Disease Team Therapy Development - Research
Stem Cell Use:
Adult Stem Cell
Successful stem cell therapy requires the replacement of diseased or dysfunctional stem cells with healthy ones. These healthy stem cells can come from either a donor or can be stem cells that are modified by gene therapy techniques. One important step in this process of repair and replacement is to eliminate the existing diseased cells so that physical space is created for the healthy ones, and competition for environmental factors that nurture and support the stem cells are removed. The oldest and most commonly used form of stem cell therapy is bone marrow transplantation (BMT). Thousands of patients undergo BMT yearly to treat cancers or disorders of blood formation. Bone marrow contains mixtures of cells, but only a minority are the blood forming stem cells, which are critically important as only stem cells can permanently generate new blood and immune cells. In a BMT, stem cells from a donor replace the recipient’s diseased stem cells. Currently, the only way to eliminate the patient’s own blood forming stem cells is to treat the recipient to accept donor cells with toxic agents such as radiation and chemotherapy. Our team will focus on the treatment of a disorder in children called severe combined immune deficiency (SCID). SCID children are born without a functional immune system and are therefore extraordinarily susceptible to serious infections. If children with SCID are not treated, most die by the age of two. BMT is the only established cure for this disease. Unfortunately, the likelihood of successful cure is reduced by the way transplants are currently performed, using toxic treatments to prepare the children to accept the donor cells. We will test an antibody (a type of protein) that recognizes a molecule called CD117 present on blood forming stem cells and leads to their elimination. When used in mice, this treatment enabled excellent donor stem cell engraftment and cured mice with a condition equivalent to human SCID with minimal side effects. We propose to test an antibody that targets human CD117 to safely prepare children with SCID to accept blood forming stem cells from a donor. Based on the animal studies we expect this antibody will allow engraftment of stem cells at high levels, rapidly replacing diseased blood cells with healthy blood cells. Such a result would mean safer and better outcomes for these patients. Success in this study would have impact far beyond a superior treatment for SCID. If the antibody treatment results in a stronger blood system originating from a donor in SCID patients, this result would prove that the antibody could be used to optimize engraftment of gene-therapy modified cells and could be applied to the treatment of many other diseases that need a BMT. These diseases include, but are not limited to sickle cell anemia, thalassemia, and Fanconi’s anemia; autoimmune diseases like diabetes and multiple sclerosis; and cancers that originate from the blood system such as leukemias and lymphomas.
Statement of Benefit to California:
Diseases of the blood and the immune system plague thousands of Californians and millions of people world-wide. These diseases are quite diverse, ranging from blood diseases such as sickle cell anemia and beta thalassemia, to immune diseases such as severe combined immunodeficiency, HIV, and autoimmune disease including type I diabetes and multiple sclerosis. Current therapies do not fully control the symptoms of these diseases, leaving severe morbidity and early mortality as ongoing consequences. For the health of the citizens of California, both physical and financial, we need to develop cures, rather than marginally effective treatments, for a variety of these devastating blood and immune illnesses. Hematopoietic stem cell (HSC) transplantation possesses the ability to provide a life-long cure for all of these diverse diseases, as it allows for the replacement of defective HSC. Although effective, the use of this form of treatment is severely limited because of the current need to administer chemotherapy or radiation prior to the transplant to permit engraftment of donor stem cells. The transplant procedure itself carries a risk of death for ~10-20% of patients, and there are long-term toxicities associated with chemoradiation such as infertility, secondary malignancies, endocrine dysfunction, organ damage, and in children, mental and physical growth impairment. By developing a novel, non-toxic antibody-based conditioning method, HSC transplants could be expanded to the treatment of non-life threatening yet debilitating diseases that are currently not transplanted due to the associated toxicities. We have achieved this goal with an antibody in mice and have identified a similar agent for use in patients. We aim to begin safely treating patients that suffer from severe combined immunodeficiency (SCID), a diverse disorder that is caused by defects in HSCs. While the incidence of SCID has been thought to be rare, preliminary results of newborn screening in California suggest the incidence is 1/30,000 newborns. In addition, a number of previously treated patients with SCID who did not engraft with donor stem cells are now developing immune failure. The clinical trial to be performed will treat immunodeficient patients from across the state of California through the network of institutions incorporated into this disease team of world-renowned stem cell and transplantation experts. After successfully treating patients with SCID, we plan to expand this conditioning technique to other diseases, and hopefully pave the way for safe transplantation of genetically modified HSC, thereby expanding stem cell transplantation in California tremendously. We hope this novel conditioning regimen will result in a direct benefit to patients who suffer from blood and immune diseases, as well as create definitive treatments that will lead to a reduction of the massive health care burden these diseases inflict on patients and their families in California.
The focus of our Disease Team is on the treatment of a lethal genetic disease in children called severe combined immunodeficiency (SCID) also known as the “bubble boy” disease. Children with SCID are born without a functional immune system and therefore are extraordinarily vulnerable to serious infections. If untreated, most of these children die by the age of two. Transplantation of blood forming stem cells is the only established cure for SCID. Unfortunately, the current ways of performing these transplantations is imperfect, so that a percent of the transplants fail. There are two major problems that are encountered in the procedure that reduces the success of the transplants. The first problem occurs because the children undergo treatments to eliminate their own blood forming stem cells so that they will accept the stem cells of healthy donors. The methods available to accomplish this stem cell depletion are toxic chemotherapies that have side effects that develop shortly after transplant or after many years. These negative side effects include, but are not limited to toxicity to the liver, delays in development and effects on the brain. Because such treatments are toxic, some children are infused with donor cells without stem cell depletion. In those cases, a percentage have relatively poor immune function. The second problem develops as a result of the cell content of the donor grafts that contain the blood forming stem cells. Healthy donor grafts contain not only the life-saving stem cells but have contaminating cells (T cells) that have the potential to attack and destroy some of the tissues in the transplanted patients. Attack of recipient tissues by donor T cells is a syndrome called graft-vs-host disease. In worse case scenario the child dies as a result of the toxicities associated with the transplant procedure. Our Team aims to eliminate these complications of transplantation. To address the problem of toxic therapies needed to make space for donor cells, our approach is to replace these regimens with a biologic reagent. The biologic agent we are testing is an antibody that recognizes a molecule called CD117. CD117 is present on the surface of blood forming stem cells. In rodent studies we have observed that targeting blood forming stem cells with an anti-CD117 antibody safely depletes recipient cells, thereby allowing the donor stem cells to engraft. There is no other biologic agent available for human use that can specifically deplete the blood forming stem cells. In the last year, we continued the development of an anti-CD117 antibody that binds human cells. We made the exciting observation that in large animals that express CD117 molecules similar to humans, the intravenous administration of the anti-CD117 antibody results in rapid depletion of blood forming stem cells, similar to what we have observed in mice. The depletion of stem cells is transient since the animals recover their stem cells after a few weeks. But the effect appears to be long enough that transplanted donor cells will have a chance to takeover. To eliminate the problem of graft-vs-host disease, we have simultaneously produced two other antibodies, called anti-CD34 and anti-CD90. These antibodies label human blood forming stem cells and allow the stem cells to be separated from other potentially harmful cells including T cells. Blood forming stem cells are a rare population comprising only one in several thousands of cells in a standard graft. In the last year we have successfully produced anti-CD34 and anti-CD90 suitable for use to purify stem cells from human grafts. In pilot studies, we have been able to produce purify stem cells away from the other graft cells so that they comprise >97% of the infused product. Our progress this year, demonstrates that we are well on our way to the initiation of our proposed clinical trial for the treatment of SCID. Children with SCID were chosen as the target population because they are highly sensitive to the negative effects of chemotherapy and, given our existing knoweldge of transplants in these patients, they are the patient group that will allow us to most clearly measure the effect of the anti-CD117 antibody. However, the implications of our study are broad. The tens of thousands of other patients that are cured by blood forming stem cell transplantation each year have the same two potential complications as children with SCID – toxicity from the regimens they need for the donor cells to take, and the possibility of graft-vs-host disease. Transplant patients include those with incurable cancers, sickle anemia, thalassemia, and many others. Blood forming stem cell transplantation can also be curative for autoimmune diseases such as childhood diabetes, multiple sclerosis, and lupus erythematosus. Thus, success in our study will open the door for the use of this approach by markedly improving the way this important form of stem cell therapy is done in the future.