CAR ART · Chimeric Antigen Receptor to generate Alloantigen-specific Regulatory T cells and promote allograft tolerance
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2017-11-01 → 2019-10-31
- EU contribution
- €171,349
- Participants
- 2
- Scheme
- MSCA-IF-GF
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Results in brief
Chimeric Antigen Receptor to generate Alloantigen-specific Regulatory T cells and promote allograft tolerance
Pathologies linked to end-stage organ failure represent the second cause of morbi-mortality worldwide and have major socio-economic consequences. Transplantation is the best therapeutic option because it improves patients’ survival and quality of life. Because the donor is genetically different from the recipient, immune system of the latter inevitably recognizes donor-specific determinants expressed by the graft. The immune response that develops against donor determinants is responsible for tissue damages, a process called rejection. Organ damage is caused either by T lymphocytes (cellular rejection) or by donor-specific antibodies (antibody-mediated rejection). Prevention of rejection currently relies upon immunosuppressive drugs, which induce a global immunosuppression and increase the risk of infectious diseases and malignancies. The overall objective of the project was to test if an innovative method of cell therapy, named Chimeric Antigen Receptor (CAR) regulatory T cells (Tregs) therapy, could be used to prevent allograft rejection and minimize immunosuppressive drugs in transplant recipients. In this approach, recipient’s Tregs cells, which have the natural ability to induce tolerance, are genetically engineered in vitro to express a CAR that recognizes donor-specific determinants and are injected to patients. In conclusion, this action has allowed to demonstrate for the first time that CAR Treg therapy prevents rejection in immunocompetent allograft recipients. This has important implications for the clinical development of CAR Treg therapy in transplant patients and possibly the minimization of immunosuppressive drugs in these patients.
Data: CORDIS, © European Union
Project objective
Organ transplantation is the best life-supporting treatment for terminal organ failure. Graft survival is however limited by rejection, a destructive process resulting from the response of recipient’s immune system against donor specific alloantigens. Prevention of rejection currently relies on immunosuppressive drugs that lack antigen specificity and therefore increase the risk for infections and cancers. Induction of donor-specific tolerance would provide indefinite graft survival without morbidity and therefore represents the Grail of transplant immunologists. Tolerance has been obtained in experimental models with adoptive transfer of ex vivo-expanded CD4+FOXP3+ regulatory T cells (Treg). Preclinical studies have indicated that the potency and specificity of Treg therapy could be markedly enhanced by the use of Treg specific for donor alloantigens. Translation of this approach in the clinic has been hindered by the lack of clinically applicable strategies to generate sufficient numbers of potent donor-specific Tregs. To overcome this limitation, Pr Levings’ group (Child and Family Research Institute, Vancouver, Canada) has just recently successfully used chimeric antigen receptor (CAR) technology to redirect the specificity of human Treg toward a transplant-relevant antigen. The objective of the 2-year action is to assess the impact of alloantigen-specific CAR Treg on cellular and humoral alloimmune responses and their ability to promote allograft tolerance. The outgoing phase of the global fellowship will be performed in Pr Levings’ lab, and the return phase in Pr Glaichenhaus’ team (Institut de Pharmacologie Moléculaire et Cellulaire, Valbonne, France) where the researcher will get in few years a tenured position. The main ambition of the program is to provide key data for the development of a clinical trial with CAR Tregs in kidney transplantation.
Original text from CORDIS.
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Data: CORDIS, © European Union