Methods: 37 subjects were transplanted in a phase 2 protocol based upon tolerogenic CD8+/TCR-facilitating cells (FCR001) to induce tolerance in recipients of living donor renal allografts (KTx). Recipients were conditioned with fludarabine (30mg/m2/dose, days -5,-4,-3), cyclophosphamide (50mg/kg/dose, day-3 and+3), 200 cGy TBI (day-1) followed by KTx (day0). A G-CSF mobilized product was apheresed from the donor, processed to remove graft-versus-host disease (GVHD)-producing cells yet retain CD34 + cells and FC, and cryopreserved until administration day+1 post-KTx. Follow up is 60 - 154 months. Pts ranged in age from 18-64 yrs and were 6/6 HLA matched related to 0/6 matched unrelated. MMF and tacrolimus immunosuppression (IS) was weaned and discontinued at 1 yr if post-Tx chimerism, normal renal fcn and normal KTx biopsy were noted.

Results: Durable chimerism allowing for full IS withdrawal developed in 26 pts (time off IS 48- 136 months); the majority (23/26) showed full (>95%) donor whole blood/T cell chimerism.  6 subjects have been IS free for > 10 years. Transient chimerism was seen in 8 pts. All stable chimeric subjects retained chimerism after removal of IS and remain rejection-free. Long term chimeric subjects off IS have no evidence of immune defect:  they show robust T, B, and NK cell reconstitution, can be safely vaccinated and develop protective immunity. Transiently chimeric pts resumed endogenous hematopoiesis and were maintained on low-dose IS. There were two cases of GVHD. 1 subject exhibited grade 1-2 acute GI GVHD that responded to corticosteroids, followed by mild chronic GVHD. The second pt presented late and died of treatment resistant GI GVHD with CMV 11 months post-Tx. There have been three graft losses, related to infections in subjects on IS.  There have been three subject deaths. Over all patient survival is 91.8% and death censored graft survival 94.1%. Tolerant FCR001 subjects have significantly better renal function than comparable KTx on SOC IS. Hypertension and hyperlipidemia is more common in SOC than tolerant FCR001 pts.

Conclusion: High levels of durable chimerism and tolerance with a low (5.5%) incidence of GVHD has been achieved in mismatched recipients of KTx. There are significant long term medical benefits to establishing tolerance in KTx recipients using the FCR001 approach.