Therapeutic Opportunities for Immunoreceptor-Engineered T Cell Therapy for Modulation of Alloimmunity

Abstract

Achieving immunosuppression-free immune tolerance to an allograft is one of the central goals of transplantation. In this article, we review recent developments in the fields of T cell-based therapies and T cell engineering using chimeric Ag receptors and their potential for effective and targeted immune modulation of T and B cell activity in an effort to eliminate pre-existing alloantibodies (desensitization) and achieve long-term tolerance. Approaches that span preclinical to early clinical studies in transplantation will be reviewed, with specific emphasis on advances in T cell immunotherapy that have shown promise. Lastly, we conclude with a forward-looking discussion of how T cell-based therapies in other fields of medicine can be potentially applied to solid organ transplantation.

Figure 1.. Schematics of MHC-based CARs targeting alloreactive lymphocytes.

(A) Conventional CARs such as CD19-directed CARs target lineage antigens and mediate non-specific B cell elimination. Antigen-based CARs may be used to recognize only antigen-specific B cells. An engineered beta-2-microglobulin that is linked to T cell signaling domains associates with endogenous MHC-I heavy chain, converting the MHC-I complex into a CAR-like receptor which could engage allo-reactive B and T cells. (B) Both MHC-I and MHC-II may be converted to T cell activating complexes by fusing signal activating domains to different components of each complex. Both autologous and allogeneic platforms are conceivable with each presenting unique advantages and challenges.