Update on BCG Clinical Trial Programs in Patients with Advanced Type 1 Diabetes

The bacillus Calmette-Guerin (BCG) vaccine was first introduced a century ago for tuberculosis prevention and is today being tested in clinical trials for treatment of diverse forms of autoimmunity, including type 1 diabetes (T1D). Long-term follow up of a Phase I study of the BCG vaccine in longstanding T1D revealed potential disease-modulating effects after repeated BCG vaccination, including long-term reductions of HbA1c, death of autoreactive cells, modest restoration of insulin secretion and induction of beneficial regulatory T cells (Tregs). Here we provide an update on the BCG clinical trial program current underway at Massachusetts General Hospital (MGH): enrollment numbers, study timelines and interim outcomes for key T1D biomarkers. To date, 236 patients have been enrolled in the randomized and open-label MGH trials and 143 patients have received at least two doses of BCG, 34 of whom are being followed in open-label, unblinded trials. Enrollment of 150 participants in a pediatric study is planned for 2021. Data from ongoing analysis of the open-label BCG trials shows lowered insulin needs and decreases in HbA1c as compared to reference populations. Patients are also being monitored by RNAseq, epigenetics, Treg cell numbers and Treg signature gene expression to better define the mechanism of beneficial effects. We show a gradual and stable 3-year time course of demethylation of signature Treg genes known to be associated with Treg potency, including Foxp3, which was observed to be over-methylated at baseline in T1D and, over 3 years after BCG vaccination, demethylated to a level close to controls without T1D. The clinical time course of BCG-related improvements (i.e., improvement in HbA1C) appears to correlate with the time course of Treg induction through epigenetic modifications. Disclosure W. Kuhtreiber: None. H. Takahashi: None. R. Keefe: None. K. Nelson: None. N. Ng: None. J. Braley: None. H. Zheng: None. D. L. Faustman: None.