Update On Phase 2 Clinical Trial To Induce Tolerance In Mismatched Living Donor Renal Transplant Recipients

Nineteen subjects have been enrolled in a phase 2 protocol (FDA IDE 13947) to induce donor-specific tolerance in HLA-mismatched related and unrelated recipients of living donor renal allografts (KTx). The protocol is based upon tolerogenic CD8⁺/TCR^- facilitating cells (FC) and nonmyeloablative conditioning. Recipients are conditioned with fludarabine (30 mg/kg/dose, days -5, -4, -3), cyclophosphamide (50 mg/kg/dose, day -3 and +3), 200 cGy TBI (day -1) followed by KTx (day 0). A G-CSF mobilized peripheral blood mononuclear cell product is apheresed from the donor > 2 weeks prior to the KTx, processed to remove GVHD-producing cells yet retain CD34⁺ cells and FC (FCRx), and cryopreserved until infusion on day +1 post-KTx. Subjects ranged in age from 18 to 65 years. All were HLA-disparate from their donors, ranging from 5 of 6 matched related to 0 of 6 unrelated. 18 of 19 subjects exhibited engraftment at 1 month; one highly sensitized subject (PRA > 50%) did not engraft. Subjects were discharged on post-operative day 2 and managed as outpatients. Mycophenolate mofetil and tacrolimus-based immunosuppression were administered for 6 months. At 6 months the MMF was discontinued if the protocol biopsy was normal and stable renal function present. Tacrolimus was weaned at month 9 (trough levels 3-6) and discontinued at 1 year if chimerism, normal renal function, and normal kidney biopsy were noted. No subjects have experienced GVHD or engraftment syndrome. Two early subjects who received a suboptimal cell dose and one other highly sensitized subject were only transiently chimeric (< 6 months); all transiently chimeric subjects resumed endogenous hematopoiesis and are maintained on low-dose tacrolimus monotherapy with stable renal function. The protocol was subsequently modified to exclude subjects with a PRA > 20%. One chimeric subject developed viral sepsis at month 3, thrombosed his kidney, and was successfully re-transplanted off study. A second subject developed CNI-induced hemolytic uremic syndrome (HUS) which resulted in graft loss. He is currently off all immunosuppression and his HUS has resolved. The remaining subjects are either off all immunosuppression (n = 9; 1 to 36 months) or are in the process of tapering. None of the chimeric subjects have developed rejection on protocol biopsy while 3 of the 5 who were not durably chimeric had Banff 1A rejection on protocol biopsy. Recurrence of autoimmune disease has occurred in 2 of 4 non-chimeric subjects, but not in any of the durable chimeric subjects. In summary, high levels of durable chimerism and tolerance without GVHD have been achieved in mismatched related and unrelated recipients of living KTx.