ICOS agonist vopratelimab modulates follicular helper T cells and improves B cell function in common variable immunodeficiency

Common variable immunodeficiency (CVID) is an immune defect characterized by hypogammaglobulinemia and impaired development of B cells into plasma cells. As follicular helper T cells (T_FH) play a central role in humoral immunity, we examined T_FH cells in CVID, and investigated whether an inducible T cell co-stimulator (ICOS) agonist, vopratelimab, could modulate T_FH, B cell interactions and enhance immunoglobulin production. CVID subjects had decreased T_FH17 and increased T_FH1 subsets; this was associated with increased transitional B cells and decreased IgG⁺ B and IgD⁻IgM⁻CD27⁺ memory B cells. ICOS expression on CVID CD4⁺ T cells was also decreased. However, ICOS activation of CD4⁺ T cells by vopratelimab significantly increased total CVID T_FH, T_FH2, cell numbers, as well as IL-4, IL-10 and IL-21 secretion in vitro. Vopratelimab treatment also increased plasma cells, IgG⁺ B cells, reduced naïve & transitional B cells and significantly increased IgG1 secretion by CVID B cells. Interestingly, vopratelimab treatment also restored IgA secretion in PBMCs from several CVID patients who had a complete lack of endogenous serum IgA. Our data demonstrate the potential of T_FH modulation in restoring T_FH and enhancing B cell maturation in CVID. The effects of an ICOS agonist in antibody defects warrants further investigation. This biologic may also be of therapeutic interest in other clinical settings of antibody deficiency.