Periodic Reporting for period 2 - CAR ART (Chimeric Antigen Receptor to generate Alloantigen-specific Regulatory T cells and promote allograft tolerance)
Berichtszeitraum: 2018-11-01 bis 2019-10-31
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.
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.
During this period, we developed an immunocompetent mouse model of CAR Treg therapy. We analyzed the effect of donor-specific CAR Tregs on alloreactivity in naive, immunocompetent mice receiving skin allografts. We generated Tregs expressing an irrelevant or anti-HLA-A2-specific CAR and validated their function in vitro. CAR Tregs were administered to Bl/6 mice at the time of transplanting an HLA-A2+ Bl/6 skin graft. We observed that donor-specific CAR-Tregs, but not irrelevant-CAR Tregs, significantly delayed skin rejection, and diminished donor-specific antibodies (DSAs) and frequencies of DSA-secreting B cells.
These results have been presented at the Basic Sciences in Transplantation Meeting (Rotterdam, Netherlands, October 2018), American Transplant Congress (Seattle, USA, June 2018). They also have been presented to a transplant patients public at the Meeting of the Transplant Research Foundation (British Columbia, Canada July, 2018).
The approach has been discussed in two review articles (Sicard A, Boardman DA, Levings MK. Curr Opin Organ Transplant. 2018 Oct and Sicard A, Levings MK, Scott DW. Am J Transplant. 2018 Jun).
Finally, the results of this study have been published in the American Journal of Transplantation (Sicard et al .Am J Transplant 2020 Jun).
These results have been presented at the Basic Sciences in Transplantation Meeting (Rotterdam, Netherlands, October 2018), American Transplant Congress (Seattle, USA, June 2018). They also have been presented to a transplant patients public at the Meeting of the Transplant Research Foundation (British Columbia, Canada July, 2018).
The approach has been discussed in two review articles (Sicard A, Boardman DA, Levings MK. Curr Opin Organ Transplant. 2018 Oct and Sicard A, Levings MK, Scott DW. Am J Transplant. 2018 Jun).
Finally, the results of this study have been published in the American Journal of Transplantation (Sicard et al .Am J Transplant 2020 Jun).
Our findings have important implications for the clinical development of CAR Treg therapy in transplant patients and possibly the minimization of immunosuppressive drugs in these patients.
We have demonstrated for the first time that CAR Treg therapy prevents the humoral anti-donor response and prevents rejection in naive immunocompetent recipients. The objective for the rest of the project is to test if mice treated with donor-specific CAR Tregs also have weaker recall antibody response against donor-antigens and have a normal antibody response against irrelevant antigens (absence of global immunosuppression). We also plan to test donor-specific CAR Tregs in recipients previoulsy sensitized against donor antigens.
We have demonstrated for the first time that CAR Treg therapy prevents the humoral anti-donor response and prevents rejection in naive immunocompetent recipients. The objective for the rest of the project is to test if mice treated with donor-specific CAR Tregs also have weaker recall antibody response against donor-antigens and have a normal antibody response against irrelevant antigens (absence of global immunosuppression). We also plan to test donor-specific CAR Tregs in recipients previoulsy sensitized against donor antigens.