Tu107 - Agonistic Effect of Alefacept on TIGIT+PD1+ Effector Memory CD4 T Cells in New-onset Type 1 Diabetes

Laura Cooney – Immune Tolerance Network; Elisavet Serti – Immune Tolerance Network; Duangchan Suwannasaen – Benaroya Research Institute; Kristina Harris – Immune Tolerance Network; Mark Anderson – Immune Tolerance Network; Cate Speake – Benaroya Research Institute; Jerry Nepom – Immune Tolerance Network; Srinath Sanda – Immune Tolerance Network; Alice Long – Benaroya Research Institute

Abstract Text: Biomarkers of treatment are an important tool in determining optimal dosage of immunomodulatory therapies, particularly in heterogenous patient populations. In the T1DAL clinical trial, C-peptide was preserved in subjects with new-onset type 1 diabetes (T1D) treated with alefacept, an LFA-3 Ig fusion protein targeting CD2-high lymphocytes for depletion. Immediate changes in T cell counts did not correlate with response, likely due to considerable heterogeneity in CD2+ cell composition across subjects. Elevated levels of exhausted CD8 T cells 78 weeks after treatment and islet-specific activated CD4 T cells at baseline both correlated with response, but have limited utility as biomarkers of treatment due to timing and rarity, respectively. CD2 is expressed on all T cells, but most highly on effector memory T cells (TEM). We found that CD2-high and PD1-TIGIT- CD4 TEM were depleted as expected, but CD2-low PD1+TIGIT+ CD4 TEM expanded by 12 weeks after treatment and were maintained to at least 78 weeks. In comparison to PD1-TIGIT- CD4 TEM pre-treatment, expanded PD1+TIGIT+ CD4 TEM were proliferative (Ki67+) in vivo with low inflammatory cytokine production; both phenotypes were enhanced 35 weeks after treatment. Prolonged expansion of PD1+TIGIT+ CD4 TEM appears to be specific to CD2-targeted therapy, as other T cell depleting therapies (ATG and anti-CD3) caused only transient changes in this population. Thus, anti-CD2 therapy led to expanded PD1+TIGIT+ CD4 TEM concurrent with reduced functionality. These findings indicate that alefacept had an agonistic effect and suggest that PD1+TIGIT+ CD4 TEM may represent an early biomarker of treatment with alefacept.