P02.11 TREM1 agonist PY159 promotes myeloid cell reprogramming and unleashes anti-tumor immunity

Background Tumor-associated myeloid cells can impede productive anti-tumor immunity. One strategy for targeting immunosuppression is reprogramming, which drives immunosuppressive to acquire an immunostimulatory phenotype. Triggering receptor expressed on cells-1 (TREM1) immunoglobulin superfamily cell surface neutrophils and subsets of monocytes tissue macrophages. TREM1 associates with DAP12 adaptor induces proinflammatory signaling, amplifies innate immune responses, implicated in the development acute chronic inflammatory diseases. also enriched tumors, specifically tumor-associated cells. To investigate potential modulation as anti-cancer therapeutic strategy, we developed PY159, afucosylated humanized anti-TREM1 monoclonal antibody, characterized it pre-clinical assays described below. Materials Methods An FcγR binding ELISA a Jurkat TREM1/DAP12 NFAT-luciferase reporter line were used assess PY159 human FcγRs respectively. responses whole blood vitro evaluated by flow cytometry, transcriptional analysis sorted leukocyte subsets, measurement secreted cytokines/chemokines MSD. A Transwell system was evaluate effects neutrophil chemotaxis. expression tumors validated scRNAseq, immunohistochemistry, cytometry. Anti-tumor efficacy surrogate anti-mouse PY159m, using syngeneic mouse tumor models, either single agent or combination anti-PD-1. Results afucosylation increased its affinity ability activate signaling. In assays, treatment did not induce depletion TREM1-expressing Rather, upregulated monocyte activation markers, promoted chemotaxis, induced cytokines chemokines, dependent afucosylation. detected neutrophils, macrophages, monocytic myeloid-derived suppressive chemokines dissociated , demonstrating that reprogram exhibited several both single-agent Conclusions These results show agonist reprograms unleashes safety are currently being first-in-human clinical trial ( NCT04682431 ) involving patients resistant refractory standard care therapies. Disclosure Information V. Juric: A. Employment (full part-time); Significant; Pionyr Immunotherapeutics Inc. E. Mayes: M. Binnewies: P. Canaday: T. Lee: S. Dash: J.L. Pollack: J. Rudolph: Huang: X. Du: N. Jahchan: A.J. Ramoth: Mankikar: Norng: C. Santamaria: K.P. Baker: L. Liang: