*Purpose: Antibodies to human leukocyte antigens (HLA) pose a significant barrier to transplantation. Strategies to reduce allosensitization have modest efficacy and may result in antibody rebound. Synergistic targeting of upstream germinal center (GC) responses with costimulation blockade (belatacept; CTLA4-Ig) and plasma cells using a proteasome inhibitor (PI) may increase efficacy and prevent rebound.

*Methods: Four highly sensitized (cPRA class I and/or II 90-100%, CDC PRA+, C1q+) heart transplant candidates were treated with belatacept and multiple cycles of PI (bortezomib and/or carfilzomib) therapy (Table 1). Plasmapheresis was added to enhance PI effects (2/4 cases). Anti-HLA antibodies were monitored by Luminex single-antigen bead (SAB) assay median fluorescence intensity (MFI), titres (1:8), C1q assay, and CDC PRA. CyTOF analysis was used to compare peripheral blood mononuclear cell (PBMC) subsets before and after desensitization.

*Results: The average MFI for both class I and II antibodies was markedly reduced in all cases, an effect that was augmented when plasmapheresis was added to enhance PI therapy (Fig 1a&b). Importantly, even high MFI, C1q+ antibodies responded to sequential cycles of treatment (Fig 1c) resulting in 4 negative CDC crossmatches (3 patients) against historic C1q binding antibodies. Preliminary CyTOF analysis comparing peripheral blood subsets before and after treatment in one case demonstrated alterations in PBMC subsets including a marked reduction in CD19+ peripheral blood B cells (Fig 2).

*Conclusions: We provide preliminary results of a synergistic approach to desensitization combining costimulation blockade with proteasome inhibition demonstrating successful reduction of anti-HLA antibodies and alterations in peripheral blood subsets.

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