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

Abstract

Management of immunosuppression after solid organ transplantation in context of chimeric antigen receptor T-cell therapy (CART) is challenging. While 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 post-transplantation lymphoproliferative disorder (PTLD) with CD19-CART as a fourth-line therapy. Immunosuppression was discontinued before leukapheresis for CART and not re-initiated ever since. While the PTLD 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 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-CART as a therapeutic option to prevent organ rejection without conventional long-term immunosuppression in selected patients.