This is an open-label, single-institution study to assess the safety and the efficacy of the Sip-Tego regimen for the induction of donor-specific immunologic unresponsiveness to a renal allograft. The investigators propose to treat 6 adult subjects in end-stage renal disease (ESRD) who do not demonstrate evidence of prior sensitization.
Male or female 18-65 years of age.
Subjects with chronic kidney disease stage V (GFR<15ml/min/1.73m2) or ESRD who are treated or imminently be treated with either hemodialysis or peritoneal dialysis.
Candidate for a living-donor renal allograft from an HLA matched or mismatched donor
First or second renal transplant.
ABO blood group-incompatible renal allograft
Participant with a donor-specific antibody (DSA) within 6 months prior to transplant
Persistent Leukopenia (WBC less than 2,000/mm3) or thrombocytopenia (<100,000/mm3)
Seropositivity for HIV-1, hepatitis B core antigen, or hepatitis C virus (confirmed by hepatitis C virus RNA); or positivity for hepatitis B surface antigen.
Parallel
Combined Kidney/Bone Marrow Transplant
Procedure/SurgeryThe conditioning regimen to be used in this protocol consists of an ordered series of procedures and treatments including thymic irradiation, low-dose cyclophosphamide, antibody administration (Siplizumab (or ATGAM), rituximab and tegoprubart), and bone marrow cell infusion.
Donation of Kidney / Bone Marrow
Procedure/SurgeryThe donor will undergo nephrectomy and under general anesthesia. Donors will undergo bone marrow harvested under general anesthesia. Sufficient marrow will be obtained to provide at least 2 x 108 nucleated cells per kilogram weight of the recipient.
Conditioning Regimen (Rituxan, Siplizumab (or ATGAM), Cyclophosphamide, Tegoprubart)
DrugRecipients will receive a conditioning regimen that includes rituximab on study day -6 and -2, Siplizumab (0.6mg/kg) on day -6, -1, 0 and +1 (or ATGAM if Siplizumab becomes unavailable), cyclophosphamide (CP, 22.5mg/kg) on days -5 and -4. Tegoprubart (Fc-modified anti-CD154 mAB, Eledon Pharm) 20mg/kg will be administered on days 0, 2, 5, 12 and 19).
Induction of mixed chimerism without chimeric transition syndrome
This will be measured by a chimerism level of \>0% donor chimerism at anytime post transplant, and when the level is returning to 0% chimerism there is no evidence of chimeric transition syndrome. This is defined in the protocol by any of the following The clinical symptoms of CTS include acute kidney injury with rapid deterioration of kidney function (elevated creatinine, decreased blood flow to the renal allograft by US), minor to moderate fever, fluid retention or peripheral edema.
Achievement of IS minimization (tacrolimus or Belatacept monotherapy)
This will be measured by a patient weaning and maintaining only one agent of immunosuppression (either Tacrolimus or Belatacept)
Number of patients who complete full immunosuppression withdrawal
The number (and therefore percentage) of patients who discontinue all immunosuppression (ie. completely stop Tacrolimus or Belatacept)
Participants who are alive at the end of the study
Kidney Graft Survival
Incidence of CTS
Incidence of Acute Rejection
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Tatsuo Kawai, MD, PhD
Lead sponsor
Massachusetts General Hospital
Sponsor institution
Eledon Pharmaceuticals
Collaborator
ITB-Med LLC
Collaborator
