Are there stem cell therapies available for GVHD?
Health Canada and the U.S. Food and Drug Administration have granted conditional approval for Prochymal, a mesenchymal stem cell product, for the treatment of steroid-resistant and/or immunosuppressant-resistant acute graft-versus-host disease (GVHD) in pediatric patients. Final approval depends on the outcome of clinical studies that are underway. Patients who are researching their options may also come across companies with websites or materials that offer fee-based stem cell treatments for curing GVHD. Many of these claims are not supported by sound scientific evidence and patients considering these therapies are encouraged to review some of the links below before making crucial decisions about their own treatment plan.
How close are we? What do we know about GVHD?
- Graft-versus-host disease (GVHD) is a man-made condition that arises when patients are transplanted with donor tissue that is not identical to their own.
- Donated hematopoietic stem cell transplants rescue the blood system of millions of patients with cancer and other blood related disorders following radiation and chemotherapy treatments. Although this approach is often the only hope for a cure, GVHD occurs in more than 40% of patients and leads to death in 15% of cases.
- Acute GVHD occurs within 100 days of transplant. It happens because T cells in the donor bone marrow see the host tissue as different and attack it in much the same way as they would attack foreign bacteria or viruses.
- The most common symptoms of acute GVHD are skin rashes, blisters, gastrointestinal complications (diarrhea, vomiting, anorexia, abdominal pain, mucosal ulcers and bleeding) and liver malfunction resulting in drug toxicity, viral infection, sepsis, and iron overload.
- The development of chronic GVHD is mysterious and is associated with autoreactive (self-attacking) T cells in the patient. This condition starts to develop some time 100 days after a transplant and may involve almost every part of the body.
- Chronic GVHD is the number one cause of death unrelated to relapses that occur after bone marrow stem cell transplantation.
- The severity of GVHD depends on the age of the patient, source of the graft, type of conditioning regimen used to prepare a patient for a transplant procedure, and the treatments used to control graft rejection.
- Drugs that suppress the immune system are used to minimize GVHD but they are not specific and also can hurt the patient’s natural immunity.
- The prognosis is not good for patients who develop steroid-resistant GVHD, and mortality rates can reach 60-90%.
- Graft-versus-tumour (GVT) effect is an important benefit of GVHD. In GVT, immune cells in the donor graft also attack tumour cells in the patient.
How can stem cells play a part?
For patients who need donated transplants for cancer or other blood disorders, there are two types of stem cells that can rebuild the blood supply and at the same time control GVHD. These are umbilical cord blood stem cells and mesenchymal stromal/stem cells (MSCs).
Cord blood is left in the umbilical cord and placenta following the birth of a baby and it contains a number of different types of stem cells, including hematopoietic stem cells and MSCs. Cord blood is easier to obtain, with no risk to the donor, and it can be readily tissue typed and easily stored for future use. The patient survival rate is the same as with bone marrow hematopoietic stem cells but the degree of GVHD is less. The creation of over 100 cord blood banks around the world has made 20,000 cord blood transplants possible. Canada now has a national public cord blood bank in operation, managed by Canadian Blood Services. The practice of banking cord blood is providing physicians with the much-needed opportunity to treat patients, in particular racial minorities for whom matched bone marrow may not be available, with the added post-transplant benefit of less GVHD.
Found in many tissues throughout the body, MSCs are most easily collected from bone marrow, fat and umbilical cord. Although MSCs have the ability to differentiate in the laboratory into a variety of different cell types, their ability to control the immune system, inhibit inflammation, stimulate blood vessel formation, repair tissue and help stem cells to engraft makes them an attractive therapy for reducing GVHD. One of the most remarkable things about these cells is that even when the main tissue typing proteins between donor and host are mismatched, MSCs don’t seem to attract much attention from the patient’s immune system and graft rejection rarely occurs.
Are there lots of groups working on developing a stem cell therapy?
There are countless research teams around the globe working to develop stem cell therapies for GVHD. Their common goals are to identify which stem cells are best suited for the job, how they work to dampen down the immune response in patients, and how best to collect, grow and store them for future use.
Although one of the most promising new therapies for GVHD takes advantage of the properties of MSCs, it has not been so easy for researchers to study exactly how MSCs work. This is partly because they are not present in high numbers in the body but also because it has been difficult to find markers that can tell them apart from neighboring cells. However, researchers have learned that MSCs are crucial for producing factors that construct and maintain the niche that nurtures stem cells in the bone marrow. A growing number of early clinical trials for a number of different diseases are demonstrating that MSCs are largely safe and can provide important growth factors and can effectively dampen and regulate the immune system. The first published success of using MSCs to mitigate GVHD was in a child who had steroid-resistant acute GVHD.
Stem cell research for GVHD is unfolding along a number of different avenues and some of the successful results have been translated into clinical trials. Most are testing the ability of stem cells to dampen the immune system and the outlook is promising. Researchers are investigating how to improve on stem cell therapies already in use, for example trying double cord blood transplants to ensure sufficient numbers of stem cells are transplanted and trying to understand the wide range of results observed in clinical trials using MSCs to treat GVHD. As researchers learn more about these stem cells, they are hopeful that the knowledge gained will be translated into effective therapies for controlling GVHD.
What research is underway?
Before basic stem cell research can be translated into the clinic for patients, it must first be rigorously tested and validated. For GVHD this involves transplanting stem cells into animals with the condition to test if inflammation can be minimized, and, if the results are favourable, testing the stem cells in a clinical setting. MSCs have reached this stage and trials are underway around the world to test the benefits for patients with GVHD.
In 2012, Health Canada gave a conditional approval for the use of a mesenchymal cell product, called Prochymal, for the treatment of steroid-resistant and/or immunosuppressant-resistant acute GVHD in pediatric patients. For this application, Prochymal may be used to treat advanced acute GVHD that affects any organ or acute GVHD that affects internal organs, such as the gastrointestinal tract and liver. The final approval of Prochymal depends on the results of clinical studies that are underway.
The road to finding a stem cell therapy for GVHD is paved with many challenges that will take time to overcome. But the wealth of information generated from labs around the globe is converging to help with the transition from basic research to the clinic.
Current research using mesenchymal stem/stromal cells
Researchers have made some interesting discoveries that are helping to shed light on the contradictory results coming from trials in Europe and America. Although the earliest American trials demonstrated that MSCs could play a role in treating acute GVHD, the more advanced Phase 3 trial (Prochymal) has shown little to no benefit. This situation is making researchers consider the logistics of MSC transplantation in more depth to see whether certain ways of selecting, handling, growing and freezing MSCs from lab to lab are affecting the outcome. There is also growing evidence that not all donated MSCs are the same because not everyone can activate them to the same extent. One way to address this would be to develop screening methods to distinguish the different types of donors so that only the most active MSCs are used as transplants.
Scientists agree that it will be crucial to distinguish the various MSC populations, in terms of their tissue of origin, and the ways in which they work in the laboratory, animal models and patients. This will help researchers to design better clinical trials, taking into account all the known factors that affect how MSCs function. It will also be important to discover ways to monitor MSCs and to track the clinical outcomes in patients who have received MSC transplants. To that end, experts have recommended that a patient registry compiling adverse side effects would be very useful for long term follow-up studies.
Although MSCs have burst onto the scene of biomedical research in the past decade, much work at the basic research level is still required before their potential as a therapy for GVHD and other diseases can be fully realized.
Current research using induced pluripotent stem cells
The revolutionary new technology for making induced pluripotent stem cells could someday provide a way to create patient-matched hematopoietic stem cells for transplantation. Japan’s Dr. Shinya Yamanaka discovered how to turn back the clock on adult skin cells and reprogram them to a younger, embryonic-like state.
A significant amount of work needs to be done before hematopoietic stem cells made from iPS technology can be used on the frontlines for patient care. Studies testing them in animals with blood disorders are underway but, as yet, there has been no demonstration of long-lasting effects. One of the difficulties is that the hematopoietic stem cells produced by iPS technology do not function like the normal counterparts. There are some who attribute this problem to the lack of a suitable niche, or microenvironment, to nurture the developing HSCs and much work is being done to find culture systems that better resemble the normal niche in the body.