Executive Summary 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. Reviewer Synopsis This proposal aims to cure autoimmune diseases using high dose allogeneic (unrelated or related) umbilical cord blood stem cell transplantation using a combination approach to maximize cell dose of CBT. An approach for increasing cell dose involving plasma depletion processing and direct infusion of plasma depleted cells has been reported to improved yield and engraftment. Double cord blood transplants will be used to further enhance engraftment. One patient has been treated successfully with this approach. Allogeneic HCT for blood diseases in patients who also have autoimmune disease has been associated with complete remission of the concomitant autoimmune disease. However, allogeneic SCT has high morbidity and mortality. Cord blood transplantation offers potential advantages, including immediate availability, reduced GvHD and less stringent HLA matching requirements. It is hypothesized that maximizing cell dose will improve the outcome of CBT. Reviewer One Comments Concept: Autoimmune diseases are a major health problem. The investigator provides a long list of autoimmune diseases that could potentially be treated with CBT. A non-autoimmune disease (amyotrophic lateral sclerosis) is also included in the list for reasons that are not clear. While it is true that many autoimmune diseases, particularly when severe, lack curative options, the investigator does not acknowledge the promise of a number of new biological therapies that are under evaluation. Furthermore, autologous transplantation after treatment with chemotherapy and lymphocyte depleting agents is only currently being explored for many of these diseases and may be curative in some settings. Since autologous transplantation is not associated with the risk of graft-versus-host disease, it deserves full exploration in order to identify which patients are least likely to benefit and in whom allogeneic transplantation should be considered. It may be argued that cord blood transplantation should not be the first type of transplant evaluated in the allogeneic setting, since the more conventional HLA-identical sibling donor transplant is associated with a lower risk of graft failure, infection and possibly graft-versus-host disease. Thus, 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. It seems unlikely that cord blood transplantation will be ready for evaluation within five years, given that these more basic studies are only just beginning. Thus, the concept may be somewhat premature. The PI’s plasma depletion processing of cord blood appears to have shown a good success rate in improving the cell yield of cord blood products and direct infusion of thawed units seems to result in further improvement, although it is unclear whether the 91% vs. 89% engraftment rate cited by the investigator is significantly different. Double cord blood transplantation appears to improve engraftment in several studies. However, the proposal does not address the severe problems with immune reconstitution and infection that have been encountered in cord blood transplantation studies. The investigator has evaluated his plasma-depleted cord blood product in a single patient with scleroderma. Success is reported in the application, though no details are provided and no publication is cited. The investigator has also conducted a large clinical study of unrelated HLA-mismatched cord blood transplantation for thalassemia, with good results. The investigator directs StemCyte, a company that maintains a large stem cell bank with donors from California, Washington, D.C., Ohio, and Georgia. While access to this bank is cited as a major advantage, the cord blood products are widely distributed through the NMDP, making it unclear how the investigator will be able to prioritize these products for his own use. Principal Investigator: Dr. Chow graduated from Harvard Medical School in 1995, then completed a residency and fellowship at UCLA Medical Center in Anatomic, Clinical and Gastrointestinal Pathology. In 1998 he founded StemCyte, of which he has served as chairman, president, and CEO, vice chairman (current position), EVP and Chief StemCyte Officer (current position), Cord Blood Bank Director and Global Medical Director (current position). He serves on the board of directors for a number of companies and foundations. He has published his cord blood processing techniques and his thalassemia results in peer-reviewed journals. He has a track record of translating basic and preclinical findings on cord blood stem cells into successful clinical studies which have become commercialized. These improvements include the plasma depletion and direct infusion procedures and unrelated cord blood transplantation for thalassemia. Dr. Chow has invented the key technologies, designed and planned the study, developed the team proposal and authored manuscripts and abstracts. Thus, he has succeeded in bringing together teams from multiple institutions and across national borders and dealing with regulatory issues. He seems well qualified to assemble the team and lead the development of the research plan. Planning Approach: The first step is considered to be identification of the appropriate potential project. Once this is identified, the team assembly will begin, and will include cord blood transplant physicians, statistical experts, regulatory experts, an institutional review board, cord blood processing and collection personnel, obstetricians, data managers and independent and external data auditors and referring rheumatologists. The multidisciplinary team will collaboratively develop a research plan and implement management. The many working collaborations already established by the PI will be of value in this project. Effective management structures have been developed for a previous project and a fair system for authorship is considered. Much of the coordination will be carried out through emails, conference calls and faxes, and meetings will be carried out at international conferences and symposia. Overall, the planning process is thoughtful, detailed and appropriately collaborative. Reviewer Two Comments Concept: Target disease: autoimmune disease (not well described). Rationale: empirical evidence that high-dose BMT may overcome AD. Proposal is to explore use of Cord Blood (CB) transplants. PI has experience with plasma depletion and direct infusion of cells without post thaw wash that increases cell yield. CB transplantation has less GVH and therefore would be an improved treatment. Uncertainty here is the characterization of AD. Which diseases are to be addressed? Is there better rationale for one versus another? The BMT field is sufficiently mature that the clinical studies, if planned appropriately, could go forward quite quickly as there is little new science or technology required. Principal Investigator: PI is Founder and Vice-Chairman of StemCyte, a commercial firm that has supplied CB from donors throughout the country. The PI has participated in major CB trials. He has the expertise to lead the studies. Planning Approach: The PI does not describe a disease team but rather the presumption is that he will identify suitable clinical collaborators with patients with Autoimmune Diseases (AD), most likely from his prior collaborators. This application would be much stronger if the PI provided more specific about how the planning would be accomplished (as this is the aim of this RFA). Also, there needs to be clarity on the nature of “AD”.