Stem Cell Clinic
Patient Application
FAQ
Contact
Locations
Our Scientific Articles
News
2009
2008
2007
2006
Videos
Research


Stem Cell Treatment for Leukemia Improved Transplant Technique Speeds Immune System Recovery

By Salynn Boyles, WebMD Health, January 19, 2010

Hematopoietic (blood-making) stem cell transplantation has been performed for decades in patients with leukemias or other blood disorders, being the only potentially curative therapy in many cases.  The concept behind this procedure is that a dose of radiation and/or chemotherapy is first given to the recipient in order to destroy their stem cells.  The radiation and/or chemotherapeutic doses given are so high that if the patient was not “rescued” by administration of donor stem cells, the patient would loose all ability to make blood.  Subsequently stem cells from a healthy donor are administered which take over the function of blood making.  Since the recipient now has a healthy blood making stem cell system in them, the previous problems associated with the original defective stem cells are now resolved.  Historically bone marrow from the donor was used as a source of stem cells.  Bone marrow stem cells are discussed in this video http://www.youtube.com/watch?v=qXGYzday7ko.  An additional point of interest is that the donor stem cells are injected intravenously, not into the bone marrow of the recipient.  This point is important because in the area of stem cell therapy for other conditions (such as heart failure, liver failure, stroke, etc), some scientists have been dubious about the ability of intravenously injected stem cells to cause effects, stating that stem cells must be injected directly into the diseased tissue.  This is clearly not the case in hematopoietic stem cell transplantation in which the stem cells “know” how to find their way to the bone marrow, based on specific molecules that are described in this video http://www.youtube.com/watch?v=VJaQkYWdJ8w.

Unfortunately there are several side effects to the procedure of stem cell transplant for blood disorders.  First of all, as we stated, the recipient is exposed to a dose of chemotherapy and/or radiotherapy that is potentially lethal.  In the time period after destruction of the recipient stem cells and the donor stem cells taking over the function of blood making, the patient effectively lacks an immune system.  Usually recipients are given transfusions in order to keep red blood cell levels adequate and high doses of antibiotics to prevent infections.  Despite this, there is a substantial risk of patient death.  The other side effect is that the donor stem cells are usually contaminated with donor immune cells.  What happens in many situations is that the immune cells of the donor start to attack the recipient.  This is called graft versus host disease (GVHD) and is one of the biggest causes of transplant-related deaths.  Several years ago researchers used cell separation technologies to take out contaminating immune system cells from the donor bone marrow in order to reduce GVHD.  Unfortunately, while GVHD was indeed reduced, recipients who were given stem cell transplants for leukemias had a much higher rate of the leukemia returning.  This prompted the generation of the theory that the contaminating immune cells of the donor were actually important in the maintenance of a leukemia-free state.  In summary, stem cell transplantation offers great hope and has cured tens of thousands of people from lethal diseases, however, the high risk of side effects remains a limiting factor.

One way to reduce the side effects associated with stem cell transplantation is to use cord blood as a donor source.  Cord blood contains several types of stem cells: In addition to the blood-making hematopoietic stem cells, it also contains mesenchymal stem cells which are capable of modulating immune responses and endothelial progenitor cells, which are involved in regeneration of blood vessels in the body.  Cord blood stem cells are described in this video http://www.youtube.com/watch?v=z6CP-OL1Kuc.  Since cord blood is a younger source of stem cells, the immune cells in the cord blood are less active as opposed to immune system cells contaminating adult bone marrow.  What this means is: a)  That cord blood transplants do not have to be matched as stringently as bone marrow transplants, thus increasing the donor pool available; and b) cord blood transplants have a much lower incidence of GVHD.  To date thousands of cord blood transplants have been performed in the area of blood disorders with a relatively high degree of success.  Additionally, cord blood has been used as a source of stem cells for non-blood disorders as well, ranging from cerebral palsy, to liver failure, and currently is in clinical trials for Type I Diabetes.  It is important to note the distinction that in the area of cord blood transplants, when the transplant is given for non-blood disorders, the recipient’s stem cell compartment does not need to be destroyed.

Unfortunately, in the area of blood disorders, the main disadvantage of cord blood transplantation has always been that it takes a longer time for the cord blood stem cells to “engraft” as compared to bone marrow stem cells.  The exact reason for this is not entirely known, however, it seems to be related to the fact that the cord blood stem cells are relatively immature as compared to the recipient, and as a result they do not properly interact with the recipient bone marrow.  One example of such an discrepancy of interaction is in the molecules found on cord blood stem cells that are not properly “fucosylated”.  Fucosylated stem cells are capable of crossing the blood vessel effectively and entering the bone marrow.  While adult stem cells are properly fucosylated, cord blood stem cells are relatively under-fucosylated.  The company America Stem Cell has developed a method of artificially fucosylating cord blood stem cells to reduce the period of immune compromise.

Besides artificially modifying the cord blood stem cells, another approach that is promising is to actually give higher numbers of cord blood stem cells by giving two or even three cords.  It is known that the more cord blood stem cells given, the faster the engraftment is based on comparison studies of patients receiving different doses of cells.  The problem with giving several cords at a time is that they require matching, which becomes more difficult when several cords are used.  As an aside, matching is critical when cord blood stem cells are given for blood diseases, however, it is not critical when cord blood stem cells are given for non-hematopoietic conditions.  This is explained in detail in the following paper http://www.translational-medicine.com/content/pdf/1479-5876-5-8.pdf.

In a recent paper (Delaney et al. Notch-mediated expansion of human cord blood progenitor cells capable of rapid myeloid reconstitution. Nat Med. 2010 Jan 17) a new way of attacking the problem of poor cord blood engraftment was reported by researchers at Seattle’s Fred Hutchinson Cancer Center.  The scientists sought to expand the stem cell component of the cord blood in vitro (in test tube), ensure the expanded stem cells are properly functioning, and subsequently administer the stem cells to patients after destruction of their own stem cells. 

To approach this problem one must be very careful.  Given that the recipient’s life depends on the ability of the expanded donor cells to actually be capable of making new blood, extensive experiments before human studies had to be performed.  The researchers used a naturally-occurring protein called Notch to activate the cord blood stem cells.  They made sure that the stem cells were indeed multiplying in vitro by counting the number of “CD34 positive” cells.  These are cells that are known historically to be stem cells.  In addition, the scientists took these cells and implanted them into mice that lack an immune system, called NOD-SCID mice.  They observed that the implanted human CD34 cells were capable of creating a human blood system in the mouse, in a similar manner to what would be expected in a stem cell transplant recipient after treatment with chemotherapy/radiotherapy.  In the animal studies the investigators noticed a much higher rate of new blood cell production with the expanded cells, as compared to non-manipulated stem cells.  The paper reports treatment of 10 patients without immediate adverse effects, and much more rapid time to production of new blood cells as compared with other protocols previously used.  One average, cord blood stem cells take about a month to begin production of significant amounts of blood cells in the recipient, whereas in the study this time period was reduced to two weeks. 

 “If we really can make stem cell sources better, this may mean we would have donors for pretty much everyone who needs a transplant,” study researcher Colleen Delaney, MD, tells WebMD.

As a safety back-up the 10 leukemia patients who received the expanded stem cells also received one unit of cord blood that was non-manipulated.  This was performed for ethical reasons in case the expanded stem cells failed to start production of new blood cells.

“We have shown that we can decrease the time to engraftment,” Delaney says. “Now we have to show a clinical benefit to the patient.”

Hematopoietic stem cell transplanter James Gajewski, MD, of Oregon Health Sciences University, told WebMD that the new research addresses one of two major issues surrounding umbilical cord blood transplants.

“Every other attempt to expand (cord blood) stem cells has basically failed,” he says. “This is really the first significant proof that these cells can be expanded, and this group should be commended for doing brilliant work.”

The demonstration that cord blood can be successfully expanded outside of the body and administered to result in clinical benefit is a major step forward for the field of cell therapy.  Previous attempts by companies to develop successful means of expanding cord blood stem cells have failed in clinical trials.  In one trial the cells initially started producing new blood cells, but subsequently stopped, resulting in need for re-transplantation.  In another trial expansion and activation of contaminating immune system cells occurred, resulting in graft versus host disease.  Thus while this is an area of great potential, it is also one that has been associated with certain inherent difficulties.

Besides immediate applicability of the current finding to the area of blood stem cell transplantation, the ability to expanded selective cell populations outside of the body will allow for development of approaches using other types of therapeutic cells.  For example, in the field of cancer research it is known that patient lymphocytes infiltrate tumors, however means of extracting these tumor-killing lymphocytes and expanding them outside of the body at sufficient concentrations have not been devised.  In the field of autoimmune disease (lupus, arthritis, type 1 diabetes, etc), it is known that a specific type of T cell, the T regulatory cell, is capable of inhibiting disease, however they cannot be expanded in sufficient numbers outside of the body for meaningful effects after administration.  The ability to use “bioreactor” systems as the one described in the current publication, to expand cells at meaningful levels will provide a basis for numerous cell therapy investigations in the future.



Copyright © 2004, 2005, 2006, 2007, 2008 Cell Medicine   Disclaimer   Terms and Conditions   10/17/2019