Executive Summary The applicant proposes to develop a treatment for Type I diabetes that involves the simultaneous transplant of three different cell types from the same donor into the patient. The cells to be transplanted are mesenchymal stem cells (MSC), which have immune modulatory properties and tissue repairing abilities, bone marrow cells and pancreatic islets. The idea behind this approach is that MSC can facilitate chimerism and help induce tolerance to allogeneic islets that are co-transplanted with the MSC, thereby avoiding high dose irradiation and Graft versus Host Disease (GVHD). The combination of MSC and bone marrow cells is thought to be necessary for mixed chimerism to take place. A non-myeloablative preconditioning regimen for the recipient is proposed to suppress inflammatory responses. The reviewers liked this idea in principle, but had reservations regarding feasibility to translate the concept to humans. Preliminary data in rodents is promising, shows this protocol works, and justifies the repeat of similar experiments in more relevant animal models as proposed. However, conduct of a clinical program was not discussed in the application, and reviewers found it difficult to understand how this protocol would function in humans for several reasons. First, the logistics of this approach would preclude sorting and expansion of the MSC before transplantation. Second, the unpredictable timing of when the human pancreas would be available for isolation would make the proposed preconditioning treatment difficult. As a result of this discussion, one reviewer concluded that the proposed approach is therefore impossible to implement in humans. Finally, the stem cell aspect of this proposal seems to be limited to the MSC to be co-transplanted with allo-islets. While this may prove beneficial over standard immunosuppression used in islet transplants, it is not furthering the use of stem cells for disease management. There will still be a lack of deceased donor pancreata to obtain islets for transplants. The qualifications of the principal investigator (PI), an endocrinologist, are very good, albeit the publication record is not extensive. S/he is the director of a department and of the clinical islet transplantation program at the home institution. This provides a unique opportunity to implement the ideas generated during the proposed planning. The PI has significant experience with clinical and translational research and has access to islets, patients for islet transplants and a Good Manufacturing Practices (GMP) facility. S/he has developed and maintained an outstanding annual meeting in diabetes and is experienced in organizing and leading multi-investigator research collaborations. The proposed approach seems to be an extension of the PI’s current research. A planning team is named including internal members with expertise in islet isolation and transplantation, bone marrow transplantation, study design, and regulatory affairs. Selection of a clinically-relevant animal model center is outlined. Two collaborators for developing immunological and metabolic assays for animal models are named as well as an external advisory board of noted experts on transplantation, transplantation immunology and FDA requirements. The detailed time line for this planning seems ambitious but possible. In summary, although the panel felt that the PI was qualified to lead the proposed multidisciplinary team, reviewers had reservations regarding the feasibility to translate this complex clinical regimen to humans, and felt that it would not significantly advance the use of stem cells for disease management. Reviewer One Comments Concept: The concept is to transplant mesenchymal stem cells (MSC) (which have immune modulatory properties and tissue repairing abilities), bone marrow cells and pancreatic islets from the same donor simultaneously in order to induce islet allograft tolerance without high dose irradiation and without Graft versus host disease (GVHD). The combination of MSC and bone marrow cells was thought to be necessary for mixed chimerism to take place. There would be a non-myeloablative preconditioning regimen for the recipient consisting of antilymphocyte serum, low dose total body irradiation and short-term treatment with 15-deoxyspergualin to suppress inflammatory response (suppresses activation of T-cells). The preliminary data that in rodents this protocol works support the repeat of similar experiments in non–human primates as proposed. Even so, it is difficult to understand how this protocol would function in humans since the unpredictability of when the human pancreas would be available for isolation would make such pretreatment difficult as well as not being able to sort and expand the MSC before transplant. Thus the proposal is more for testing mixed chimerism using freshly isolated bone marrow (that includes MSCs) from same donor as the islets. While this may prove beneficial over standard immunosuppression used in islet transplantation, it is not furthering the use of stem cells for disease management; there will still be a lack of pancreata for cadaveric islets for transplant. Thus this may be more appropriate for an ITN or ICR trial than a stem cell trial. Principal Investigator: Dr. Kandeel is an endocrinologist and Director of the Department of Diabetes, Endocrinology and Metabolism at City of Hope and Associate Clinical Professor at UCLA. Additionally, he is the Director of the Southern California Islet Cell Resource Center and has developed and maintained one of the outstanding annual meetings in diabetes (The Rachmiel Levine Symposium). He is experienced in organizing and leading multi-investigator research collaborations. Planning Approach: A planning team is named including internal members with expertise in islet isolation and transplantation, bone marrow transplantation, study design, and regulatory affairs. A selection of a non–human primate center is outlined. Two collaborators for developing immunological and metabolic assays for non-human primates are named as well as an external advisory board of noted experts on transplantation, transplantation immunology and FDA requirements. The detailed time line for this planning seems ambitious but possible. Reviewer Two Comments Concept: Concept/ Rationale. This proposal is centered on the idea that mesenchymal stem cells (MSC) can facilitate chimerism and help induce tolerance to islets that are co-transplanted with the MSC. The authors propose to develop techniques to transplant donor MSC along with the islets and donor bone marrow. This regimen has been shown to be effective in Lewis rats. The author proposes to use (in the animal studies) non-myeloablative, low dose (3-5 Gy) total body irradiation, antilymphocyte antibodies and immunosuppressive drugs to establish chimerism. How a clinical program would be conducted was not discussed. The stem cell aspect seems to be limited to the MSC to be co-transplanted with allo-Islets. The PI is director of the SC-ICRC and has access to islets, patients for islet transplants and the GMP facility which is a positive for this application. Maturity: The concept of MSC co-transplantation is a very hot topic, with promising results mainly in hematopoietic malignancies. The studies with rodents presented here were preliminary but promising. The movement of this technology to clinical application would seem to require that the donor bone marrow, islets and MSC be used. It is not clear how one could expand the MSC in time to transplant along with the donor islets. Considerable organization will be required to get all three tissues from the same donor. Also, since mild to complete myeloablative treatment may be needed for this regimen, careful consideration of every aspect of this project must be considered. Significance. Moderate to high Principal Investigator: Qualifications. Dr. Kandeel’s qualifications are very good. Although his publication record is not extensive, he is director of the dept of Diabetes, Endocrinology and Metabolism, and the Southern California Islet Cell Resource Center (SC-ICRC) and the clinical islet transplantation program at City of Hope. As director of the SC-ICRC, this provides a unique opportunity to implement ideas generated during the proposed research. Dr. Kandeel has significant experience with clinical and translational research and has access to a GMP facility. Planning Approach: The approach seems to be an extension of the PI’s current research and will be conducted mostly by his internal collaborators with input from external advisors. The external advisors listed are highly qualified (David Harlan, David Sachs, Ali Naji, Bernhard Hering, Darin Weber). Other key collaborators associated with a non-human primate center were listed.