Abstract LB128: Timely resolution of TREM-1-mediated inflammation after chemotherapy improves complete response rate and survival in experimental pancreatic cancer

Field: Pharmacology, Toxicology and Pharmaceutics (Life Sciences)

Abstract Pancreatic ductal adenocarcinoma (PDAC), is the third leading cause of cancer-related death in the US. Despite recent advances, the 5-year survival rate for all stages combined is as low as 13%, necessitating the development of new approaches. Similar to other cancer treatments, current chemotherapy standard of care for PDAC represents a double-edged sword: it reduces tumor burden by killing cancer cells, however, the resulting dead tumor cells, or debris, induce inflammation that promotes tumor recurrence and metastasis. We hypothesized that blockade of triggering receptor expressed on myeloid cells 1 (TREM-1), an inflammation-amplifying receptor expressed on myeloid cells including tumor-associated macrophages (TAMs), can resolve chemotherapy-induced inflammation and improve response rate and survival. To address the problem of multiplicity and promiscuity of natural TREM-1 ligands and reduce the risk of drug failure in clinical efficacy testing, we developed a first-in-class TREM-1 inhibitory peptide sequence GF9 that employs a novel, ligand-independent mechanism of action. In this study, we used lipopeptide complexes (LPC) of a 31-mer peptide GA31 (GA31-LPC) to predominantly inhibit TREM-1 expressed on macrophages. GA31 is rationally designed to combine the TREM-1 inhibitory activity of a 9-mer peptide GF9 with the lipid-binding and macrophage-targeting capabilities of an oxidatively modified peptide PA22, a 22-amino acid amphipathic peptide that originates from human apolipoprotein A-I. Formulation of GA31 into LPC significantly extends its half-life and improves targeting. We found that the sub 120 nm-sized GA31-LPC formulation is stable, non-immunogenic, non-cytotoxic and well-tolerable, and effectively suppresses inflammation in vitro and in vivo. In xenograft mouse models of PDAC, TREM-1 blockade reduces plasma cytokines and TAM content and when started after standard chemotherapy, significantly improves complete response rate and survival. The magnitude of this effect depends on the chemotherapy agents used and their dosage. When started simultaneously with chemotherapy, TREM-1 blockade does not exhibit anti-tumor activity. In summary, this animal proof-of-concept study shows for the first time the critical importance of timing in the suppression of TREM-1-mediated inflammation in chemotherapy-treated cancers. This may have important clinical implications in the treatment of patients with not only PDAC, but also other inflammation-associated, hard-to-treat solid tumors. By supplementing current first-line cancer treatments (chemo- and immunotherapies, radiation and surgery), pharmacological interventions that timely resolve TREM-1-mediated inflammation may improve quality of life and extend survival of cancer patients. Citation Format: Alexander B. Sigalov. Timely resolution of TREM-1-mediated inflammation after chemotherapy improves complete response rate and survival in experimental pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB128.