia; the units are carefully collected, cord blood and more stringent requirements sure] was literally a three-year, incredibly tracked and stored under specified conditions. for the handling of the cord blood units within intensive, incredibly expensive process," says The US Food and Drug Administration (FDA) licensed banks7. The enforcement of FDA Kurtzberg, whose bank recently completed the first started regulating cord blood in the mid- oversight has raised concerns that only the new FDA licensing. "The value added is not 1990s, says Pablo Rubinstein, vice president larger clinical centers will be able to afford proportional to the resources that are required and program director of the New York Blood the cost and negotiate the cumbersome and and it [has] complicated the whole process of Center's National Cord Blood Program, the complex process of liaising with the FDA. banking, made it much more expensive with first public cord blood bank, started in 1992. Cord blood units banked before the new very little impact on the final product." nature biotechnology volume 31 NumBeR 7 JulY 2013
The future of banking
Rubinstein. "And if you do, and you tell them, focused on taking care of the mother and the In comparison to public centers, private banks ‘well, I also want to use your money to sup- infant, who might be very sick, and can't always have built a profitable business—$4.5 billion in port the public banking', then, of course, that's attend to saving the cord blood, too. "If our 2010 according to BCC Research in Wellesley, fine," he says.
studies or other studies with autologous cord Massachusetts—on the basis of the fees paid StemCyte's hybrid model of storing both blood show benefits in childhood diseases, then by parents for banking cord blood for use by public and private units of cord blood provides there may be a different algorithm or paradigm family members. Most researchers in the cord an example of how the two models can exist for banking," Kurtzberg says. Hypothetical y, blood community remain skeptical of purely side by side. The accreditation procedures and parents might be able to donate cord blood to private banks, in part because of the market- FDA oversight are similar for both the pub- a public bank but have the unit sequestered for ing pitch to parents that is heavy on promises lic and private units at StemCyte, according a period of time, until it became clear that their but short on actual benefits for their children. to Taylor. The differences come from the end child didn't need it, she says.
"Most private banks are just focused on mak- use of the cord blood, she says, within a fam- Rubinstein adds, "In the future, we hope the ing money, marketing, or finding ways to ily rather than for the general public. Thus, all need to develop personalized cel ular therapy compete with one another to get parents to private units are banked, regardless of size or may occur, and, in that case, having your cord use them over some other private bank. They family history.
blood stored away would be a remarkable really have not demonstrated earnest efforts or investments in research. And they haven't Banking on it
Sarah Webb, Chattanooga, Tennessee
even demonstrated earnest interest in quality," Eventual y, with further research, like the trial Kurtzberg says.
on HIV/AIDS and others on genetic diseases 1. Laughlin, M.J. et al. N. Engl. J. Med. 344, 1815–1822
But the financial squeeze being experienced like cerebral palsy, the thinking on public versus 2. rocha, V. et al. abstract 2342, presented at the by public banks may point to a role for pri- private banking may evolve (Box 1). Kurtzberg
54th annual Meeting and exposition of the american vate banking, which in partnership with pub- and her col eagues are also working on autolo- Hematology association, atlanta. December 9, 2012.
3. wagner, J.e. et al. abstract 359, presented at the lic banks, could provide financial support. gous cord blood as a way to facilitate repair after 54th annual Meeting and exposition of the american However, it could be complicated as public brain injury. They're currently studying chil- Hematology association, atlanta. December 10, 2012.
4. fernandez, M.N. et al. Exp. Hematol. 31, 535–544
banks might be uncomfortable associating dren with hypoxic-ischemic encephalopathy with what they consider unsavory market- and hypoplastic left heart syndrome, which puts 5. de Lima, M. et al. N. Engl. J. Med. 367, 2305–2315
All rights reserved.
ing tactics employed by some private banks. children at risk for stroke and hypoxic injury. 6. Delaney, C. et al. Nat. Med. 16, 232–236 (2010).
"In my opinion, there is nothing wrong with One chal enge with this treatment approach is 7. allison, M. Nat. Biotechnol. 30, 304 (2012).
doing private banking provided you tell peo- that it requires a baby's own cord blood, and 8. Nietfeld, J.J. et al. Biol. Blood Marrow Transplant. 14,
ple exactly what it is that you're doing," says in the delivery room, doctors and nurses are 316–322 (2008).
America, Inc.
2013 Nature
volume 31 NumBeR 7 JulY 2013 nature biotechnology



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