Abstract 4053: Genetic and molecular profiling of ICOS hi CD4 T cells demonstrates clonal expansion of Th1 effector cells following JTX-2011 treatment in subjects with solid tumors
Authors: Harvey Christopher , Hanson Amanda , Fan Martin , McGrath Lara , Felitsky Daniel , Johnson Calvin , Lacey Sean , Hirsch Heather , Hooper Ellen , McClure Ty , Trehu Elizabeth , Law Deborah , Laken Haley 
Published: August 2019

Abstract
Background: Inducible T cell Co-stimulator (ICOS) is a costimulatory molecule expressed primarily on T lymphocytes that is upregulated upon cell activation. JTX-2011 is a first-in-class ICOS agonist antibody whose primary mechanism of action is the stimulation of primed CD4 T effector cells. Clinical and biological activity of JTX-2011 was assessed in the advanced solid tumor setting in the Phase I/II ICONIC trial (NCT02904226). Clinical responses to JTX-2011 were associated with the emergence of an ICOS hi CD4 T cell population, which was subsequently demonstrated to be due to activity of JTX-2011 and not a PD-1/L-1 inhibitor.
Methods: Assessment of phenotype and function of ICOS hi CD4 T cells was conducted using serial collections of peripheral blood mononuclear cells (PBMCs), whole blood, and tumor samples from a subset of evaluable subjects treated with JTX-2011 at 0.1mg/kg and 0.3mg/kg monotherapy and in combination with nivolumab. Biological activity was assessed through ex vivo functional assays, flow cytometry-based profiling, and genomic analysis including assessment of changes in T cell clonality. Mutational analysis of tumor samples was used to identify neoantigens for functional assessment of antigen specificity.
Results: Flow-based phenotyping revealed ICOS hi CD4 T cells as T effector cells of primarily the Th1 lineage. Analysis of changes in clonal abundance in the peripheral blood T cell receptor repertoire identified significant on-treatment expansion of clones in 18/22 (~82%) of subjects following JTX-2011 treatment, including those from monotherapy. Expanded clones detected in the periphery were tumor-associated clones present in archival tumor samples, suggesting that JTX-2011 may function to enhance cell-mediated anti-tumor immunity. Assessment of tumor mutational burden identified several potential MHC Class II neoantigens, again raising the potential of agonism of CD4 effector cell immunity. In independent experiments using tetanus based priming of donor PBMCs, ex vivo stimulation by soluble JTX-2011 was active only if ICOS hi CD4 T cells were already present, with JTX-2011 inducing potent polyfunctional cytokine responses characterized by a 4-fold average increase in both IFNγ and TNFα.
Conclusion: Emergence of a distinct ICOS hi population of peripheral CD4 T cells correlates with response to JTX-2011 treatment. Independent characterization of ICOS hi CD4 T cells induced by recall antigens demonstrate potent effector function induced by JTX-2011, but only if the cells were already ICOS hi, which is hypothesized to contribute to biological activity. The emergence of this population is being used to guide clinical development by informing sequencing of combination approaches that maximize the potential for a combination agent to induce ICOS hi CD4 T cells, followed by subsequent agonism with JTX-2011.
Citation Format: Christopher Harvey, Amanda Hanson, Martin Fan, Lara McGrath, Daniel Felitsky, Calvin Johnson, Sean Lacey, Heather Hirsch, Ellen Hooper, Ty McClure, Elizabeth Trehu, Deborah Law, Haley Laken. Genetic and molecular profiling of ICOS hi CD4 T cells demonstrates clonal expansion of Th1 effector cells following JTX-2011 treatment in subjects with solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4053.