New Standard of Care for Umbilical Cord Blood Transplants


New research led by John Wagner, Jr., M.D., director of the Pediatric Blood and Marrow Transplantation program at the University of Minnesota and a researcher in the Masonic Cancer Center, University of Minnesota, has established a new standard of care for children who suffer from acute myeloid leukemia (AML).

In a recent paper in the New England Journal of Medicine, Wagner and his coworkers compared clinical outcomes in children who suffered from acute leukemia and myelodysplastic syndrome who received transplants of either one unit or two units of partially matched cord blood. This large study was conducted at multiple sites across the United States, between December 2006 and February 2012. Coordinating the study was the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) in collaboration with the Pediatric Blood and Marrow Transplant Consortium and the Children’s Oncology Group.

Umbilical cord blood provides a wonderfully rich source of blood-forming stem cells, and has been demonstrated to benefit many diseases of the blood or bone marrow, as in the case of leukemia and myelodysplasia, or bone marrow failure syndromes, hemoglobinopathies, inherited immune deficiencies and certain metabolic diseases. For leukemia patients cord blood offers several advantages since there is no need for strict tissue-type matching (human leukocyte antigen or HLA matching) or for a prolonged search for a suitable donor.

Wagner and others discovered that the survival rates of children who received either one or two units of umbilical cord blood were about the same, but, overall, their recorded survival rates were better than those reported in prior published reports. These higher survival rates, therefore, represent a new standard of care for pediatric patients, for whom there is often an adequate single cord blood unit, and for adults for usually require double units, since a single unit with an adequate number of blood-forming stem cells simply may not exist at time.

“Based on promising early studies using two cord blood units in adults for whom one unit is often not sufficient, we designed this study in order to determine if the higher number of blood forming stem cells in two cord blood units might improve survival,” explained Wagner. “What we found, however, was that both treatment arms performed very well with similar rates of white blood cell recovery and survival.”

Children with blood cancers who receive transfusions of umbilical cord blood show quantifiable clinical benefits even though the blood may not match their own tissue types. The reason stems from the immaturity of cord blood stem cells and their ability to suppress rejection from the immune system. This is an important aspect of umbilical cord blood transplants, since patients who cannot find a matched unrelated donor also benefit from cord blood transplants. However, cord collection from the placenta after birth often results in a limited number of blood-forming stem cells, which decreases the potential benefits of cord blood. The “double UCB approach” was pioneered at the University of Minnesota as a strategy to overcome this inherent limitation in the use of umbilical cord blood.

Despite the similarities in survival rates between children who received one unit or two units of cord blood, some differences were noted. Children transplanted with a single cord unit had faster recovery rates for platelets and lower risks of Graft Versus Host Disease; a condition in which the transplanted donor blood immune cells attack the patient’s body, which causes several complications.

“This is helpful news for physicians considering the best treatment options for their patients,” said Joanne Kurtzberg, M.D., chief scientific officer of the Robertson Clinical and Translational Cell Therapy Program, director of the Pediatric Blood and Marrow Transplant Program, co-director of the Stem Cell Laboratory and director of the Carolinas Cord Blood Bank at Duke University Medical Center. “We found children who have a cord blood unit with an adequate number of cells do not benefit from receiving two units. This reduces the cost of a cord blood transplant for the majority of pediatric patients needing the procedure. However, for larger children without an adequately dosed single cord blood unit, using two units will provide access to a potentially life-saving transplant.”

“The involvement of multiple research partners was instrumental to the success of the study completion,” added Dennis Confer, M.D., chief medical officer for the National Marrow Donor Program® (NMDP)/Be The Match® and associate scientific director for CIBMTR. “This trial is a testament to the importance of the BMT CTN and the collaboration of partners like the Children’s Oncology Group.”

Mary Horowitz, M.D., M.S., chief scientific director of CIBMTR and professor of medicine at the Medical College of Wisconsin, concurred. “Because of this tremendous collaboration, we were able to expand the scale of this research to multiple transplant centers across the United States and Canada. And the results will undoubtedly improve clinical practice, and most importantly, patient outcomes.”

Interestingly, in this study, patients who received cord blood with significant HLA mismatches showed no detrimental effects on their outcomes. Future studies will examine a closer look at how the HLA match within the cord blood unit impacts outcomes for patients, particularly those within minority populations.

When To Use Umbilical Cord Blood Stem Cells


Umbilical cord blood stem cells (UCB-SCs) have been used in a variety of clinical trials and treatments. Their use in treatment bone marrow-based conditions is very well-known, but they have also been used in other experimental treatments as well.

Treatments with UCB-SCs suffer from inconsistent results that stem from a variable number of viable cells in UCB-SC samples. Establishing high numbers of viable cells in UCB-SC samples is not easy, and there is a great interest in being able to grow UCB-SCs in culture and expand them. However, even though UCB-SCs can be grown in culture, the effects of culturing UCB-SCs is presently unclear.

To address this question in a rigorous fashion, Miguel Alaminos at the University of Granada and his colleagues grew UCB-SCs in culture and analyzed cell viability and gene expression at every passage.

What they discovered was astounding. When UCB-SCs were passaged two or three times, the cells showed signs of cells death, and gene expression studies revealed that many of the cells expressed genes associated with programmed cell death. Cells passaged eight, nine, or ten times also showed extensive cell death. However, cells passaged five or six times showed the highest viability.

This suggests that different studied have used cells that were grown for different periods of time and probably had different viabilities. This explains why UCB-SCs have performed so variably in experiments and clinical trials. This suggests that therapies that utilize UCB-SCs should use them after they are passaged for the fifth or sixth time in order to ensue the highest levels of viability.

Highly Efficient Method for Converting Blood Stem Cells into Induced Pluripotent Stem Cells Without Viruses


A research group from Johns Hopkins University has designed a protocol that reliably converts stem cells from umbilical cord blood into a primitive stem cell state. From this primitive state, these cells can differentiate into any other type of cell in the body.

This paper was published in the August 8th issue of Public Library of Science (PLoS), and serves as the second publication in an ongoing effort to efficiently and consistently convert umbilical cord blood stem cells and other types of stem cells into stem cells that are usable for use in clinical and research settings in place of human embryonic stem cells, according to Elias Zambidis, M.D., Ph.D., who is an assistant professor of oncology and pediatrics at the Johns Hopkins Institute for Cell Engineering and the Kimmel Cancer Center.

Zambidis said: “Taking a cell from an adult and converting it all the way back to the way it was when that person was a 6-day-old embryo creates a completely new biology toward our understanding of how cells age and what happens when things go wrong, as in cancer development.”

The first paper that is sometimes designated ‘Chapter One‘ of this work was published last spring in PLoS One. In this paper, Zambidis’ group described the successful use of a method that safely transformed several different types of human pluripotent stem cells into heart muscle cells. In the latest experiments, Zambidis and his colleagues describe methods that convert umbilical cord blood stem cells into induced-pluripotent stem cells (iPS), which are adult or fetal cells reprogrammed to an embryonic like state.

According to Zambidis, he and his team developed a “super-efficient, virus-free” method for making iPS cells. This overcomes some troubling difficulties for those scientists who work with iPS cells; namely, the vast inefficiency of making iPS cells from adult cells and the use of mutation-causing viruses to introduce those genes into adult cells required to convert adult cells into iPS cells. Generally, out of hundreds of blood cells, only one or two typically revert into iPS cells. However, with Zambidis’ method, 50-60% of blood cells were engineered into iPS cells.

To circumvent the use of viruses to deliver genes, Zambidis’ team used plasmids, or small circles of DNA that replicate briefly inside cells and then degrade. By using plasmids, the cells receive the genes required to drive adult cells into the iPS state, but because these genes are only required transiently, the plasmids do their job and then go away. Therefore, the production of mutations by viral DNAs that insert themselves into the host cell genome is not a problem with this method from Zambidis’ laboratory.

In order to introduce the genes into the cells, Zambidis’ team used a technique called electroporation. They treated the umbilical cord blood cells with the plasmids and then delivered an electrical pulse to the cells, which made tiny holes in the surface through which the plasmids could slip to the cell interior. Once inside, the plasmids triggered the cells to revert to a more primitive cell state. After genetic engineering, the blood cells were also given an additional new step in which they were stimulated with their natural bone-marrow environment. To do this, the Johns Hopkins team took some of the treated cells in a dish alone, and cultured them together with irradiated bone-marrow cells.

When iPS cells made from umbilical cord blood were compared to iPS cells made from hair cells and from skin cells, they found that the most superior iPS cells came from those made from blood stem cells treated with just four genes and cultured with the bone marrow cells. These cells reverted to a primitive stem cell state within seven to 14 days. Their techniques also successfully converted blood stem cells from adult bone marrow and from circulating blood into iPS cells.

In ongoing studies, Zambidis and colleagues are testing the quality of their newly formed iPS cells. They are also interested in the ability of these iPS cells to differentiate into other cell types, as compared with iPS cells made by other methods. These efficient methods to produce virus-free iPS cells will hopefully speed research to develop stem cell therapies that use nearly all cell types, and may provide a more accurate picture of cell development and biology.

Umbilical Cord Stem Cells and Cancer


The umbilical cord blood stem cells have been used to treat cancer patients whose bone marrow tissues have been wiped out by radiation or chemotherapeutic treatments. Several clinical trials have addresses the capacity of umbilical cord blood to reconstitute the bone marrow of cancer patients.

The first set of clinical trials have examined the use of umbilical cord blood in children. Gluckman and her colleagues reported the use of umbilical cord blood to treat children who had suffered from a variety of blood maladies. 74 patients were treated with umbilical cord blood. 63% of the patients survived one year after the procedure, and the rate of graft-versus-host disease (GVHD) was only 9%. Now this study showed that umbilical cord blood could be used to reconstitute the bone marrow, but how well does it work compared to bone marrow transplants?

To answer this question, Rocha and his colleagues compared kids who had received umbilical cord blood transplants with those who had received bone marrow transplants. 113 cord blood transplant patients were compared to 2052 bone marrow transplant recipients. In this study, the umbilical cord blood recipients took longer to have their bone marrow reconstituted, but the rate of graft-versus-host disease was lower. The survival rate of the two groups three years after the procedure was also about the same (64% for the umbilical cord blood recipients and 66% for the bone marrow recipients). Thus, umbilical cord blood seemed to work as well as bone marrow when it came to reconstituting the bone marrow.

Since the rates of GVH disease were so low, could umbilical cord blood that was not properly tissue matched to the recipient also work? The answer was yes. Once again Gluckman and her colleagues showed that the rate of GVH disease was rather low, and the rate of recovery in a group of 65 patients was quite high (87%). Such a treatment with unmatched bone marrow would be a disaster, since GVH disease would almost certainly result from such a treatment. The results of Gluckman’s small study were confirmed by a much larger study by Rubinstein and others in 1998.

Can cord blood be used to treat adults with similar maladies? Clinical studies have confirmed that the answer is yes. Survival rates from a host of clinical trials have ranged from 15%-70%, but clearly adults can benefit from umbilical cord blood transplantations. Once again, the rates of GVH disease were lower in umbilical cord blood recipients when compared to bone marrow recipients, but once again, the time required for bone marrow recovery was greater.

In Minnesota, Wagner and his colleagues pioneered the use of “double umbilical cord blood grafts” in which umbilical cord blood is taken from two different babies to treat an adult patient. This overcomes the limited volume and cell numbers in an umbilical collection from a single donor. These are only used for patients who are very ill, but studies have shown that patients who have received double umbilical cord blood grafts have a ten-fold lower decrease in the risk of relapse of blood cancers.

Thus over the past two decades, umbilical cord blood transplants have become rather attractive sources of material to reconstitute bone marrow. Although low cell numbers are still a chronic problem with them, the ability to culture and expand these cells in culture may give a new life to this useful treatment.

New Clinicals Trials Use Umbilical Cord Blood Stem Cells to Treat Neurological Conditions and Hearing Loss


Umbilical cord and umbilical cord blood contains a wealth of stem cells for multiple uses. Cord blood contains a blood cell-making stem cell that can be used to constitute bone marrow (see Gluckman E., Blood Rev. 2011;25(6):255-9). It also contains two mesenchymal stem cell populations: Wharton’s Jelly Mesenchymal Stem Cells (WJ-MSCs) and Human Umbilical Cord Perivascular Cells (HUCPVCs). Both of these cell populations have remarkable potential or regenerative medicine (Carvalho MM., et al. Curr Stem Cell Res Ther. 2011;6(3):221-8). Other umbilical cord stem cells include unrestricted somatic stem cells (USSCs; Arien-Zakay H, Lazarovici P, Nagler A., Best Pract Res Clin Haematol. 2010;23(2):291-303), embryonic-like stem cells, blood vessel-based endothelial stem cells, and a stem cell that comes from those cells that cover tissues (epithelial stem cells; see Harris DT., Stem Cell Rev. 2008;4(4):269-74, & Harris DT., Br J Haematol. 2009;147(2):177-84).

The usefulness of cord blood has been recognized by the medical community for some time, and there are now umbilical cord blood registries that bank cord blood for medical use and for research. One of these registries, the Cord Blood Registry (CBR) works with various research laboratories to help discover ways to use a child’s own cord blood stem cells to treat conditions like pediatric brain injury or even acquired hearing loss. Because different laboratories use different protocols or equipment to process umbilical cord blood, the experimental results derived from experiments or clinical trials that use cord blood might vary widely. Therefore, to ensure consistency in the storage and processing of cord blood stems, three separate clinical trials have used cord blood that provided by the CBR in their FDA-authorized protocols. These research institutions include the University of Texas Health Science Center at Houston (UTHealth) in partnership with Children’s Memorial Hermann Hospital, and Georgia Health Sciences University, which is the home of the Medical College of Georgia (MCG). CBR is the only family stem cell bank that pairs researchers conducting clinical trials with prospective patients for their studies.

Heather Brown, MS, CGC, Vice President of Scientific & Medical Affairs at Cord Blood Registry, put it this way: “Partnering with a series of specialists who want to research the use of a child’s own newborn blood stem cells on a variety of disease states allows CBR to help advance medical research for regenerative therapies by connecting the child whose family banked with CBR to appropriate researchers. The pediatric specialists from UTHealth, Children’s Memorial Hermann Hospital, and Georgia Health Sciences University are at the forefront of stem cell research as they evaluate cord blood stem cells’ ability to help facilitate the healing process after damage to nerves and tissue.”

One of the clinical trials examined the ability of cord blood stem cells to treat hearing loss. Hearing loss can result from problems with the middle ear, which conducts sound to the cochlea (conductive hearing loss) or from problems with the inner ear, in which the cochlea itself is damaged or defective (sensorineural hearing). Sensorineural hearing loss affects approximately 6 per 1,000 children by 18 years of age, with 9% of the cases resulting from various external causes (e.g., viral infection and head injury). Samer Fakhri, M.D., surgeon at Memorial Hermann-Texas Medical Center and associate professor and program director in the Department of Otorhinolaryngology – Head & Neck Surgery at UTHealth, heads the research team investigating the use of cord blood to treat sensorineural hearing loss. His collaborator is James Baumgartner, M.D.

The Fakhri-Baumgartner study is a Phase I safety study that uses cord blood-based stem cells to treat children who suffer from acquired hearing loss. The inspiration for this trial comes from animal studies that used cord blood to repair damaged organs in the inner ear. The paper (Revoltella RP., et al., Cell Transplant. 2008;17(6):665-78), used mice that had been made deaf from treatment with aminoglycoside antibiotics, which cause irreversible deafness at particular dosages, and intensely loud noises, which also cause deafness. Intravenous administration of hematopoietic stem cells from umbilical cord blood stimulated some structural recovery in the inner ear that was due to umbilical cord stem cells that had survived and become part of the inner ear tissues.

Parents of children 6 weeks to 2 years old that had experiences hearing soon after birth are eligible for this year-long study. Baumgartner explains, “The window of opportunity to foster normal language development is limited. This is the first study of its kind with the potential to actually restore hearing in children and allow for more normal speech and language development.”

Another clinical trial is examining the ability of cord blood to treat brain trauma. Children who experience brain injury heal better than adults who experienced the same injury. Having said that brain trauma is one of the leading causes of childhood death. Charles S. Cox, M.D., distinguished professor of pediatric surgery and pediatrics at UTHealth, initiated a clinical study that will enroll 10 children ages 18 months to 17 years old, all of whom have umbilical cord blood banked with CBR, and have suffered some type of traumatic brain injury. These children will enroll in the study within 6-18 months of suffering brain injury. This trial grows from a growing corpus of studies that have demonstrated the efficacy of umbilical blood stem cells to treat neurological conditions. Read more about the trial here.

According the Charles Cox, “The reason we have become interested in cord blood cells is because of the possibility of autologous therapy, meaning using your own cells. And the preclinical models have demonstrated some really fascinating neurological preservation effects to really support these Phase 1 trials. There’s anecdotal experience in other types of neurological injuries that reassures us in terms of the safety of the approach and there are some anecdotal hints at it being beneficial in certain types of brain injury.”

James Carroll professor and chief of pediatric neurology at the GHSU in Augusta, Georgia, launched the first FDA-regulated clinical trial to test the ability of cord blood stem cell infusions to improve the condition of children with cerebral palsy. This clinical trial will include 40 children whose parents have banked their umbilical cord blood at CBR and meet all the criteria for inclusion in the trial.

Dr. Carroll explains: “Using a child’s own stem cells as a possible treatment is the safest form of stem cell transplantation because it carries virtually no threat of immune system rejection. Our focus on cerebral palsy breaks new ground in advancing therapies to change the course of these kinds of brain injury–a condition for which there is currently no cure.”

Brain injuries or lack of oxygen either before birth, during birth, or during the first years of life can damage specific motor pathways in the brain and lead to an inability properly move, learn, hear, see, or think normally. According to the Centers for Disease Control, 2-3 / 1,000 children are affected by cerebral palsy.

These clinical trials are part of an innovative push that partners clinical researchers with patients. They also represent a move from preclinical studies with cord blood stem cells in animals, to human clinical trials with genuine human patients. Heather Brown put it this way: “The benefits of cord blood stem cells being very young, easy to obtain, unspecialized cells which have had limited exposure to environmental toxins or infectious diseases and easy to store for long terms without any loss of function, make them an attractive source for cellular therapy researchers today. We are encouraged to see interest from such diverse researchers from neurosurgeons to endocrinologists and cardiac specialists.”

Fate Therapeutics Clinical Trial with FT1050 Improves Stem Cell Engraftment In Umbilical Cord Blood Transplant Recipients


Patients who receive umbilical stem cell treatments after bone marrow-ablating cancer treatments usually have to wait for the cells the “engraft” or proliferate and fill the bone marrow. During this engraftment time, these patients are prone to life-threatening infections, since their immune systems are effectively wiped out. However, a natural compound called FT1050 (marketed as Prohema) might improve the ability of stem cells from umbilical cord blood to engraft in patients. A phase I clinical trial led by Dana-Farber Cancer Institute scientists provides genuine hope that this compound might decrease the engraftment time for umbilical cord stems cells.

FT-1050 (16,16-dimethyl Prostaglandin E2) is the first drug candidate from Fate Therapeutics’ platform of Stem Cell Modulators (SCMs). SCMs are small molecules that influence adult stem cells. By treating stem cell patients with SCMs, physicians hope to guide stem cells treatments toward desired outcomes, and these can include cell regeneration, healing or blocking cancer growth. In the case of blood cell-making stem cells (also known as “hematopoietic stem cells” or HSCs), FT1050 can mediate their ability to home to the bone marrow and eventually repopulate the patient’s blood and immune system. Because FT-1050 seems to affect fundamental pathways present in all blood cell-making stem cells, it could improve the efficiency and success of treatments with stem cells from any source, including from bone marrow, peripheral blood, and umbilical cord blood.

This clinical trial involved 12 patients who underwent reduced-intensity chemotherapy and then received a transplant of cord blood stem cells that had been treated with FT1050. FT1050-treated blood-forming stem cells might solve a long-standing problem with umbilical cord transplants – a relatively small number of stem cells are infused during such procedures, and therefore, they often take longer to engraft (or take root) in patients than do the more numerous stem cells involved in transplants from adult donors. These delays during engraftment can leave patients susceptible to dangerous infections and other complications.

Trial leader Corey Cutler, MD, MPH, of Dana-Farber and Brigham and Women’s Hospital put it this way: “There is a significant need to improve the speed and quality of engraftment of cord-derived stem cells. FT1050 has shown the ability in preclinical research to activate hematopoietic [blood-forming] stem cells so they engraft more quickly and with a higher degree of success.”

Umbilical cord stem cell transplants are an excellent option for patients who do not have a closely-matched adult donor. Since the current pool of potential donors is smaller for non-Caucasians than for Caucasians, members of ethnic minorities tend to receive transplants from cord blood at a higher rate than Caucasians.

The goal of this phase I trial was to assess the safety of FT1050-treated cord blood cells in adult patients who receive umbilical cord blood stem cell transplants. Additionally, this trial determined if the treated cells show accelerated engraftment. In the 12 patients who participated in the trial, engraftment occurred approximately three to four days faster than normal. Also the patient’s levels of particular types of white blood cells (neutrophils) returned to normal in the patients after a median of 17.5 days, which is similar to the rate in standard stem cell transplants. Side effects of the FT1050-treated cord blood cells were minimal, and in none of the study patients did the stem cells fail to engraft.

The phase I trial was sponsored by Fate Therapeutics, Inc., of San Diego, Calif., which is developing ProHema, a biologic product that consists of blood cell-making stem cells treated with FT1050 for patients who require a stem cell transplant. FT1050 was identified by Leonard Zon, MD, a hematologist and director of the Stem Cell Program at Children’s Hospital Boston, who used a chemical screens that was conducted in zebrafish. FT1050 is the first potential therapeutic derived from a zebrafish model to make it to clinical trials.

“We’re encouraged by the results of this study for patients receiving umbilical cord stem cell transplants after reduced-intensity chemotherapy treatment,” Cutler says. “Further studies are planned to test FT1050-treated hematopoietic stem cells in a larger group of these patients.”