Chimeric Antigen Receptor (CAR) Regulatory T-Cells in Solid Organ Transplantation

Abstract

Solid organ transplantation is the treatment of choice for various end-stage diseases, but requires the continuous need for immunosuppression to prevent allograft rejection. This comes with serious side effects including increased infection rates and development of malignancies. Thus, there is a clinical need to promote transplantation tolerance to prevent organ rejection with minimal or no immunosuppressive treatment. Polyclonal regulatory T-cells (Tregs) are a potential tool to induce transplantation tolerance, but lack specificity and therefore require administration of high doses. Redirecting Tregs towards mismatched donor HLA molecules by modifying these cells with chimeric antigen receptors (CAR) would render Tregs far more effective at preventing allograft rejection. Several studies on HLA-A2 specific CAR Tregs have demonstrated that these cells are highly antigen-specific and show a superior homing capacity to HLA-A2+ allografts compared to polyclonal Tregs. HLA-A2 CAR Tregs have been shown to prolong survival of HLA-A2+ allografts in several pre-clinical humanized mouse models. Although promising, concerns about safety and stability need to be addressed. In this review the current research, obstacles of CAR Treg therapy, and its potential future in solid organ transplantation will be discussed.

The potential of regulatory T cell-based therapies for alopecia areata

“…It should be pointed out that choosing the appropriate costimulatory domain is also crucial. The costimulatory domains of CAR-T reg cells currently used are the same as those used in conventional CAR-T cells, but they could result in different effector functions ( 150 ). A typical example is that 4-1BB may reduce the suppressive function of CAR-T reg cells ( 151 , 152 ).…”

Combining Treg Therapy With Donor Bone Marrow Transplantation: Experimental Progress and Clinical Perspective

“…In the meantime, Treg products are being further developed. Treg bearing a donor-specific chimeric antigen receptor are more potent than polyclonal Treg 45,[47][48][49]93,94 and is currently being tested in kidney and liver transplant trials (NCT04817774 and NCT05234190). [95][96][97] Besides the generation of CAR Treg, which are able to recognize antigens directly without the need for presentation by MHC, the possibility of engineered T-cell receptors on Treg is studied, which can target antigens via antigen-MHC-peptide complexes.…”

Foxp3+ regulatory T cell therapy for tolerance in autoimmunity and solid organ transplantation

“…MLR assays with a Treg to responder cell ratio of (1:10) to (1:250), demonstrated the presence of significant recipient cell growth inhibition induced by antigen specific Tregs ( 126 ). The benefit of using antigen specific Tregs as compared to polyclonally expanded Tregs is in their ability to induce highly specific immunosuppression with fewer numbers of cells; however, assumptions about the absence of off-targeted immunosuppression by antigen specific Tregs cannot be assumed ( 138 ). Additionally, Treg expansion using donor APCs results in low yield of post expansion cells due to the limited antigen specific Tregs present within the entire Treg population of an individual.…”