Ruxolitinib reduces severe CRS response by suspending CAR-T cell function instead of damaging CAR-T cells.

The therapeutic effect of CAR-T is often accompanied by sCRS, which is the main obstacle to the promotion of CAR-T therapy. The JAK1/2 inhibitor ruxolitinib has recently been confirmed as clinically effective in maintaining control over sCRS, however, its mechanism remains unclear. In this study, we firstly revealed that ruxolitinib significantly inhibited the proliferation of CAR-T cells without damaging viability, and induced an efficacy-favored differentiation phenotype. Second, ruxolitinib reduced the level of cytokine release not only from CAR-T cells, but also from other cells in the immune system. Third, the cytolytic activity of CAR-T cells was restored once the ruxolitinib was removed; however, the cytokines released from the CAR-T cells maintained an inhibited state to some degree. Finally, ruxolitinib significantly reduced the proliferation rate of CAR-T cells in vivo without affecting the therapeutic efficacy after withdrawal at the appropriate dose. We demonstrated pre-clinically that ruxolitinib interferes with both CAR-T cells and the other immune cells that play an important role in triggering sCRS reactions. This work provides useful and important scientific data for clinicians on the question of whether ruxolitinib has an effect on CAR-T cell function loss causing CAR-T treatment failure when applied in the treatment of sCRS, the answer to which is of great clinical significance.

Early Intervention in Living Kidney Transplantation Based on Dynamic Monitoring of Donor Specific Antibodies.

This study aims to analyze the clinical application of HLA donor specific antibodies (DSA) detected by Luminex single antigen beads and to discuss the impact of early intervention on renal function in DSA positive kidney transplant patients. In 64 cases of living-related renal transplantation, DSA was detected using Luminex single antigen bead assays before and after transplantation. The positive recipients were given intravenous immunoglobulin (IVIG) and increased doses of mycophenolate mofetil (MMF). The relationship between DSA and renal function was analyzed. In all transplant recipients, DSA was negative prior to transplantation. Ten DSA positive recipients were found after HLA mismatched transplantations. With intervention, two DSA positive recipients became DSA negative. In six cases, the patients' DSA intensity decreased more than 50%. In the remaining two cases, DSA intensity did not significantly decline, and within 3-6 months, antibody-mediated rejection (AMR) appeared and renal function was impaired. From our research, we conclude that dynamic monitoring of DSA using Luminex single antigen beads may help predict future changes in renal function. In addition, early application of IVIG and increasing doses of MMF can reduce the incidence of AMR.