SITC 2023 Poster 1119

Selective Reversal of Key Features of T cell Exhaustion in an In Vitro Model by a SMARCA4/2 ATPase Inhibitor

Eden Kleiman, Linda Liang, Elizabeth Epps, Jared Gunn, Mingfa Zang, Marrit Putker, Ludovic Bourre and Pirouz Daftarian

Crown Bioscience, Inc., 16550 West Bernardo Drive, Building 5, Suite 525, San Diego, CA 92127

JSR Life Sciences, Sunnyvale, California

This research describes a study in which the previously reported in vitro T cell exhaustion model was employed to test a novel inhibitor of SMARCA4/2 ATPase activity, FHT-1015.

CD3⁺ T cells were isolated from 2 healthy donor PBMC collections. Purified T cells were stimulated with Dynabeads 4x times at 48-hour intervals. Cells were treated additionally with DMSO every 48 hours (4x DMSO), 1x to 4x times with 100nM FHT-1015 (SMARCA4/SMARCA2 ATPase (BRG1 and BRM) inhibitor) every 48 hours or left untreated. On day 8, medium was collected for cytokine analysis, and T cells were immunophenotyped by flow cytometry for co-inhibitory receptor expression.

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• Cell viability, CD4, and CD8 % after FHT-1015 treatment
  
  
• FHT-1015 progressively reduces hallmarks of T cell exhaustion
  
  
• FHT-1015 decreases terminally exhausted cells while increasing progenitor-like T cells
  
  
• FHT-1015 inhibits secretion of homeostatic and inflammatory cytokines

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