Abstract 5536: ICOS hi CD4 T cells emerging on vopratelimab treatment have Th1 central memory characteristics and may contribute to durability of clinical responses

Background: Inducible T cell Co-stimulator (ICOS) is a costimulatory molecule expressed primarily on T lymphocytes that is upregulated upon cell activation. Vopratelimab (vopra) is a novel ICOS agonist antibody whose primary mechanism of action is the stimulation of primed CD4 T effector cells. Clinical responses in the Phase 1/2 ICONIC trial (NCT02904226) were associated with the emergence of ICOS hi CD4 T cells. In a separate study of PD-1/L1 monotherapy, this phenotype was not observed, demonstrating ICOS hi CD4 T cell emergence in ICONIC was due to vopra. Ex vivo stimulation of antigen-primed ICOS hi CD4 T cells by soluble vopra demonstrated induction of a polyfunctional cytokine response. Previous studies have shown that sustained ICOS upregulation was associated with clinical benefit in subjects treated with anti-CTLA-4 inhibitors, with preclinical data confirming a role for ICOS signaling in optimal anti-tumor activity. Vopra is currently being tested as a sequenced combination with ipilimumab (ipi) in the Phase 2 EMERGE trial (NCT03989362). Methods: Assessment of phenotype and function of ICOS hi CD4 T cells was conducted using serial collections of peripheral blood mononuclear cells (PBMCs) from a subset of evaluable subjects in the ICONIC trial. A mouse syngeneic tumor model was developed to assess the kinetics of ICOS hi emergence as well as determine functionality and combination efficacy. Biological activity was assessed through ex vivo functional assays, with phenotypic assessments by flow cytometry-based profiling and genomic analysis. Results: Phenotypic profiling of ICOS hi CD4 T cells demonstrated a T central memory phenotype with Th1 characteristics, and ICOS hi CD4 T cells increased as a % of the CD4 compartment longitudinally. Potent effector molecules, including perforin and granzyme, were significantly upregulated in isolated ICOS hi CD4 T cells relative to ICOS lo CD4 T cells from subjects. In a syngeneic tumor-bearing mouse system, ICOS hi CD4 T cells were induced in lymphoid organs following ipi treatment, with emergence detectable at day 3 and peaking at day 7 post-treatment, where up to 40% of CD4 T cells were ICOS hi. Relative to monotherapy, enhanced anti-tumor efficacy was observed in mice treated with combination ICOS agonist and ipilimumab. Conclusion: Emergence of a peripheral ICOS hi CD4 T cell population correlates with response to vopra treatment and occurs independent of anti-PD-1 activity. Transcriptional profiling of