Periodic Reporting for period 1 - PHOENIX (NANOMEDICINE FOR ORGAN TRANSPLANTATION TOLERANCE (PHOENIX))
Okres sprawozdawczy: 2023-04-01 do 2024-09-30
Solid organ transplantation is the only option for millions of patients with end-stage organ failure. While transplantation success rates have improved in recent years, the requirement for life-long immunosuppression results in broad inhibition of the host’s immune system, exposing patients to unacceptable risks of cancer and infection due to unspecific immunosuppression as well as side effects of cardiovascular and metabolic diseases. These complications place physicians in a dilemma, balancing diminished immunosuppression with the high risk of rejection and graft loss on the one hand, and high risk of progression of infection and cancer on the other.
Therefore, there is an urgent need for therapies that induce immunological tolerance toward the graft, minimizing or possibly eliminating life-long immunosuppression – this is the promise of PHOENIX.
The immune response toward graft activates both graft-destructive T cells and graft-protective regulatory T cells (Tregs). The balance between effector T cells and Tregs dictates the ultimate outcome of the host’s immune response, whether tolerance or rejection.
The objective of PHOENIX is the development of a novel nano-immunotherapy consisting of nanoparticles (NPs) coated with protein complexes (ligand-loaded major histocompatibility complex (MHC) molecules) that re-program the host’s specific anti-graft immune cells into graft-tolerating regulatory cells. This will induce a tolerogenic environment, local to the transplanted organ, without systemic effects. PHOENIX builds on our published work on the re-programming of autoreactive T cell responses to mitigate autoimmune diseases and extends this approach to the suppression of graft rejection. The aim of PHOENIX is to preclinically validate this new approach in transplants of two organs (kidney and liver) in two animal species (mice and pigs), to provide robust evidence for future clinical trials.
The project opens the door to successful organ transplantation without life-long non-specific immunosuppression, benefiting millions of patients, healthcare system and society as a whole.
Therefore, there is an urgent need for therapies that induce immunological tolerance toward the graft, minimizing or possibly eliminating life-long immunosuppression – this is the promise of PHOENIX.
The immune response toward graft activates both graft-destructive T cells and graft-protective regulatory T cells (Tregs). The balance between effector T cells and Tregs dictates the ultimate outcome of the host’s immune response, whether tolerance or rejection.
The objective of PHOENIX is the development of a novel nano-immunotherapy consisting of nanoparticles (NPs) coated with protein complexes (ligand-loaded major histocompatibility complex (MHC) molecules) that re-program the host’s specific anti-graft immune cells into graft-tolerating regulatory cells. This will induce a tolerogenic environment, local to the transplanted organ, without systemic effects. PHOENIX builds on our published work on the re-programming of autoreactive T cell responses to mitigate autoimmune diseases and extends this approach to the suppression of graft rejection. The aim of PHOENIX is to preclinically validate this new approach in transplants of two organs (kidney and liver) in two animal species (mice and pigs), to provide robust evidence for future clinical trials.
The project opens the door to successful organ transplantation without life-long non-specific immunosuppression, benefiting millions of patients, healthcare system and society as a whole.
In this proposal we will advance the nano-immunotherapy to the field of solid organ transplantation.
MHC-based nanomedicines have been re-designed and re-built to induce local immunosuppression in solid organ transplantation. We are then validating the approach in a series of pre-clinical studies of two organs (kidney and liver), two animal species (mice and pigs) and three technical approaches (nanomedicines based on organ-specific epitopes, nanomedicines based on universal epitopes, and nanomedicines based on αGalCer glycolipid).
We are carrying out experiments testing and comparing ubiquitous PDC-E2 peptide and kidney specific uromodulin-based NPs in murine kidney and liver transplants. Specifically, donor or host MHCII molecules carrying PDC-E2 and uromodulin peptides have been directionally coated onto NPs to induce the formation of TR1 cells to inhibit effector T cells with direct or indirect/semidirect specificity, respectively. We will also evaluate the immunomodulatory effects of αGalCer/CD1d-NPs in murine and porcine liver transplant to ascertain whether liver-specific iNKT cells are re-programmed by αGalCer/CD1d-NPs and blunt liver allograft rejection. Following the completion of the above studies, we will analyse the data to identify the optimal approach to clinical therapy. After a fully capture of Regulatory requirement and based on their guidance, we will create a draft protocol for a first-in-human clinical trial with this immunotherapy in clinical kidney and liver transplantation.
PHOENIX commenced on 1 April 2023, in the first scientific step led by WP1, we commenced the project by engineering, optimising and producing novel murine kidney and liver transplantation -relevant pMHCII complexes, using PDC-E2 and uromodulin epitopes. For liver transplants, we have refined and produced murine and porcine CD1d/β2microglobulin complexes loaded with αGalCer. The murine kidney experiments have progressed well with good results and the murine liver transplant procedure is being optimised.
In the first half of the PHOENIX project, the initial set up from the perspective of communication and dissemination, data management and first considerations toward innovation management have been completed, as has preparatory work to establish the regulatory strategy roadmap for post-project. Preparations have been made to commence the porcine experiments, including scheduling and securing ethical approval.
MHC-based nanomedicines have been re-designed and re-built to induce local immunosuppression in solid organ transplantation. We are then validating the approach in a series of pre-clinical studies of two organs (kidney and liver), two animal species (mice and pigs) and three technical approaches (nanomedicines based on organ-specific epitopes, nanomedicines based on universal epitopes, and nanomedicines based on αGalCer glycolipid).
We are carrying out experiments testing and comparing ubiquitous PDC-E2 peptide and kidney specific uromodulin-based NPs in murine kidney and liver transplants. Specifically, donor or host MHCII molecules carrying PDC-E2 and uromodulin peptides have been directionally coated onto NPs to induce the formation of TR1 cells to inhibit effector T cells with direct or indirect/semidirect specificity, respectively. We will also evaluate the immunomodulatory effects of αGalCer/CD1d-NPs in murine and porcine liver transplant to ascertain whether liver-specific iNKT cells are re-programmed by αGalCer/CD1d-NPs and blunt liver allograft rejection. Following the completion of the above studies, we will analyse the data to identify the optimal approach to clinical therapy. After a fully capture of Regulatory requirement and based on their guidance, we will create a draft protocol for a first-in-human clinical trial with this immunotherapy in clinical kidney and liver transplantation.
PHOENIX commenced on 1 April 2023, in the first scientific step led by WP1, we commenced the project by engineering, optimising and producing novel murine kidney and liver transplantation -relevant pMHCII complexes, using PDC-E2 and uromodulin epitopes. For liver transplants, we have refined and produced murine and porcine CD1d/β2microglobulin complexes loaded with αGalCer. The murine kidney experiments have progressed well with good results and the murine liver transplant procedure is being optimised.
In the first half of the PHOENIX project, the initial set up from the perspective of communication and dissemination, data management and first considerations toward innovation management have been completed, as has preparatory work to establish the regulatory strategy roadmap for post-project. Preparations have been made to commence the porcine experiments, including scheduling and securing ethical approval.
PHOENIX is yet to publish any of the initial results achieved.