CTLA4-Ig + Anti-IL-6/IL-6R Treatment Results in Long-term Allograft Survival and Function in Highly HLA-sensitized...

Highly HLA-sensitized (HS) patients are at increased risk for cell-mediated rejection (CMR)/antibody-mediated rejection (AMR) posttransplant and require intense immunosuppression to prevent these events. HS patients who experience calcineurin inhibitor (CNI) neuro/nephrotoxicity have few options as conversion to CNI-free regimens with cytotoxic T-lymphocyte-associated antigen (CTLA4)-Ig may risk donor specific antibody (DSA) rebound, CMR, and AMR. This remains an unmet medical need. Anti-interleukin (IL)-6/IL-6R treatment is useful in treating AMR and CMR and preventing rejection in HS patients after transplantation (tx). Here, we examined the utility of combining CTLA4-Ig with anti-IL-6/IL-6R treatment in 4 HS patients with CNI toxicity.

Four HS patients (3 with calculated panel reactive antibodies >97% at tx and 1 who developed chronic-active AMR (c-aAMR) 14 y post-tx were evaluated. Two patients, 100% calculated panel reactive antibody and +flow crossmatch at transplantation, were desensitized with plasma exchange + clazakizumab (anti-IL-6) and maintained on clazakizumab post-tx and transitioned from CNI to CTLA4-Ig. Two patients treated with anti-IL-6R (tocilizumab) were transitioned to CTLA4-Ig at 2 and 11 y post-tx. Patients were monitored for renal function (RF), DSA, de novo DSA (dn-DSA), immune cell subsets, and patient and graft survival.

Clazakizumab and tocilizumab treated patients showed improvements in RF, with elimination of existing DSAs, except for 1 patient and no dn-DSAs (>6 y). We also saw reductions in CD8⁺ T_EFF/MEM, T_FH, B_MEM, and NK cells post-CTLA4-Ig + Anti-IL-6/IL-6R treatment. T_REG and B_REG cell populations also increased, suggesting, but not confirming, possible immune modulation.

Combining CTLA4-Ig + anti-IL-6/IL-6R appears to offer benefits in sustaining RF, DSA reduction, possibly immune cell modulation, and prevention of dn-DSA. Importantly, CNI toxicity abated in all patients.