*Purpose: The goals of tolerance in patients with kidney transplants (KTxp) are to eliminate the lifelong need for immunosuppressive drugs (IS) and to prevent graft loss due to rejection or drug toxicity. We evaluated the ability of MDR-101, a novel cellular immunotherapy, to produce persistent mixed chimerism without graft versus host disease (GvHD), eliminate the need for IS without rejection, and, thus, produce operational tolerance as compared to the standard of care (NCT03363945).

*Methods: Eligible adult subject pairs (donor/recipient) of a first kidney allograft from an HLA-identical LD were enrolled and randomized 2:1 to either the Investigational Arm (IA; n=20) or Control Arm (CA; n=10). Donors in the IA received G-CSF mobilization for 5 days before undergoing apheresis (1 or 2 cycles); apheresis products were shipped to a central facility for manufacture of MDR-101. After KTxp, IA recipients received ATG conditioning, low-dose total lymphoid irradiation (TLI) over 10 days and IS followed by an infusion of infusion of MDR-101 on D11. After 180 days of persistent mixed chimerism, subjects initiated a 6 month IS taper and could withdraw all IS by D365. Subject pairs in the CA were treated as institutional standard of care.

*Results: As of December 2019, 22 subject pairs were enrolled, comprising 13 subject pairs randomized to the IA and 7 subject pairs randomized to the CA. MDR-101 infusion occurred in 11 subjects in the IA. To date, 5 of the 11 subjects in the IA have 6 months of positive mixed chimerism and initiated IS taper at D180, and 3 of the 5 subjects have reached D365 and completely withdrew from all IS. The remaining subjects in the IA display positive mixed chimerism, and there have been no events of GvHD, BPAR, or dnDSA to date. A total of 282 AEs were reported in 26 subject pairs; 63% (178/282) were reported in the IA arm; 37% (104/282) in the CA. Most AEs (61%) were Gr 1 (mild) severity. Grade 3 (severe) severity represented 6% (18/282) of AEs, of which 2 were reported in the IA donors, 6 in the IA recipients and 10 in the CA donors. No Gr 4 or 5 AEs were reported.

*Conclusions: Administration of MDR-101 in HLA-identical LD KTxp recipients conditioned with ATG and TLI have produced promising results to date. These results show that MDR-101 induces persistent mixed chimerism without GvHD and permits withdrawal of IS without rejection or dnDSA. Further evaluation continues.

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