Overcoming barriers to widespread use of CAR-Treg therapy in organ transplant recipients.

Preventing allograft rejection has been the main challenge of transplantation medicine since the discovery of immune responses against foreign HLA molecules in the mid-20th century. Prevention of rejection currently relies on immunosuppressive drugs, which lack antigen specificity and therefore increase the risk for infections and cancers. Adoptive cell therapy with donor-reactive regulatory T cells (Tregs) has progressively emerged as a promising approach to reduce the need for pan-immunosuppressive drugs and minimize morbidity and mortality in solid-organ transplant recipients. Chimeric antigen receptor (CAR) technology has recently been used successfully to generate Tregs specific for donor HLA molecules and overcome the limitations of Tregs enrichment protocols based on repetitive stimulations with alloantigens. While this novel approach opens new possibilities to make Tregs therapy more feasible, it also creates additional challenges. It is essential to determine which source of therapeutic Tregs, CAR constructs, target alloantigens, safety strategies, patients and immunosuppressive regimens are optimal for the success of CAR Treg therapy. Here, we discuss unmet needs and strategies to bring donor-specific CAR Treg therapy to the clinic and make it as accessible as possible.