Table 1.
Clinical trials investigating IL-6/IL-6R signaling inhibition in solid organ transplantation
| Author/trial name (NCT number) | Study design | Study population | Intervention | Endpoints/outcomes | Results |
|---|---|---|---|---|---|
| Tocilizumab | |||||
| Vo et al. [59••] (NCT01594424) | Single-center, phase I/II open-label study | - N = 10 highly HLA-sensitized patients (cPRA > 50%) w/ ESRD awaiting transplant who failed DES w/ IVIg +rituximab +/− plasma exchange |
- IVIg 2 g/kg monthly for 2 doses +TCZ 8 mg/kg monthly for 6 months In transplanted patients: - IVIg 2 g/kg for 1 dose +TCZ 8 mg/kg monthly for 6 months post-transplant |
- Rate of transplantation - DSA levels - SAEs and AEs In transplanted patients: - Time to transplant - Graft survival - Rate of AMR |
- 50% transplantation rate - Decreased DSA - 40% of patients w/ SAEs; 5/7 total SAEs likely related to TCZ In transplanted patients: - Mean time to transplant 8 months post-TCZ (25 months after 1st DES treatment) - No graft loss at 1 year - No AMR on 6-month post-transplant biopsies |
| Choi et al. [115••] | Single-center, open-label case study | - N = 36 kidney transplant recipients w/ cAMR, DSA+, TG who failed IVIg +rituximab +/− plasma exchange | - TCZ 8 mg/kg monthly for 6–25 months (max dose 800 mg) |
- Renal function - DSA levels - Graft/ patient survival - AEs and SAEs |
- Stabilized renal function - Significantly reduced DSA - 80% graft survival, 91% patient survival 6 years post-cAMR diagnosis - Graft loss 2/2 cAMR in 4 patients - 13 patients w/ infectious AEs, no SAEs |
| Lavacca et al. [116] | Single-center, open-label case study | - N = 15 kidney transplant recipients w/ previously untreated cAMR | - TCZ 8 mg/kg monthly (max dose 800 mg) for median 20 month follow up |
- Renal function - DSA levels - Graft/patient survival - AEs |
- Stabilized renal function - Significantly reduced DSA - Reduced microvascular inflammation on 6 month biopsies - Graft loss in 1 patient (6.7%), no patient deaths - 5 patients w/ infectious AEs, 6 w/ other AEs |
| Pottebaum et al. [117] | Single-center, observational study | - N = 7 kidney transplant recipients w/ acute AMR | - TCZ 8 mg/kg IV (max dose 800 mg) monthly for 1–6 months |
- Renal function - DSA levels - AEs |
- Stabilized/improved renal function - Reduced DSA - 1/7 patients w/ mixed rejection, 2/7 w/ ACR at 6–24 months post-TCZ therapy - 2 patients w/ AEs, unclear relation to TCZ |
| Chandran et al. [118•] (NCT02108600) | Single-center, randomized-controlled study | - N = 30 kidney transplant recipients w/ graft inflammation on biopsy ≤ 1 year post-transplant | - 1:1 randomization to standard triple-drug immunosuppression +/ - TCZ 8 mg/kg IV monthly for 6 months |
- Inflammation on 6 month biopsy (Banff ti-score) - De novo DSA formation - Development of AMR/ACR - AEs - Renal function - Graft/patient survival - Change in circulating immune profile |
In TCZ-treated group: - Significantly improved Banff ti-score - No de novo DSA formation - No AMR or ACR at 6 months - No graft loss or patient deaths - Stable renal function - No unexpected AEs Compared to control group: - Significantly increased Treg frequency - Blunted T-effector cytokine response |
| Targeting Inflammation and Alloimmunity in Heart Transplant Recipients with Tocilizumab (ALL IN) [119] (NCT03644667) | Multicenter, phase II randomized-controlled trial | - N = 200 heart transplant recipients | - 1:1 randomization to standard triple-drug immunosuppression +/− TCZ 8 mg/kg IV monthly for 6 months |
- De novo DSA - Development of AMR, ACR, hemodynamic compromise rejection - Graft/patient survival |
- Not yet available |
| Clazakizumab | |||||
| Vo et al. [120•] (NCT03380962) | Single-center, phase I/II trial | - N = 10 highly HLA-sensitized patients (cPRA > 50%) w/ ESRD awaiting transplant |
- DES w/ plasma exchange ×5 followed by IVIg 2 g/kg ×1 dose - Then clazakizumab 25 mg SC monthly for 6 months In transplanted patients: - Clazakizumab 25 mg SC monthly for 12 months post-transplant |
- Rate of transplantation - HLA MFI In transplanted patients: - Time to transplant - Presence of DSA - Graft survival |
- 90% transplantation rate - Significantly reduced HLA MFI In transplanted patients: - Mean time to transplant 5.5 months post-clazakizumab - No detectable DSA at 6 months post-transplant - 2 patients with rejection from ACR/AMR and cAMR |
| Jordan et al. [121] (NCT03380377) | Single-center, phase I/II open-label study | - N = 10 DSA+ kidney transplant recipients w/ cAMR and TG |
- Clazakizumab 25 mg SC monthly for 12 months - Then long-term extension w/ clazakizumab 25 mg SC every other month |
- DSA levels - Renal function - Treg responses - SAEs |
- Reduced DSA - Stable renal function - Increased Tregs - No clazakizumab-related SAEs |
| Doberer et al. [122, 123] (NCT03444103) | Investigator-initiated, multicenter, phase II randomized-controlled trial | - N = 20 kidney transplant recipients w/ DSA+ cAMR > 1 year post-transplant |
- 1:1 randomization to clazakizumab 25 mg SC monthly or placebo for 12 weeks - Then open-label extension w/ clazakizumab 25 mg SC monthly for 40 weeks in both groups |
- DSA levels - Renal function - AEs - Rejection-related gene expression patterns |
Compared to control group: - Significantly decreased DSA - Reduced decline in renal function In clazakizumab-treated group: - Infectious AEs/diverticulitis in 7 patients (35%) - On 1-year post-treatment biopsies: - Negative molecular AMR score in 7 patients (39%) - Disappearance of C4d in 5 patients (27.8%) - Resolution of morphologic AMR activity in 4 patients (22.2%) |
| Clazakizumab for the Treatment of Chronic Active Antibody Mediated Rejection in Kidney Transplant Recipients (IMAGINE) [124] (NCT03744910) | Industry-sponsored, multicenter, randomized-controlled phase III trial | - N = 350 patients w/ DSA+ cAMR > 6 months post-kidney transplant | - Randomization to clazakizumab vs placebo for up to 5 years treatment |
- DSA levels - Renal function - Graft/patient survival - Development of ACR/AMR |
- Not yet available |
Abbreviations: TCZ, tocilizumab; cPRA, calculated panel reactive antibody; DES, desensitization; ESRD, end-stage renal disease; DSA, donor-specific antibody; AMR, antibody-mediated rejection; TG, transplant glomerulopathy; ACR, acute cellular rejection; AE, adverse event; SAE, serious adverse event; cAMR, chronic antibody-mediated rejection; Treg, regulatory T-cell; MFI, mean fluorescence intensity