Preoperative Carfilzomib and Lulizumab based desensitization prolongsgraft survival in a sensitized NHP model

Sensitized patients are difficult to transplant due to pre-formed anti-donor immunity. We have previously reported successful desensitization using carfilzomib and belatacept in a non-human primate (NHP) model. Here we evaluated selective blockade of the co-stimulatory signal (CD28B7) with Lulizumab, which preserves the co-inhibitory signal (CTLA4-B7). Five maximally MHC-mismatched pairs of NHPs were sensitized to each other with two sequential skin transplants. Individuals from each pair were randomized to either desensitization with onceweekly Carfilzomib (27mg/m2 IV) and Lulizumab (12.5mg/kg SC) over four weeks, or no desensitization (Control). NHPs then underwent life-sustaining kidney transplantation from their previous skin donor. Rhesus-specific anti-thymocyte globulin was used as induction therapy and immunosuppression maintained with tacrolimus, mycophenolate, and methylprednisolone. Desensitized subjects demonstrated a significant reduction in donor-specific antibody, follicular helper T cells (CD4+PD-1+ICOS+), and proliferating B cells (CD20+Ki67+) in the lymph nodes. Interestingly, regulatory T cell (CD4+CD25+CD127lo) frequency was maintained after desensitization in addition to increased frequency of naïve CD4 T cells (CCR7+CD45RA+) and naïve B cells (IgD+CD27−CD20+) in circulation. This was associated with significant prolongation in graft survival (MST = 5.8 ± 4.0 vs. 64.8 ± 36.3; p<0.05) and lower antibody-mediated rejection scores compared to control animals. However, all desensitized animals eventually developed AMR and graft failure. Desensitization with CFZ and Lulizumab improves allograft survival in allosensitized NHPs, by transient control of the germinal center and shifting of the immune system Address all correspondence and requests for reprints to: Jean Kwun, PhD, 207 Research Drive, Jones 362, DUMC Box 2645, Durham, NC 27710, USA Phone: 919-668-6792; Fax: 919-684-8716; jean.kwun@duke.edu; Stuart J Knechtle, MD, 330 Trent Drive, DUMC Box 3512, Durham, NC 27710, USA Phone: 919-613-9687; Fax: 919-684-8716; stuart.knechtle@duke.edu. Author Contributions: PMS participated in research design, conducting experiments, acquiring data, analyzing data, and writing of the manuscript. RS, ZWF, BE, and JY participated in research design, conducting experiments, and acquiring data. MS and ABF participated in conducting experiments and acquiring data (Histology and histological grading). AYC, AB, FL, and BC participated in conducting experiments. JK and SJK participated in research design, conducting experiments, analyzing data and writing of the manuscript. Disclosures: Data were presented as an oral presentation at the American Transplant Congress 2019 in Boston, MA. Conflict of Interest Statement The authors have no relevant conflicts of interest. HHS Public Access Author manuscript Kidney Int. Author manuscript; available in PMC 2021 January 06. Published in final edited form as: Kidney Int. 2021 January ; 99(1): 161–172. doi:10.1016/j.kint.2020.08.020. A uhor M anscript