Newsletter - December 2014
First US patient treated in South Korea for Cerebral Palsy
Nina and Zach Miller were the first parents from the United States to take their daughter Josephine, who has cerebral palsy, to South Korea for therapy with donated cord blood.
Theirs is not another story about parents seeking an unproven stem cell therapy - perhaps with stem cells of uncertain provenance - at a for-profit overseas clinic. The Millers traveled to an established medical research center, the CHA Bundang Medical Center in Seoul S. Korea, to participate in a registered clinical trial led by MinYoung Kim, MD PhD.
Josephine is the Miller's first child and she has cerebral palsy. As an infant, Josephine could barely sleep for more than 2 hours at a time. She could not take any food by mouth and had to survive on feedings delivered via a G-tube surgically implanted into her stomach.
Desperate to ameliorate Josephine's cerebral palsy, the Millers researched all their options in stem cell therapy. Based on publications in the medical literature and anecdotes from other parents who had tried stem cell therapy, the Millers concluded that cord blood stem cells held the most promise. But Josephine's cord blood had not been saved.
The question became, was there any way to get cerebral palsy therapy for Josephine with stem cells from donated cord blood? In the US, our FDA has not approved donated stem cells for use in children who have brain injuries like cerebral palsy. The FDA has approved several clinical trials in which children receive their own stem cells as therapy for brain injury. To date about 400 children who have brain injuries and have their own cord blood stored have been treated in US clinical trials. But no child has received donated cord blood for cerebral palsy in the US (except for one borderline case of an identical twin).
For those US families that have a child with a brain injury and who did not save their child's cord blood, access to stem cell therapy has remained elusive. An industry of for-profit clinics has popped up outside US borders to offer "stem cell therapy" to this community. But since none of these clinics holds an accreditation in cord blood banking, nor has a known relationship with an accredited cord blood bank, it is hard to know what exactly they are infusing into their patients. Do they really provide cord blood stem cells? Did the donating mothers give informed consent, and were they screened for infectious diseases? Questions abound. The Millers did not want to go down that route, they wanted to work with a research center that has rigorously supervised laboratory conditions.
Meanwhile, the CHA Bundang Medical Center, in Seoul S. Korea, has been running a series of clinical trials to treat children with cerebral palsy. In 2012 they published the world's first proof that cerebral palsy treatment with donated cord blood has efficacy. A follow-up trial on 300 patients has been submitted for publication. Korean TV has followed the trials on Arirang News.
Nina Miller contacted Dr. MinYoung Kim, the lead investigator of the cerebral palsy trials in Seoul. The team at CHA Bundang Medical Center was willing to accept Josephine into their program.
There was just one catch: Josephine needed to find a matching cord blood unit for the therapy. Josephine is not of Asian heritage and the Korean banks did not have a cord blood unit that was a close enough match for her. Her doctors initiated a search of the international registry, BMDW, and found that Josephine had four matches around the world, including three units in three US public cord blood banks.
Getting one of those matching units for Josephine proved to be surprisingly difficult, and revealed that the NMDP network of public cord blood banks is not ready to handle an influx of patients who seek donor cord blood for regenerative medicine. Roughly half of the cord blood transplants facilitated by the NMDP involve a patient and donor located in different countries; they are very experienced with international transplants, including transplants under clinical trials. But because Josephine's case was a request to use cord blood for regenerative therapy (not a traditional transplant), the NMDP classified her request as "research use", and this passed the responsibility for handling the request to the individual banks that held the cord blood units. The first two US public banks that were approached refused to release their matching cord blood unit to Josephine.
Fortunately, a third matching cord blood unit was in the Cleveland Cord Blood Center, and they decided to release their unit to Josephine as a case of "compassionate use". In making this decision, the bank gave careful consideration to its intended use in a controlled clinical trial, at an established bona-fide research institution.
The Miller's challenges were still not over, because there was still a financial hurdle to surmount. Public cord blood banks routinely charge about $30,000 to release one of their units. When the cord blood is required for a transplant, that cost is covered by the patient's health insurance. But the Millers did not have insurance coverage to participate in a clinical trial in a foreign country. They were looking at a $30,000 out of pocket cost to obtain a matching cord blood unit for their child's therapy.
Once again, compassionate strangers came to the rescue, and a philanthropic foundation covered most of the cost of Josephine's matching cord blood unit.
Finally, in Feb. 2014 the Miller family made the 17 hour plane trip to Seoul with Josephine. Their airfare alone cost thousands of dollars. Upon arrival they found that the CHA University hospital had built a beautiful clinic, the Chaum Global Stem Cell Clinical Trials Center, to accommodate patients who travel to S. Korea from other nations.
The protocol for cerebral palsy treatment at CHA Bundang Medical Center consists of immune suppression with cyclosporine followed by peripheral infusion of the donor stem cells. Prior to the infusion, Josephine underwent numerous tests of her baseline skills and a PET scan of her brain. Because she was taking immune-suppressing drugs to prevent rejection of the donor stem cells, Josephine had to stay in the hospital for three weeks.
The Millers felt that "the best part of Korea was the physical therapy and the therapists". Whereas children in the US who have cerebral palsy may receive physical therapy once or twice a week, during their stay at CHA University Josephine received multiple half hour sessions of therapy every day, adding up to about 3 hours of therapy per day. The sessions included physical therapy (PT), occupational therapy (OT), electric stimulation, and optional stimulation with art and music.
The PT at CHA University emphasizes building from fundamental skills. Every day, each patient spends a great deal of time simply loosening muscles with stretching and electric stimulation. Therapists focus primarily on developing correct posture and core muscle strength. The therapy relentlessly repeats the muscle relaxation and basic skills before moving on to specific skills.
The Millers paid $25,000 in advance to cover Josephine's treatment in S. Korea. This covered the stem cell infusion, immune-suppressing drugs and other medications, the hospital room, the family's accommodations, and the many hours of PT over the course of three weeks.
On the way home from S. Korea, Josephine caught a bad bronchial infection and ended up on antibiotics. This illustrates the risks involved in traveling long distance for a therapy that requires immune suppression. Since coming home, the Millers have continued to work with Josephine daily using the PT techniques that they learned in S. Korea.
Josephine has made the following advances over the nine months since her cord blood therapy in S. Korea: Ever since she was a baby, Josephine had chronic reflux, threw up 10-15 times per day, and was fed with a G-tube. Once she had the therapy, her reflux completely disappeared and within four weeks she began drinking milk from a cup. She still uses the G-tube for other foods. When Josephine went to S. Korea at age 19 months, her hands were always balled into fists, she could not roll over, and she could not sit without support. Within five weeks she learned to roll over. Now she can use her hands to grasp and she can maintain a sitting position for a half hour to an hour, depending on whether she is having a good day.
This story is one family's experience and is not an endorsement or indictment of any of the institutions involved. It is important to tell the Millers' story because it poignantly illustrates the issues that are currently involved in delivering stem cell therapy as a treatment for brain injury at birth.
First, families who have children with neurologic disorders should appreciate the difference between the services offered by a for-profit "stem cell clinic" versus a hospital research center. The International Society for Stem Cell Research (ISSCR) has developed resources for patients considering stem cell therapy. They have a website titled a closer look at STEM CELL treatments that is full of helpful information, and their main website has a link to download a patient handbook.
Second, researchers who are designing clinical trials to treat children with cerebral palsy and other neurologic disorders should take into account that patients in the S. Korea trials receive very intensive physical therapy. When comparing the outcomes of clinical trials, using the same stem cell sources, differences in the simultaneous PT must be taken into consideration.
Third, both individual public cord blood banks and national networks of public banks around the world should establish committees and protocols for handling requests on behalf of patients who seek a matching cord blood unit for cerebral palsy therapy or other regenerative medicine therapy. Formal procedures would help ensure that these decisions are carefully weighed, that there is a record of the request and the decision, and that the decision is not unduly influenced by any personal bias or conflict of interest.
Fourth, increasing use of donor cord blood for cerebral palsy therapy could be good news for public cord blood banks. The GAO has issued a report that documents the failure of public cord blood banks in the US to attain financial self-sufficiency. Releasing allogeneic cord blood units for cerebral palsy therapy could be the financial salvation of public cord blood banks, especially since this therapy could use the older bank inventory of smaller cord blood units that are less desirable for transplants.
First in West: MSC from Cord Tissue used to treat Graft-versus-Host Disease
Graft-versus-Host Disease (GvHD) is a common and serious complication following a stem cell transplant from an unrelated donor. GvHD is divided into acute and chronic form according to the clinical course and time of the diagnosis. It is a life-threatening condition, which contributes greatly to early mortality after stem cell transplants. Survivors may suffer organ damage and have impaired quality of life.
The first line of prevention and treatment for GvHD is steroids. When GvHD does not respond to steroids or is not resolved by steroids it is said to be "steroid-refractory". In this situation there are many second-line therapies, but none of them is considered to be clearly superior and most effective.
Mesenchymal stem cells (MSC), because of their unique immune properties, have great potential as a treatment option for steroid-refractory GvHD. One attribute of MSC is that donor and patient do not have to be matched, so that MSC can easily be supplied from a bank of donations. Another helpful attribute is that many studies show MSC tend to suppress auto-immune reactions and thus potentially could suppress the conflict between graft and host immune systems. Moreover, MSC can be supplied intravenously, which is highly convenient for the patient.
In this article we report on a series of patients treated for GvHD in Poland with MSC from the Wharton's jelly in cord tissue (WJ-MSC). Wharton's jelly is an abundant source of MSC with several advantages: harvesting cord tissue is non-invasive and MSC are easily isolated, and the MSC from cord tissue have good proliferation and differentiation capabilities.
Polski Bank Komórek Macierzystych S.A. (PBKM) is the largest family cord blood bank in Poland and is the leader of an EU network of banks called "Famicord Group". In parallel to their commercial activity, PBKM runs a public bank of cord blood and cord tissue with inventory of over 3000 units funded by PBKM and the Polish Ministry of Health. PBKM is one of the eight European private stem cell banks having AABB accreditation. PBKM has supplied stem cells for 34 therapies to date (18 of cord blood and 16 of MSC from Wharton's Jelly).
Ten GvHD patients were treated in the years 2011-2013 at four different clinics in Poland. They underwent treatment with MSC derived from Wharton's jelly as a salvage therapy for GvHD. Each application was preceded by bioethical committee approval. The patient ages ranged from 3 to 20 years. Among them were three people with extensive chronic GvHD and seven with acute GvHD, including six patients with grade IV and one with grade III.
The patients had originally received stem cell transplants due to the following underlying diseases: acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), myelodysplasia syndrome (MDS) transformed into AML, MDS, severe aplastic anemia and non-Hodgkin lymphoma. All patients failed to respond to the first-line GvHD therapy with steroids and had unsatisfactory response to the second-line therapies including: cyclosporine A, mycophenolate mofetil, tacrolimus, antithymocyte globulin, etanercept, intravenous immunoglobulin, extracorporeal photopheresis and monoclonal antibodies.
The GvHD patients received 1-3 intravenous infusions of WJ-MSC from a few third-party donors within a 1-2 week interval. They received a median overall dose of 1.5 million cells per kg of body weight. The Wharton's Jelly was isolated by mechanical dissection of collected umbilical cords, then plastic-adherent cells (MSC) were isolated without enzymatic treatment, cultured, and cryopreserved in liquid nitrogen. The laboratory processing took place in a GMP ISO 5 environment. Reference samples of MSC were used to check cell count, viability, and immunophenotype. The MSC were administered immediately after thawing.
The patients were monitored for adverse effects during the infusion and follow-up period. The median time of observation equaled 9.5 months. No adverse effects were described during or after WJ-MSC application apart from transient tachycardia that subsided without intervention.
Six of the ten GvHD patients responded to the therapy and their doses of immunosuppressive treatment could be reduced, including one with chronic GvHD who showed improvement 3 months after MSC application. Two patients showed complete response and were cleared of GvHD symptoms. The first cleared patient was 7-year-old girl with grade IV intestinal acute GvHD who had been transplanted for ALL in second remission. The second cleared patient was a 3-year-old boy with grade IV skin and intestinal acute GvHD who suffered from MDS that transformed to AML. Both of these cleared patients had received MSC treatment early after GvHD diagnosis. Out of four remaining patients who responded to therapy, two of them have limited chronic GvHD (previously was extensive), and one died 3 months after MSC infusion due to central nervous bleeding and sudden cardiac arrest. The last one is currently being evaluated, however 1 month after MSC treatment the patient's GvHD severity grade decreased from IV to I.
Among the four of ten patients who did not respond to the therapy, one is stable with chronic extensive GvHD and the other three died: two because of GvHD progression and sepsis, and one (with grade IV acute GvHD with skin, intestinal and hepatic involvement) due to hepatic coma. No relapses or de novo malignancies occurred during the follow-up period.
The application of WJ-derived MSC from third party donors is a safe procedure that brings clinical effects even when administered as a salvage therapy. In more than half of these patients, WJ-MSC infusion ameliorated symptoms of GvHD and allowed them to reduce immunosuppressive treatment. In one fifth of the patients, the WJ-MSC therapy led to disappearance of GvHD symptoms. Outcomes seemed to be improved when the time between diagnosis and MSC infusion was shorter.
Nowadays, MSC are officially considered as a second-line treatment for acute GvHD. However, further studies are needed to establish infusion timing, optimal cell doses, as well as number of injections and intervals between them. These cases were published in an abstract book of the 40th Annual Meeting of the European Group for Blood and Marrow Transplantation. (see below)
The First in Poland Follow-Up of 10 Patients with Steroid-Refractory Graft-versus-Host Disease
Treated with Intravenously Applied Wharton's Jelly-derived Mesenchymal Stem Cells as a Salvage Therapy.
Abstract PH-AB232. Bone Marrow Transplant. 2014 Mar;49:S537.
D. Gladysz1, M. Murzyn1, I. Czaplicka1, A. Olkowicz1, T. Oldak1, M. Mielcarek2, K. Kalwak2, K. Drabko3, J. Styczynski4, K. Pawelec5, M. Boruczkowski6, J. Baran1, & D. Boruczkowski1
- Medical Department, The Polish Stem Cell Bank, Warszawa, Poland
- Department of Bone Marrow Transplantation, Paediatric Oncology and Haematology, Wroclaw Medical University, Wroclaw, Poland
- Department of Paediatric Haematology, Oncology and Transplantology, Medical University, Lublin, Poland
- Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland
- Department of Paediatrics, Haematology and Oncology, Medical University, Warszawa, Poland
- Department of Immunology, Poznan University of Medical Sciences, Poznan, Poland