Session Name: Tolerance: Clinical Studies
Session Date & Time: None. Available on demand.
*Purpose: 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).
*Methods: 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 48 – 136 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 37- 124 months); the majority (23/26) showed full (>95%) donor whole blood/T cell chimerism. 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 clinical 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. Two additional deaths have occurred in pts off IS: one in a heavy (>100 pack year) smoker from advanced stage lung cancer 4.5 years after KTx, the second in a pt 3.5 years after KTx who developed pneumococcal sepsis after noncompliance with recommended vaccinations. Overall 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.
*Conclusions: In summary, 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.
To cite this abstract in AMA style:Leventhal J, Galvin J, Mathew J, Gallon L, Belshe D, Gibson M, Ravindra K, Horwitz M, Ildstad S. Long-Term Follow-Up of a Phase 2 Clinical Trial to Induce Tolerance in Living Donor Renal Transplant Recipients [abstract]. Am J Transplant. 2021; 21 (suppl 3). https://atcmeetingabstracts.com/abstract/long-term-follow-up-of-a-phase-2-clinical-trial-to-induce-tolerance-in-living-donor-renal-transplant-recipients-3/. Accessed September 23, 2021.
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