PROJECT ABSTRACT HLA sensitization is a significant barrier in organ transplantation. Kidney transplant candidates who are very highly sensitized (cPRA ≥99.9%) continue to have very poor access to a compatible donor and are more likely to be removed from the list or die than undergo transplantation. Desensitization has a clear survival benefit; however previous approaches have met with limited success especially in patients with the highest levels of HLA antibodies, and are hamstrung by the problem of antibody rebound. We hypothesize that durable reduction in HLA antibodies can be achieved by a two pronged approach: elimination of plasma cells plus prevention of the compensatory expansion of the germinal center. Both anti-CD38 antibodies and chimeric antigen receptor (CAR) T cells directed against plasma cells have emerged as novel therapeutic options in multiple myeloma. Germinal center activation can be inhibited by blockade of the IL-6 or CD40/CD40L pathway. Furthermore, we have identified a novel biomarker (specific HLA/KIR genotype combinations) which predicts poor plasma cell killing by NK cells in response to anti- CD38 antibodies. We propose to conduct a multicenter, prospective, open-label, interventional study in 68 patients with cPRA ≥99.9% who will be assigned to receive dual biologic therapy (n=60) or cellular therapy (n=8) for desensitization. Allocation into the dual biologic therapy or cellular therapy will be based on our novel biomarker using a precision medicine approach. Those assigned to dual biologic therapy will be further randomized to receive the anti-CD38 antibody, isatuximab, in combination with either VIB4920, a CD40L antagonist (n=30) or sarilumab, an IL- 6R antagonist (n=30). Those assigned to the cell therapy arm will receive a single infusion of ide- cel, a CAR T cell therapy targeting B-cell maturation antigen (BCMA), which is expressed on the surface of plasma cells. The primary efficacy endpoint is a ≥0.4% reduction in cPRA or receipt of transplant from a previously incompatible donor and is assessed at 16 weeks after completion of therapy. The primary safety endpoint is freedom from ≥grade 3 infusion reactions, ≥grade 3 or higher infections, and malignancy assessed at 16 weeks after completion of therapy or until receiving a transplant, whichever occurs earlier. Mechanistic analyses will focus on changes in the bone marrow and circulating T and B cell compartments after treatment, as well as in the lymph nodes of those who receive a transplant during the study. Transplanted subjects will receive additional study-directed therapy after transplant and be evaluated for post-transplant outcomes including freedom from rejection, graft loss and death.