title: A Phase I/II Trial of the Interleukin-6 Receptor-Specific Humanized Monoclonal (Tocilizumab) + Intravenous Immunoglobulin in Difficult to Desensitize Patients.
abstract: BACKGROUND
  Current desensitization (DES) methods are not always effective. Thus, novel, more effective approaches are desirable. Interleukin (IL)-6 is an attractive target as it promotes B-cell differentiation to plasma cells, is important for immunoglobulin production, and induces Th17 cells. Here, we undertook a phase I/II pilot study of DES using a novel drug (anti-IL-6 receptor (IL-6R),Tocilizumab [TCZ]) + intravenous Ig (IVIg) to assess safety and limited efficacy.
  
  
  METHODS
  From July 2012 to November 2013, 10 patients unresponsive to DES with IVIg + Rituximab were treated with IVIg + TCZ. Patients received IVIg on days 0 and 30 at 2 g/kg and TCZ 8 mg/kg on day 15 then monthly for 6 months. If transplanted, patients received IVIg once and TCZ monthly for 6 months.
  
  
  RESULTS
  No differences in baseline characteristics were seen in patients not transplanted versus transplanted. Two patients in each group developed serious adverse events: not transplanted- pulmonary congestion with epilepticus (likely not related) versus transplanted infective colitis with colonic perforation and Bell Palsy (both possibly related). Five of 10 patients were transplanted. Mean time to transplant from first DES was 25 +/- 10.5 months but after TCZ was 8.1 +/- 5.4 months. Six-month protocol biopsies showed no antibody-mediated rejection. Donor-specific antibody strength and number were reduced by TCZ treatment. Renal function at 12 months was 60 +/- 25 mL/min.
  
  
  CONCLUSIONS
  Tocilizumab and IVIg appear to be safe. From this pilot trial, we are cautiously optimistic that targeting the IL-6/IL-6R pathway could offer a novel alternative for difficult to desensitize patients. Larger controlled studies are essential to prove efficacy
authors.forename: Ashley A
authors.initials: AA
authors.lastname: Vo
authors.forename: Jua
authors.initials: J
authors.lastname: Choi
authors.forename: Irene
authors.initials: I
authors.lastname: Kim
authors.forename: Sabrina
authors.initials: S
authors.lastname: Louie
authors.forename: Kristen
authors.initials: K
authors.lastname: Cisneros
authors.forename: Joseph
authors.initials: J
authors.lastname: Kahwaji
authors.forename: Mieko
authors.initials: M
authors.lastname: Toyoda
authors.forename: Shili
authors.initials: S
authors.lastname: Ge
authors.forename: Mark
authors.initials: M
authors.lastname: Haas
authors.forename: Dechu
authors.initials: D
authors.lastname: Puliyanda
authors.forename: Nancy
authors.initials: N
authors.lastname: Reinsmoen
authors.forename: Alice
authors.initials: A
authors.lastname: Peng
authors.forename: Rafael
authors.initials: R
authors.lastname: Villicana
authors.forename: Stanley C
authors.initials: SC
authors.lastname: Jordan
mesh_terms: D000328:Adult; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage* / Q000009:adverse effects; D015415:Biomarkers / Q000097:blood; D003888:Desensitization, Immunologic / Q000009:adverse effects / Q000379:methods*; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005260:Female; D006084:Graft Rejection / Q000097:blood / Q000276:immunology / Q000517:prevention & control; D006085:Graft Survival / Q000187:drug effects; D006648:Histocompatibility / Q000187:drug effects; D006650:Histocompatibility Testing; D006801:Humans; D016756:Immunoglobulins, Intravenous / Q000008:administration & dosage* / Q000009:adverse effects; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000009:adverse effects; D007518:Isoantibodies / Q000097:blood; D016030:Kidney Transplantation / Q000009:adverse effects; D015141:Los Angeles; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D015415:Biomarkers; D016756:Immunoglobulins, Intravenous; D007166:Immunosuppressive Agents; D007518:Isoantibodies; C502936:tocilizumab