Extracorporeal photopheresis as a promising strategy for the treatment of GvHD after CAR-T cell therapy

Abstract

Graft-versus-host disease (GvHD) occurs in about 10-33% of patients receiving "al-logeneic" or "autologous" CAR-T cells after preceding allogeneic hematopoietic stem cell transplantation (allo-HSCT) due to the substantial presence of alloreactive T cells. Extracorporeal photopheresis (ECP) shows promising clinical outcomes in the treatment of GvHD after allo-HSCT without hampering anti-tumor and anti-viral effects. This raises an interesting question: whether ECP might constitute a new way to treat patients with GvHD after CAR-T cell therapy without compromising CAR-T cells significantly. Third-generation CD19-specific CAR-T cells were generated and an in vitro ECP protocol was established. The impact of ECP on CAR-T cells was comprehensively investigated in two models: the non-dilution model reflects days following CAR-T cell infusion and the dilution model weeks after infusion. The ther-apeutic effect of ECP on GvHD was examined in an in vitro mixed lymphocyte reac-tion (MLR) assay. We found out that ECP treated CAR-T cells demonstrated reduced potency in inducing alloreaction compared to the group without ECP treatment in MLR assay. ECP could selectively induce apoptosis, thereby enriching the naive and central memory CAR-T cells with a reduced alloreactivity. The cytokine milieu of CAR-T cells could be switched from immune stimulation to immune tolerance in both models. Moreover, ECP could modulate the proliferative capacity of CAR-T cells without hampering their long-term functionality in the dilution model. In con-clusion, ECP constitutes a promising treatment strategy for GvHD after allo-HSCT and CAR-T cell transfusion, as ECP reduces the alloreactivity without hampering CAR-T cell functionality.