Antigen-Specific Peptide Immunotherapy for Type 1 Diabetes: Proof of Safety, Hope for Efficacy  Ken Coppieters, Matthias von Herrath  Cell Metabolism  Volume 26, Issue 4, Pages 595-597 (October 2017) DOI: 10.1016/j.cmet.2017.09.016 Copyright © 2017 Terms and Conditions

Figure 1 Four Hypotheses Would Have to Hold True to Justify the Use of Biomarkers as a Correlate for Therapeutic Mechanism, Dose Guidance, and Efficacy Potential, in Particular in Small Phase 1 Safety Trials Hypothesis 1 is that the sampled blood content reliably mirrors the reportedly subtle, lobular autoimmune events at the target site, both quantitatively and qualitatively, and without excessively random longitudinal variation. Findings from some longitudinal studies and investigations looking at certain cell types and their sequestering in target organs argue that this might often not hold true. Hypothesis 2 is that beta cell destruction at the target site around diagnosis is driven by the autoimmune markers being looked at. Hypothesis 3 is that changes in blood-derived immune biomarkers not only correlate with the natural history of beta cell decline, but also predict future metabolic outcome with less error and higher reliability than the metabolic outcome measure itself. Otherwise, the biomarker’s utility in a smaller study versus a more fully powered phase 2 study would not be justified. The evidence that this assumption might hold true is, to our opinion, non-existent. Hypothesis 4 is that blood-derived biomarkers dose-dependently parallel metabolic benefit experienced as a consequence of therapeutic intervention, antigenic or otherwise. In our opinion, there is little evidence for dose-dependent biomarkers in antigenic tolerance of Th1 diseases. Examples of immune biomarkers measured by Alhadj Ali et al. include autoreactive CD4 and CD8 T cell (red cells) frequency and function, regulatory T cell frequency and phenotype (green cells), T cell cytokines (small filled circles), autoantibodies (blue V-shapes), and proinsulin/C-peptide ratios (blue/red stripes). Metabolic indicators of clinical benefit included stimulated C-peptide, insulin usage, and HbA1c. Cell Metabolism 2017 26, 595-597DOI: (10.1016/j.cmet.2017.09.016) Copyright © 2017 Terms and Conditions