IL-6 receptor blockade does not slow β cell loss in new-onset type 1 diabetes

Abstract

Background IL-6 receptor (IL-6R) signaling drives development of T cell populations important to type 1 diabetes pathogenesis. We evaluated whether blockade of IL-6R with monoclonal antibody tocilizumab would slow loss of residual β cell function in newly diagnosed type 1 diabetes patients. Methods We conducted a multicenter, randomized, placebo-controlled, double-blind trial with tocilizumab in new-onset type 1 diabetes. Participants were screened within 100 days of diagnosis. Eligible participants were randomized 2:1 to receive 7 monthly doses of tocilizumab or placebo. The primary outcome was the change from screening in the mean AUC of C-peptide collected during the first 2 hours of a mixed meal tolerance test at week 52 in pediatric participants (ages 6–17 years). Results There was no statistical difference in the primary outcome between tocilizumab and placebo. Immunophenotyping showed reductions in downstream signaling of the IL-6R in T cells but no changes in CD4 memory subsets, Th17 cells, Tregs, or CD4 + T effector cell resistance to Treg suppression. A DC subset decreased during therapy but regressed to baseline once therapy stopped. Tocilizumab was well tolerated. Conclusion Tocilizumab reduced T cell IL-6R signaling but did not modulate CD4 + T cell phenotypes or slow loss of residual β cell function in newly diagnosed individuals with type 1 diabetes. Trial Registration ClinicalTrials.gov NCT02293837. Funding NIH National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and National Institute of Allergy and Infectious Diseases (NIAID) UM1AI109565, UL1TR000004 from NIH/National Center for Research Resources (NCRR) Clinical and Translational Science Award (CTSA), NIH/NIDDK P30DK036836, NIH/NIDDK U01DK103266, NIH/NIDDK U01DK103266, 1UL1TR000064 from NIH/NCRR CTSA, NIH/National Center for Advancing Translational Sciences (NCATS) UL1TR001878, UL1TR002537 from NIH/CTSA; National Health and Medical Research Council Practitioner Fellowship (APP1136735), NIH/NIDDK U01-DK085476, NIH/CTSA UL1-TR002494, Indiana Clinical and Translational Science Institute Award UL1TR002529, Vanderbilt Institute for Clinical and Translational Research UL1TR000445. NIH/NCATS UL1TR003142, NIH/CTSA program UL1-TR002494, Veteran Affairs Administration, and 1R01AI132774.

100 years post-insulin: immunotherapy as the next frontier in type 1 diabetes

“…This is in line with data from NOD mouse studies of IL-1 receptor- or IL-1β-deficient NOD mice, where no protection from diabetes development was observed [ 92 , 93 ]. Likewise, blocking IL-6Ra in a recent trial in individuals with newly diagnosed T1D does not appear to provide benefit [ 94 ].…”

IL-6-Driven pSTAT1 Response Is Linked to T Cell Features Implicated in Early Immune Dysregulation

“…To determine the impact of mbIL-6R blockade on IL-6-related T cell phenotypes in vivo , we analyzed data from the EXTEND clinical trial, which investigated the impact of tocilizumab, a monoclonal antibody targeting global IL-6 signaling by blocking both mbIL-6R and soluble IL-6R, on beta cell loss in pediatric patients with new onset T1D ( 29 ). The EXTEND trial reported a lack of clinical efficacy and no significant changes in the frequency of FOXP3 + Treg, IL-17 + Th17, and IL-21 + Tfh cells.…”

“…Supplementary Table 1 lists the individual subjects including demographics, genotypes, and assays performed for each subject. In addition, a post-hoc analysis was performed on data generated in the EXTEND Study, a placebo-controlled, double-blinded, randomized clinical trial of adult and pediatric participants with newly diagnosed T1D testing whether tocilizumab would lead to clinical improvements in T1D ( 29 ).…”

Ladarixin, an inhibitor of the interleukin‐8 receptors CXCR1 and CXCR2, in new‐onset type 1 diabetes: A multicentre, randomized, double‐blind, placebo‐controlled trial

“…In line with this observation, other anti‐inflammatory strategies have been tested in type 1 diabetes patients at the onset of the disease. Findings from small pilot clinical trials suggest that inhibition of IL‐1, 23 TNF‐α 24 or IL‐6 signals might have a beneficial effect in type 1 diabetes, but the results were only partially confirmed in randomized phase 2 trials 12,25,26 . On the other hand, six immunotherapies mainly targeting the adaptive lymphocyte‐mediated attack of beta cells have been shown to preserve insulin secretion in stage 3 type 1 diabetes (teplizumab, 3 otelixizumab, 4 rituximab, 5 abatacept, 6 low‐dose antithymocyte globulin 7 and alefacept 8 ) and teplizumab have been shown to delay the onset of stage 2 disease 9 .…”