Abstract 1678: Integrated genomics and histology based studies of triple negative breast cancer identify ICOS as potential target for therapeutic intervention
Authors: Hirsch Heather A. , Zi Tong , Fontana Rachel , Wu Yun , Reeves Jason , Needham Alexander , Stack Edward , Lee David , Lees Emma , Law Deborah A. , Trehu Elizabeth , Mittendorf Elizabeth A. 
Published: August 2018

Abstract
ICOS (Inducible CO-Stimulator of T cells) is a co-stimulatory molecule expressed primarily on T lymphocytes. ICOS was prioritized as a target of interest based on nonclinical and clinical data that identified ICOS as a potentially key molecule in providing optimal anti-tumor benefit following anti-CTLA-4 therapy. We are developing JTX-2011, an ICOS agonist antibody that is designed to generate an anti-tumor immune response through stimulation of T effector cells and preferential reduction of intratumoral T regulatory (Treg) cells. In preclinical mouse tumor models, efficacy of an ICOS agonist was greatest in tumors with the highest levels of intra-tumoral ICOS, suggesting a potential predictive biomarker approach for clinical development. In assessing ICOS expression across multiple tumor types at both the RNA and protein level, we have identified triple negative breast cancer (TNBC) as a potential indication for an ICOS-targeted immunotherapy approach.
Integrated analysis of RNA, DNA and clinical data from the Cancer Genome Atlas (TCGA) was performed to understand the context in which ICOS is expressed. Additionally, ICOS levels were assessed by IHC in human tumor samples from an orthogonal data set. IHC and RNA analyses revealed a dynamic range of ICOS expression across indications and identified a subpopulation of breast cancer tumors enriched for high ICOS expression. Further analysis of both IHC and RNA data sets revealed that the triple negative subtype has higher enrichment of ICOS expression than other breast cancer subtypes. ICOS levels were correlated to gene signatures of immune infiltrate as well as other clinical attributes and molecular markers. There was a correlation between ICOS, ICOS signature, PD-L1 and IFNγ signatures. We then assessed TNBC samples obtained pre and post-neoadjuvant treatment to further understand the impact of chemotherapy on the tumor microenvironment. This included analysis of ICOS and PD-L1 protein expression as well as assessment of tumor-infiltrating immune cell subsets. While the distribution of certain immune cell subsets differed in pre and post-treatment samples, the expression of ICOS remained consistent. Based on these data, a TNBC cohort, enriched for the ICOS IHC biomarker, is included in the Phase 2 portion of the ICONIC study that is designed to assess the potential for a combination of JTX-2011 with a PD-1 checkpoint in this difficult to treat patient population.
Citation Format: Heather A. Hirsch, Tong Zi, Rachel Fontana, Yun Wu, Jason Reeves, Alexander Needham, Edward Stack, David Lee, Emma Lees, Deborah A. Law, Elizabeth Trehu, Elizabeth A. Mittendorf. Integrated genomics and histology based studies of triple negative breast cancer identify ICOS as potential target for therapeutic intervention [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1678.