Desensitizing highly sensitized heart transplant candidates with the combination of belatacept and proteasome inhibition

Abstract

HLA antibodies pose a significant barrier to transplantation and current strategies to reduce allosensitization are limited. We hypothesized that augmenting proteasome inhibitor (PI) based desensitization with costimulation blockade (belatacept) to mitigate germinal center (GC) responses might increase efficacy and prevent rebound. Four highly sensitized (calculated panel reactive antibody [cPRA] class I and/or II >99%, complement-dependent cytotoxicity panel reactive antibody [CDC PRA+], C1q+) heart transplant candidates were treated with the combination of belatacept and PI therapy, which significantly reduced both class I and II HLA antibodies and increased the likelihood of identifying an acceptable donor. Three negative CDC crossmatches were achieved against 3, 6, and 8 donor-specific antibodies (DSA), including those that were historically C1q+ binding. Posttransplant, sustained suppression of 3 of 3, 4 of 6, and 8 of 8 DSA (cases 1-3) was achieved. Analysis of peripheral blood mononuclear cells before and after desensitization in one case revealed a decrease in naïve and memory B cells and a reduction in T follicular helper cells with a phenotype suggesting recent GC activity (CD38, PD1, and ICOS). Furthermore, a shift in the natural killer cell phenotype was observed with features suggestive of activation. Our findings support synergism between PI based desensitization and belatacept facilitating transplantation with a negative CDC crossmatch against historically strong, C1q binding antibodies.

Recent progress and remaining hurdles toward clinical xenotransplantation

“…Moreover, as xenotransplantion could be planned on an elective basis, virtually all recipient candidates could benefit from desensitization protocols. New and future agents that are either being tested or which will be tested include anti‐IL‐6, 100 costimulation blockers (which may prevent the development of DSA and AMR such as in the allotransplantation setting 101 ), and proteasome inhibitors; a combination of both has recently shown to be promising in highly sensitized candidates 102 (Figure 1). The combination of bortezomib, belatacept, and anti‐CD40 is efficient as well, but may have prohibitive toxicity 103,104 .…”

Lung Transplantation and the Era of the Sensitized Patient

“…Several centers have reported lower incidence of DSA and superiority in constraining preexisting HLA antibody responses compared with calcineurin inhibitor-based immunosuppression ( 45 , 46 ). When use in combination with desensitization strategies that focus on eliminating antibodies (plasmapheresis) and/or precursor cells responsible for antibody production (proteasome inhibitors and anti-CD20 antibodies) the hope is a more effective, durable “immune modulating” strategy that reliably and sustainably reduces HLA antibodies both before and after transplant ( 45 – 47 ).…”

“…Indeed there has been some promising data with the addition of belatacept to desensitization regimens in other solid organ transplant patients ( 47 ). Alishetti et al.…”

“…Additionally, the chances of finding a donor to whom the recipient did not have high MFI antibodies increased markedly after desensitization (based on calculated likelihood ratios of cPRA). Of note, two infectious complications were reported which resolved with treatment ( 47 ). To date, the small cohort described in lung candidate above is the only known use of CD28 co-stimulation blockade in multimodal lung transplant desensitization protocols and larger scale trials are needed ( 42 ).…”

Management of the Sensitized Cardiac Transplantation Recipient

“…C1 inhibitor has shown promise in animal studies in preventing AMR after transplantation [58]. Imlifidase (IdeS) [59], Belimumab [60], Tocilizumab [61] and Belatacept [62] have been used sporadically and might hold promise in the future.…”