Sustained allogeneic kidney graft operational tolerance despite discontinued conventional immunosuppression after CD19-CAR-T cell therapy for relapsed/refractory posttransplant lymphoproliferative disorder

Abstract

Management of immunosuppression after solid organ transplantation in context of chimeric antigen receptor T cell therapy (CART) is challenging. Although required to prevent graft rejection, systemic immunosuppression can interfere with biological functions of apheresis products and adoptively transferred T cells. We treated a 33-year-old kidney transplant recipient who developed relapsed/refractory posttransplant lymphoproliferative disorder with CD19-directed CART as a fourth-line therapy. Immunosuppression was discontinued before leukapheresis for CART and not reinitiated ever since. Although the posttransplant lymphoproliferative disorder remained in complete remission, we did not observe any signs of graft rejection (clinically and by determination of donor-derived cell-free DNA) until last follow-up at 23 months after CART. Phenotyping of peripheral blood immune cell subsets showed stable recovery of T and B cell compartments with dominant naïve differentiation. Immune responses against foreign antigens were shown by T cell cytokine production after stimulation with virus-derived peptide pools and absence of torque teno virus DNA. The lack of human leukocyte antigen antibodies and absence of T cell proliferation in a mixed leukocyte reaction with peripheral blood cells of the kidney donor confirmed tolerance against donor antigens. We envision CD19-directed CART as a therapeutic option to prevent organ rejection without conventional long-term immunosuppression in selected patients.

Keywords: CAR-T cell therapy; kidney transplantation; tolerance.