Abstract A041: FHD-286, a potent and selective inhibitor of BRG1 and BRM, shifts metastatic uveal melanoma tumor towards a less immunosuppressive state in patient samples
Authors: Johannessen Liv H , Wan Jessica , Horrigan Kim , Collins Mike , Elliott GiNell , Ichikawa Kana , Adam Ammar , Agresta Sam , Piel Jessica , Hentemann Martin 
Published: December 2023

Abstract
BRG1/BRM are key components of the SWI/SNF complex that are critical in regulation of transcriptional programs that control cell fate and identity. Tumor cells aberrantly hijack and upregulated BRG1 levels, hijacking “stemness features”. Furthermore, BRG1 has been shown to impact immune cell polarization, driving programs associated with T cell exhaustion and an immunosuppressive cell state. Our group previously demonstrate that the combination of FHD-286 and anti-PD-1 antibody is synergistic in syngeneic mouse models from various lineages, and substantially shifted with tumor microenvironment (TME) towards a more tumor killing state (Ichikawa, K. 2022, SITC). FHD-286 was evaluated in a phase 1 dose escalation (FHD-286-001, NCT04879017), in metastatic uveal melanoma (mUM) a tumor with low response rate to standard immune checkpoint therapy as well as high levels of immunosuppressive cell infiltration. Thus, we endeavored to determine if there was evidence of biological changes in peripheral blood and TME shifts in samples taken from our phase 1 dose escalation in patients with metastatic uveal melanoma. Subjects were on a daily dosing regimen ranging from 2.5 to 10 mg or an intermittent regimen of 1-week on/1-week-off ranging from 10 to 22.5 mg in 73 patients. RNA sequencing was performed in 46 patient blood samples collected in Paxgene tubes during dose escalation (2.5 mg- 15mg, C1D1, C1D15, C3D1 and other intermediate timepoints) and analyzed for transcriptional changes associated with shifts in immune polarization and activation. Tumor biopsies were collected at screening and either Cycle 3 or end of treatment. Biomarker changes in the tumor were quantified using multiplex IF (mIF) panel (Neogenomics) to assess co-localization and spatial orientation of 20 different immune related markers in 16 patients, 13 of which had samples from screening and on-treatment. Further changes were assessed using RNA sequencing of paired biopsies in 9 patients. Analysis of peripheral blood identified changes in expression of genes associated with a reduction in immunosuppressive signatures, particularly a dose dependent reduction of FOXP3 from baseline, as well as an increase in transcripts associated with activation of neutrophils. The mIF panel highlighted a reduction in immunosuppressive cells of multiple lineages including in on treatment samples, with 12/13 patients showing a reduction of one or more of the following: FOXP3+ Tregs (8/13), PD-L1+ Macrophages (8/13), an increase in the M2 Mf to tumor cells distance (8/13), markers of T cell exhaustion (PD1) on both CD4 (7/13) and CD8 T cells (8/13), or an increase in CD8/Treg ratio (5/13). Taken together these results suggest FHD-286 may reduce the immunosuppressive “blockade”, priming mUM patients to response in combination with an immune checkpoint inhibitor.
Citation Format: Liv H Johannessen, Jessica Wan, Kim Horrigan, Mike Collins, GiNell Elliott, Kana Ichikawa, Ammar Adam, Sam Agresta, Jessica Piel, Martin Hentemann. FHD-286, a potent and selective inhibitor of BRG1 and BRM, shifts metastatic uveal melanoma tumor towards a less immunosuppressive state in patient samples [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A041.