SaO011
A PHASE-I CLINICAL TRIAL OF DONOR-DERIVED MIC CELL INFUSION FOR THE INDUCTION OF DONOR-SPECIFIC HYPORESPONSIVENESS AFTER LIVING DONOR KIDNEY TRANSPLANTATION (TOL-1 STUDY)

INTRODUCTION AND AIMS: MIC cells are donor-derived monocytes that gain immunosuppressive properties after incubation with the proliferation inhibitor mitomycin C.

METHODS: PBMCs were harvested from living donors by leukapheresis and MIC cells were manufactured under GMP conditions. Kidney transplant recipients received either 1.5x10E6 MIC cells per kg body weight on day -2 (N=3, group A), or 1.5x10E8 MIC cells per kg body weight on day -2 (N=3, group B) or day -7 (N=4, group C) before living donor kidney transplantation. Patients received immunosuppressive therapy with CyA, EC-MPS and CS. Primary outcome measure was the frequency of adverse events (AE) on day 30.

RESULTS: A total of 70 AEs including 4 severe AEs occurred in treated patients that were unrelated to MIC cell infusion. No positive cross match results, de novo donor specific antibodies, or rejection episodes but 2 infectious complications were recorded. Median serum creatinine on day 30 was 1.4 mg/dL with no significant proteinuria. In vitro, MIC cells were capable of inducing tolerogenic dendritic cells with low expression of costimulatory molecules CD80, CD86 and a 30% increase of immunosuppressive molecule CD103. During the observation phase beyond day 30 after surgery, serum creatinine remained stable (median 1.48 mg/dL on day 180) with no significant proteinuria (median 10 g/mol creatinine on day 180) and no rejection episodes. The patients from group C who received low-dose CyA and low-dose EC-MPS during the observation phase had no or only minimal reactivity against irradiated donor lymphocytes in mixed lymphocyte culture while reactivity against 3rd party lymphocytes was preserved. CD19+ B cells increased to a median of 300/µL until day 30 but decreased to a median of 35/µL on day 180. CD19+CD24highCD38high transitional Bregs increased from a median of 2% on day 30 to a median of 20% of the total CD19+ B cell pool on day 180. There was a strong increase in the plasma IL-10/TNFalpha ratio from a median of 0.05 before cell therapy to a median of 0.11 on day 180.

CONCLUSIONS: In summary, MIC cell therapy represents a promising option for individualized immunosuppression after living donor kidney Transplantation.