Chimeric HLA antibody receptor T cells for targeted therapy of antibody‐mediated rejection in transplantation

Abstract

The presence of donor‐specific antibodies (DSA), mainly against HLA, increases the risk of allograft rejection. Moreover, antibody‐mediated rejection (ABMR) remains an important barrier to optimal long‐term outcomes after solid organ transplantation. The development of chimeric autoantibody receptor T lymphocytes has been postulated for targeted therapy of autoimmune diseases. We aimed to develop a targeted therapy for DSA desensitization and ABMR, generating T cells with a chimeric HLA antibody receptor (CHAR) that specifically eliminates DSA‐producing B cells. We have genetically engineered an HLA‐A2‐specific CHAR (A2‐CHAR) and transduced it into human T cells. Then, we have performed in vitro experiments such as cytokine measurement, effector cell activation, and cytotoxicity against anti‐HLA‐A2 antibody‐expressing target cells. In addition, we have performed A2‐CHAR‐Tc cytotoxic assays in an immunodeficient mouse model. A2‐CHAR expressing T cells could selectively eliminate HLA‐A2 antibody‐producing B cells in vitro. The cytotoxic capacity of A2‐CHAR expressing T cells mainly depended on Granzyme B release. In the NSG mouse model, A2‐CHAR‐T cells could identify and eradicate HLA‐A2 antibody‐producing B cells even when those cells are localized in the bone marrow. This ability is effector:target ratio dependent. CHAR technology generates potent and functional human cytotoxic T cells to target alloreactive HLA class I antibody‐producing B cells. Thus, we consider that CHAR technology may be used as a selective desensitization protocol or an ABMR therapy in transplantation.

Immunotherapy targeting B cells and long-lived plasma cells effectively eliminates pre-existing donor-specific allo-antibodies

“… 24 Recently two groups reported the use of HLA-based CARs, termed CHARs, to specifically target allo-reactive B cells. 25 , 26 While CHAR T cells were able to lyse allo-specific B cell hybridomas, this approach, on its own, may not be effective given the lack of surface Ig expression in human LLPCs. In this regard, a combination of CHAR-T cells with additional PC-targeted therapy may provide a more selective depletion than the present Combo-CART strategy.…”