Abstract Kidney transplant is the treatment of choice for patients with end-stage renal disease (ESRD), as it extends survival, improves quality of life and is highly cost-effective. However, for about a third of patients on the waitlist, pre-existing anti-HLA antibodies (i.e. allo-sensitization) presents a major barrier to successful transplant. HLA antibody responses are maintained by memory B cells (Bmem) and plasma cells (PC). Unfortunately, desensitization approaches have been largely ineffective due to incomplete depletion of allo-specific B cells and PCs. WE HYPOTHESIZE that stringent depletion of donor-specific B cells and PCs is required for a clinically significant reduction of allo-antibodies necessary to achieve successful kidney transplantation. We have shown that engineered T cell immunotherapies employing synthetic chimeric antigen receptors (CARs) can induce durable remission of B cell lineage and plasma cell malignancies. Two CAR-T cell therapies that target CD19 (CART-19) and B cell maturation antigen (CART-BCMA) result in depletion of malignant cells but also physiologic B cells and PCs. Importantly, we have shown that CART-BCMA and CART-19 can be safely administered together. Based on this experience, our GOAL is to leverage this innovative platform to target Bmem and PCs and promote reduction of preformed anti-HLA antibodies, thus providing a window of opportunity for transplantation. Specifically, we propose a single-arm proof-of-concept CLINICAL TRIAL that combines CART-19 with CART-BCMA as a novel desensitization measure in kidney transplant candidates with a cPRA ≥99.9%. MECHANISTIC studies will evaluate the cellular, humoral and molecular immune correlates of CART-19 + CART-BCMA immunotherapy in highly sensitized kidney transplant candidates. These are focused on the CAR T cells, T- and B-cell immunity (both allo-specific and protective) and, in the event of successful transplantation, the allograft biology. An INFECTIOUS DISEASE STUDY proposal will evaluate vaccine response and immune function in our renal transplant candidates, including our study cohort. The multi-center team (Penn, NYU, MGH) brings together investigators with extensive experience in CART therapy, desensitization, and outstanding depth of laboratory expertise to carry out robust mechanistic studies.