Abstract 5850: AXA-042, a systemically administered TLR2/6 agonist, demonstrates innate immune engagement and Th1 polarization in patients with advanced solid tumors

Abstract Background: AXA-042 is a novel, systemically delivered synthetic toll-like receptor (TLR) 2/6 agonist in development for the treatment of advanced solid tumors. A first-in-human study evaluating the safety, tolerability, pharmacokinetics, and pharmacodynamics of AXA-042 as monotherapy and in combination with a checkpoint inhibitor in subjects with advanced solid tumors is currently ongoing (ACTRN12622000993796). Cytometry by time-of-flight (CyTOF) analysis was performed to characterize AXA-042 immune modulation signatures in patient whole blood samples. Methods: AXA-042 was administered intravenously q21d. Informed consent was obtained and whole blood samples were collected pre-dose on C1D1, and 24h and 168h post-treatment (C1D2, C1D15) across three dose levels of AXA-042. Stabilized whole blood samples were immunophenotyped using a 43-marker CyTOF panel. Results: In pre-dose samples, TLR2 was most frequently expressed on Monocytes (>80%), cDCs (47%) and in 20-30% of CD8, CD4 and γδ-T cell subsets. AXA-042 treatment led to the re-distribution of neutrophil, monocyte and cDC subset frequencies on C1D2, consistent with the expected acute inflammation response to a TLR2 agonist. Furthermore, AXA-042 increased the frequency of activated CD69+ cytolytic NK cells and γδ-T cells on C1D2. A general immune reset to baseline levels occurred for most populations on C1D15. Notably, a decrease in CTLA4+ Tregs and an increase in T-bet+ NK, γδ-T cells and TCF1+ CD8, CD4 T-cell subset frequencies, indicating a potential increase in Th1 polarization and preservation of effector function, was observed on C1D15 (Table 1 Table 1. Subset Frequency Timepoint Median % Change (* FDR<0.05, ** FDR<0.01) Dose Level 1 (n=6) Dose Level 2 (n=3) Dose Level 3 (n=3) ↑CD16lo Neutrophils C1D2 8.7** 38.8** 48.3 ** ↓CD16hi Neutrophils C1D2 -7.8** -37.8** -48.6 ** ↑CD44+ Neutrophils C1D2 13.2 23.6** 17.4** ↓CD39+ Monocytes C1D2 -20.1** -15.9** -29.5** ↓CD39+ cDCs C1D2 -14.9** -12.8* -5.0* ↓HLA-DR+ Monocytes C1D2 -17.5** -15.6** -0.9* ↓CD11b+ Monocytes C1D2 -8.6** -17.3* -27.3** ↑CD69+ Cytolytic NKs C1D2 10.5 36.5** 16.7** ↑CD69+ γδ-T C1D2 -0.7 * 14.4 18.2 ** ↓CTLA4+ Tregs C1D15 -2.3 * -11.1 ** -15.9 ** ↑Tbet+ Cytolytic NK C1D15 5.5* 30.5** 23.9** ↑Tbet+ γδ-T C1D15 4.4 16.2** 13.1** ↑TCF1+ CD8 TCM T cells C1D15 2.6 14.5* 12.9** ↑TCF1+ CD4 TCM T cells C1D15 0.03 14.5* 9.8** ↑TCF1+ CD8 Naïve T cells C1D15 0.42 21.1* 15.5** ↑TCF1+ CD4 Naïve T cells C1D15 5.3 15.6** 14.7** ↑HLA-DR+ ncMonocytes C1D15 -4.1 9.0* 25.9** ↑HLA-DR+ cDCs C1D15 -0.2 7.4* 32.5* ). Conclusions: The whole blood immunophenotyping analysis identified early pharmacodynamic markers of innate immune response engagement in response to AXA-042 and demonstrated sustained presence of Th1-polarized NK and T cell subsets with potential for enhanced cytotoxicity and effector function on C1D15. Citation Format: Ben Tran, Sophia Frentzas, Charlotte Rose Lemech, Michael Millward, Daphne Day, Jayesh Desai, Ardian Latifi, Paul Wabnitz, Phil Kearney, Anna V. Galkin. AXA-042, a systemically administered TLR2/6 agonist, demonstrates innate immune engagement and Th1 polarization in patients with advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5850.