Objective
To advance immune tolerance technologies for use in people with T1D who undergo transplantation of stem cell-derived islets, with the objective to eliminate the need for chronic immunosuppression in transplant recipients.
More specifically, the objective of the proposed work is to adapt tolerance induction by donor antigen delivery on immunomodulated cells to transplantation of stem cell-derived islets.
Background Rationale
Transplantation of insulin-secreting pancreatic islet cells has been investigated for several decades as an alternative treatment option for people with type 1 diabetes. Until recently, these insulin-secreting cells have been isolated from the pancreases of deceased organ donors. Transplanted islet cells have restored tight blood sugar control, protection from dangerously low blood sugar levels, and in some recipients, insulin independence.
Despite these achievements, only very few patients with type 1 diabetes were treated with islet cell transplants, mainly for two reasons. First, the availability of suitable pancreases from organ donors has been very limited, and second, to prevent rejection of transplanted islets, long-term treatment with drugs that suppress the immune system was required.
Nevertheless, the progress made in transplanting islets from deceased donors has spurred academic and commercial initiatives to generate an unlimited supply of new islet cells from stem cells. These efforts have recently culminated in the restoration of insulin independence in ongoing trials following transplantation of stem cell-derived islets in immunosuppressed recipients with type 1 diabetes. The clinical testing has advanced very rapidly with excellent outcomes in recipients, leading to conversion of the ongoing Phase 1/2 trial to a pivotal Phase 1/2/3 licensure trial. These developments are remarkable and suggest that an unlimited and approved source of islets will soon become available for the treatment of diabetes.
Progress has also been made with respect to overcoming the second limitation of islet transplantation; i.e., the reliance on chronic and generalized immunosuppression. Several of the strategies in development to overcome the need for immunosuppression have been advanced to late preclinical or early clinical testing. Our research team has succeeded in attaining long-term survival of transplanted donor islets in diabetic monkeys after all immunosuppressive drugs were discontinued (considered a breakthrough when first reported). To induce immune tolerance to transplanted islets, the monkey recipients were given specially prepared cells from the donor monkeys to prepare the recipients’ immune system to accept and tolerize the transplanted islets.
Description of Project
Transplantation of insulin-secreting pancreatic islet cells has been investigated for several decades as an alternative treatment option for people with type 1 diabetes. Until recently, these insulin-secreting cells have been isolated from the pancreases of deceased organ donors. Transplanted islet cells have restored tight blood sugar control, protection from dangerously low blood sugar levels, and in some recipients, insulin independence.
Despite these achievements, only very few patients with type 1 diabetes were treated with islet cell transplants, mainly for two reasons. First, the availability of suitable pancreases from organ donors has been very limited, and second, to prevent rejection of transplanted islets, long-term treatment with drugs that suppress the immune system was required.
Nevertheless, the progress made in transplanting islets from deceased donors has spurred academic and commercial initiatives to generate an unlimited supply of new islet cells from stem cells. These efforts have recently culminated in the restoration of insulin independence in ongoing trials following transplantation of stem cell-derived islets in immunosuppressed recipients with type 1 diabetes. The clinical testing has advanced very rapidly with excellent outcomes in recipients, leading to conversion of the ongoing Phase 1/2 trial to a pivotal Phase 1/2/3 licensure trial. These developments are remarkable and suggest that an unlimited and approved source of islets will soon become available for the treatment of diabetes.
Progress has also been made with respect to overcoming the second limitation of islet transplantation; i.e., the reliance on chronic and generalized immunosuppression. Several of the strategies in development to overcome the need for immunosuppression have been advanced to late preclinical or early clinical testing. Our research team has succeeded in attaining long-term survival of transplanted donor islets in diabetic monkeys after all immunosuppressive drugs were discontinued (considered a breakthrough when first reported). To induce immune tolerance to transplanted islets, the monkey recipients were given specially prepared cells from the donor monkeys to prepare the recipients’ immune system to accept and tolerize the transplanted islets.
The primary objective of the proposed work is to adapt this tested technology for tolerance induction to transplanted stem cell-derived islets in recipients with type 1 diabetes. Work towards that end will require the substitution of a suitable, stem cell-derived, tolerance-inducing cell for the immune-modified cells previously prepared from the deceased organ donor. Our proposed research will evaluate important attributes of the tolerance inducing cells that are prepared from stem cells. First and foremost, we will determine the ability of these cells to condition the immune system of the recipient to accept and tolerize stem cell-derived islet transplants without the need for immunosuppression. Before clinical trials testing this technology can be considered, we will have to document in studies in the immunology laboratory that the tolerizing cells prepared from stem cells can protect islets prepared from the same stem cells from rejection and recurrent autoimmunity.
The significance of this work to type 1 diabetes lies expressly in the application of a tested immune tolerance technology to the particular needs of stem cell-derived islet transplants in patients with type 1 diabetes, thereby enhancing the benefit-risk profile and utilization of stem cell-islet transplants for the purpose of improving the lives of individuals with type 1 diabetes.
Anticipated Outcome
We anticipate that the success of tolerance induction to primary islets (isolated from a donor pancreas) translates to tolerance induction to stem cell-derived islets, with the implication of a substantially improved benefit-risk profile of transplantation of stem cell-derived islets in recipients afflicted with T1D.
We further anticipate our assays to identify islet cell transplant candidates at risk of T1D recurrence in transplanted islets, thereby opening the possibility of tailored treatment strategies that will address ultimately improve outcomes in patients undergoing islet cell replacement therapies.
Relevance to T1D
The significance of this work to type 1 diabetes lies expressly in the application of a tested immune tolerance technology to the particular needs of stem cell-derived islet transplants in patients with type 1 diabetes, thereby enhancing the benefit-risk profile and utilization of stem cell-islet transplants for the purpose of improving the lives of individuals with type 1 diabetes.