| Cord Blood Banking and Its Potential Clinical Applications
Bone marrow transplantation (BMT) is an often used means of
therapy for a variety of diseases, including chemotherapy-resistant malignancies and
genetic blood diseases. If BMT is needed, the patient's family is tested for suitably
HLA-matched members. However, there is only a 1 in 4 chance that a patient's sibling will
be a suitable match. It is highly unlikely that other members of the patient's family will
match the patient. If a family member is not identified, then a search can be performed
through the National Marrow Donor Program (NMDP) for an HLA-matched, unrelated volunteer
bone marrow donor. However, the chances of finding a suitably matched unrelated donor are
approximately 30 percent for Caucasians, and significantly less for ethnic minorities.
Also, the search process can take from 3-6 months and is often very expensive. Although it
is possible to use bone marrow from a volunteer donor (which is frequently done), there
are a number of serious side-effects from this process. The most serious side-effect is a
condition called graft-versus-host disease (GVHD), in which cells in the transplanted bone
marrow graft start to attack the patient. GVHD is a major cause of death when it occurs,
and it occurs 60-90 percent of the time in unrelated BMT. Due to the problems of a lack of
donors and the high incidence of GVHD, researchers have looked to alternate sources of
cells for transplant.
Work that was begun in the early 1980s revealed that cord
blood (i.e., the leftover blood in the umbilical cord and placenta after the birth of a
child) was comparable to bone marrow in terms of transplant. Cord blood offered a number
of advantages over bone marrow. With over 4 million births per year in the United States,
the potential donors were essentially unlimited. Over the past 6 years clinical use of
cord blood has shown that more ethnic minority patients have been able to be transplanted,
the incidence and severity of GVHD has been significantly reduced, and the costs of
transplant have been considerably less than with BMT.
In 1989, my laboratory began a series of studies examining
the use of cord blood for transplantation. These studies convinced us that cord blood
would be the future for transplantation. During this work we developed (in collaboration
with Dr. Peter Yorgin, Dept. Pediatrics) a small animal model for cord blood
transplantation that has proven useful in developing new approaches for cord blood use.
Further, we established the methodologies that were needed for efficient and reproducible
cord blood collection, processing and storage so that cord blood could begin to be used on
a larger clinical scale.
In June of 1992, my laboratory established the first Cord
Blood Bank in the world with the initial sample coming from my son, Alexandre. In early
1994 we opened the bank to the general public.
Since that time we have banked over 1,200 cord blood
samples for personal use (including my daughter, Stefanie) and have received over 900
donated samples that can be used for anyone in need. It is expected that the numbers of
both types of samples will increase over the next several years with additional monies
from federal grants and biotechnology collaborations. To date, 2 cord blood transplants
have been performed with samples from the Cord Blood Bank. Currently, the Cord Blood Bank
is the largest personal cord blood bank in the world, and the second largest donated cord
blood bank in existence.
In addition to our efforts in cord blood banking and
patient/physician education/outreach, we have begun a number of studies to expand the use
of cord blood. Over the past year, in collaboration with private companies, we have
investigated the use of cord blood and gene therapy to treat a variety of diseases. We
have focused our efforts in this field of molecular medicine at treating AIDS and cancer.
In terms of AIDS, we have been successful in transferring genes into cord blood cells so
that after transplant the patient will develop a new immune system resistant to HIV
infection. It is hoped that this approach will be in clinical trials in the next year. We
have taken a similar approach for treating cancer, in that after gene therapy and
transplant, the patient will develop an immune system targeted to any remaining tumor
cells in the body. This approach will be tested in animal models in the near future. We
are also developing approaches for gene replacement to treat a variety of genetic diseases
(e.g., hemoglobinopathies) via cord blood gene therapy. Finally, we are in the process of
establishing a large animal model for cord blood transplantation and gene therapy that
will be more directly relevant to the human condition than our current animal model.
It is apparent that the immediate future holds much
excitement in terms of research into cord blood transplantation. The successful
establishment and enlargement of the cord blood bank offers hope to thousands of patients
in need of transplant. The development of new gene therapy approaches however, will offer
hope and treatment to hundreds of thousands of patients.
This work has been funded in part by the following : the
American Cancer Society, the Steele Memorial Children's Research Center, the Arizona
Disease Control Research Commission, and private donations.
Benefits of Cord Blood
Transplantation
1. Easily obtained without risk or pain to mother or infant
2. Can be stored for personal use of donated for others to
use
3. Important for ethnic minorities for whom bone marrow
donors are difficult to locate
4. Less risk of infectious disease contamination
5. Less stringent HLA-matching required for use in
transplantation
6. Fewer side-effects after transplantation
7. An inexpensive form of biological insurance
Cord Blood Transplantation : A
Promising Alternative to Bone Marrow Transplantation
Bone marrow transplantation (BMT) is often used as a means
of therapy to treat a variety of malignant and genetic diseases. For certain diseases
(e.g., leukemias and certain immunodeficiencies) it is the only proven treatment for
long-term patient survival. For other diseases (e.g., autoimmune diseases) it could offer
the hope of a long-term cure. However, BMT is limited by the shortage of suitable donors
(especially for ethnic minorities) and the severity of its side-effects. If a patient does
not have a suitably HLA-matched family member to provide bone marrow, it is necessary to
search for an unrelated donor. This search process is often a long and expensive
procedure, with Caucasian patients having a 30 percent chance of finding a suitable donor
and ethnic minorities having an even lower probability. Further, BMT using an unrelated
donor often (60-90 percent of the time) results in graft-versus-host disease (GVHD), which
if severe is a major cause of death (50 percent survival at 2 years post-transplant).
In an effort to solve some of these problems, efforts have
focused upon alternate sources of cells for use in transplant. Research performed in the
1980s indicated that cord blood should be comparable to bone marrow for use in
transplantation. In late 1988, the first cord blood transplant was performed for a child
with a genetic disease (Fanconi anemia). In 1991, the first cord blood transplant was
performed for a child with cancer (chronic myelogenous leukemia). Both of these
transplants were successful and generated much interest in using cord blood as an
alternative to bone marrow. The initial transplants were encouraging in that the incidence
of GVHD was significantly reduced as compared to BMT, and ethnic minorities were now able
to locate donors.
Currently, there have now been over 120 cord blood
transplants performed worldwide. Approximately one-half of these transplants have been
between siblings with the other one-half generated from suitably matched unrelated donors.
Approximately two-thirds of the cord blood transplants have been for various malignancies,
with one-third being used to treat a variety of genetic diseases.
The median volume of cord blood used for transplant has
been 100 cc for sibling transplants, and between 60-70 cc for the unrelated transplants.
On average, approximately 3 x 107 nucleated cells/kg patient weight have been administered
for transplant (with the minimum used being 1 x 107 nucleated cell/kg patient weight). It
should be noted that these data translate into numbers of cells and blood volumes that are
approximately 1/10 of that which would routinely be used for BMT. Thus, questions have
been raised as to whether cord blood transplantation would ever be suitable for adult use,
or restricted to use in children. To date, the smallest amount of cord blood ever used in
a successful transplant has been 43 cc, and the largest patient ever successfully
transplanted is now 85 kg. Thus, it appears that a typical cord blood collection is of
sufficient size for use in almost all transplant conditions.
Significantly, the clinical outcomes of cord blood
transplants has been extremely encouraging. There has been a 2 percent incidence of severe
GVHD in sibling cord blood transplants (as compared to an approximately 20 percent
incidence of severe GVHD in comparable BMT), and a less than 10 percent incidence of
severe GVHD in unrelated cord blood transplants (as compared to a 60-90 percent incidence
of severe GVHD in comparable BMT). These incidences of GVHD have been observed even in
cases of less than perfect matching between donor and recipient. The failure to engraft
rate and the relapse rate for patients with malignancies has been comparable to that seen
with BMT. Recovery of patient neutrophils has been equivalent to BMT patients, although
platelet recovery is somewhat longer. The overall probability of disease-free survival has
been 45 percent for patients treated for malignancies and 80 percent for patients treated
for genetic diseases, comparable to BMT.
Thus, over the past 7 years it has been demonstrated the
cord blood is a clinically acceptable alternative to BMT. In fact, in many instances cord
blood transplantation offers many advantages not found with BMT. With the creation of cord
blood banks at The University of Arizona and at The New York Blood Center in the early
1990s, and recently in Germany and Italy, cord blood offers hope to many individuals
(especially ethnic minorities) unable to locate bone marrow donors. Further, the use of
cord blood offers the promise of the clinical benefits of transplantation without the
serious drawbacks and side-effects. In effect, one of the miracles of birth, previously
disregarded, now offers the miracle of life to thousands of patients.
Dr. David T. Harris
Director, Cord Blood Stem Cell Bank
Associate Professor of Immunology
Member, Steele Memorial Children's Research Center
Member, Arizona Cancer Center (520) 621-6271
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