Right Column

DT1-00699-1: Feasibility and benefit-risk ratio of high cell dose allogeneic umbilical cord blood stem cell transplantation as a curative stem cell therapy for severe forms of autoimmune diseases

Recommendation: Not recommended for funding

Public Abstract (provided by applicant)

The proposed research will directly contribute to the development of related and unrelated donor umbilical cord blood stem cell transplantation (CBT) as a curative stem cell therapy with potentially acceptable benefit-risk ratio for patients suffering from the myriad of severe forms of autoimmune diseases (AD) for which no satisfactory treatment is currently available. These diseases include but are not limited to scleroderma, rheumatoid arthritis, multiple sclerosis, amyotrophic lateral sclerosis, Crohn's disease, ulcerative colitis, type I diabetes mellitus, juvenile idiopathic arthritis, dermatomyositis, mixed connective tissue disease, Behcet, ankylosing spondylosis, Sjogren's syndrome and psoriasis. The proposal will demonstrate the feasibility of this approach in achieving a permanent cure for patients with AD, and assess the benefit-risk or survival-mortality ratio of this approach. CBT is the latest form of stem cell transplantation which first gained proof of concept in a Fanconi's Anemia patient in 1998 (Gluckman et al. NEJM). Since then, it is estimated that over 10,000 such transplants have been performed worldwide for patients with both malignant and non-malignant disorders. Like other stem cell transplantation (SCT) such as bone marrow or peripheral blood transplantation, unrelated or related donor CBT can theoretically achieve a cure for AD patients by removing the offending autoimmune immune system and replacing it with one that will not attack the host. This approach gained proof of concept when AD patients with diseases such as leukemias achieved complete remission of their AD when SCT was performed for their leukemias. Unlike most approaches to the treatment of AD, SCT treats the underlying cause of the disease and not the symptoms, thus it is able to achieve a cure. Unfortunately, unrelated SCT is a highly risky procedure with an average 1-year mortality is around 53.2% for the 6,265 patients transplanted in the US (NMDP 2005 Transplant Center Directory) and ~40% for non-malignant diseases, which makes the procedure unacceptable for patients. Recently, CBT has made significant advances and shown to achieve outstanding survival in patients with non-malignant indications when high cell doses are used, such as thalassemia (Jaing et al. 2007) and Krabbe's disease (Escolar NEJM 2005 ). By taking a similar high cell dose CBT approach, it is anticipated that superior survival and cure rates may be achieved such that this may be one of the viable options for patients suffering from severe forms of AD.

Statement of Benefit to California (provided by applicant)

If successfully carried and with the anticipated results achieved, the proposed research will benefit California and its citizens in numerous ways. 1. Most importantly, California patients with autoimmune diseases will benefit from the availability of a curative stem cell therapy option. These diseases include scleroderma, rheumatoid arthritis, multiple sclerosis, amyotrophic lateral sclerosis, Crohn's disease, ulcerative colitis, type I diabetes mellitus, juvenile idiopathic arthritis, dermatomyositis, mixed connective tissue disease, Behcet, ankylosing spondylosis, Sjogren's syndrome, psoriasis etc... Currently, there are no good treatment options for many of these patients, especially the ones with severe forms of these diseases. A curative option will extend their survival significantly 2. These diseases impact adversely on the quality of life of these patients and their families. A cure will greatly improve their quality of life. 3. Severe chronic diseases such as autoimmune diseases exact a heavy financial burden on society in numerous ways. These debilitating theses costs billions of dollars each year on the economy of the State in terms of medical costs and lost productivity. A curative option will save billions of dollars for California and greatly improve the productivity and lives of these patients and their families. 4. Obviously, the clinical benefit of a cure for autoimmune diseases does not stop at the borders of California, but will extend to patients around the world, which will enhance California's reputation as an entrepreneurial developer and pioneer of stem cell therapy. This will help California attract and retain talented stem cell researchers and scientists to work in the academic or industry sectors of the State. 5. Currently, thousands of cord blood transplants are performed annually with an outstanding safety and efficacy record, which means that this is an approach that can be translated clinically and commercially in a few years, relatively quickly compared to many of the other stem cell therapies that are proposed. It is important to note that patients with autoimmune diseases can be transplanted today at numerous centers around the world. 6. Moreover, since the project principal investigator has already achieved proof of concept in an autoimmune disease patient using the approaches outlined in this proposal and has used similar approaches to demonstrate superior patient survival in other non-malignant disease models, this project has excellent probability in demonstrating feasibility and achieving acceptable benefit-risk ratio. 7. Since most of the funding for CIRM appear to be earmarked for embryonic stem cell research, funding of projects involving non-embryonic stem cells, such as cord blood, will be help achieve a balanced approach to funding stem cell research. 8. This proposal will create quality jobs for California stem cell transplant centers and companies.

Review

Allogeneic stem cell transplantation (SCT) for blood diseases in patients who also have autoimmune diseases (AD), has been associated with complete remission of the concomitant autoimmune disease. However, allogeneic SCT is not without high morbidity and mortality. The primary goal of this proposal is to establish clinical proof of concept that the autoimmune diseases (AD) can be cured using high dose allogeneic (unrelated or related) umbilical cord blood stem cell transplantation. Cord blood transplantation (CBT) offers potential advantages, including immediate availability, reduced graft versus host disease (GvHD) and less stringent HLA matching requirements. However, use of umbilical cord blood in stem cell transplantation is limited because of relatively low yield of stem cells in umbilical cord blood. Some technical advances have been made in recent years to increase the yield by plasma depletion and by double cord blood transplantation (combination approach). It is hypothesized in the proposal that maximizing cell dose will improve the outcome of CBT.

There was general agreement among the reviewers that autoimmune diseases represent a significant unmet medical need. However it was felt that the concept of the use of allogeneic umbilical cord blood for the autoimmune disease may be somewhat premature at this stage, and that it was unlikely that cord blood transplantation will be ready for clinical evaluation within five years. Specific weaknesses of the proposal were identified. A major criticism of the proposal was the lack of a specific disease which this program will target. While the investigator has evaluated the plasma-depleted cord blood product in a single patient with scleroderma and success is reported in the application, no details are provided and no publication is cited, so it was difficult to assess maturity of the concept. Reviewers also noted that the application does not acknowledge the promise of a number of new biological therapies that are under evaluation in this patient population, including autologous transplantation after treatment with chemotherapy and lymphocyte depleting agents which may be curative in some settings. It is reasonable to expect that initial trials of this unexplored therapeutic approach should most appropriately be performed with HLA-identical sibling transplants in patient groups who have been shown to be unlikely to respond to autologous transplantation. Finally, the proposal does not address the severe problems with immune reconstitution and infection that have been encountered in cord blood transplantation studies.

The PI was viewed as a major strength of the proposal. Reviewers noted that PI has a track record of translating basic and preclinical findings on cord blood stem cells into successful clinical studies which have become commercialized. He/she has succeeded in bringing together teams from multiple institutions and across national borders and dealing with regulatory issues and seems well qualified to lead the development of the research plan. Reviewers were divided in their opinions about the robustness of the planning process, but ultimately agreed that the entire application would be stronger had the PI addressed the target autoimmune disease.

In summary, the panel did not recommend this application for funding, given the lack of a named disease target and the failure to consider many of the clinical issues in taking the potential therapy to the clinic.

The following Working Group members had a conflict of interest with this application and were therefore recused from participating in review of, discussion of, and voting on the application:

• Heimfeld, Shelly
• Kurtzberg, Joanne