Proteasome inhibitor (PI)-based desensitization (DS) in humans has demonstrated variable reduction in HLA antibody levels that is often associated with variable rebound following treatment cessation.The biological mechanisms underlying these phenomena are unknown. We describe recent studies in primates and humans that may mitigate effectiveness of PI-based DS therapy.

Methods: A presensitized model in Rhesus macacques included two successive allogeneic skin transplants, in which high level alloantibodies were demonstrated by flow cytometry crossmatch assay against donor lymphocytes. Sensitized recipients were then desensitized with a four week bortezomib (BTZ) regimen. Human studies were conducted under an IRB/IND trial of carfilzomib (CFZ)-based DS (NCT02442648). Bone marrow (BM) sampling was performed prior to and following CFZ treatment and CD138+ bone marrow plasma cells (BMPCs) were analyzed.

Results: BTZ therapy in primates resulted in significant depletion in PC populations, which interestingly, was not accompanied by alloantibody reduction. Marked expansion of lymph node germinal centers was observed to be associated with B cell proliferation. In humans, CFZ monotherapy induced significant reductions in HLA antibody levels (80-95% decreases) that persisted for varying time intervals, but was associated with substantial rebound. Bone marrow sampling revealed depletion of 65-80% of BMPCs at the end of CFZ treatment. Bulk RNAseq analysis of CD138+ BMPCs performed prior to and following CFZ showed induction of mitotic responses in the CD138+ BMPC population. Single cell RNAseq analyses indicated heterogeneity within the CD138+ BMPC population with asubpopulation of BMPCs with significant mitotic gene expression prior to CFZ, with expansion of the population with mitotic gene expression following CFZ.

Conclusion: Primate and human studies indicate that depletion in B cell and PC populations induced by PI therapy are accompanied by proliferative responses in B cell and PC populations. These B cell and BMPC proliferative responses may be involved in the alloantibody rebound and/or in limiting alloantibody reduction by PI therapy. These results suggest the feasibility of pathway-based secondary targeting of the recovering cell populations to ehnance response.

The 1st, 2nd, 10th and 11th authors contributed equally.

CITATION INFORMATION: Driscoll J, Knechtle S, Kwun J, Tremblay S, Salomonis N, Potter S, Aronow B, Manook M, Alloway R, Singh H, Woodle E. Induction of Proliferative Responses in B Cell and Plasma Cell Populations Following Proteasome Inhibitor Desensitization Treatment in Rhesus Macacques and Humans. Am J Transplant. 2017;17 (suppl 3).

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