Abstract A044: LP-184, a Novel Acylfulvene, Sensitizes Immuno-refractory Triple-Negative Breast Cancers (TNBCs) To Anti-PD1 Therapy by Affecting the Tumor Microenvironment

Abstract Drugs that induce DNA double strand breaks (DSBs) can activate the cGAS/STING pathway, leading to immune responses. Lantern Pharma is advancing a novel acylfulvene small molecule therapeutic, LP-184, a DNA damaging alkylating agent that creates DNA DSBs. LP-184 is a prodrug requiring bioactivation by the enzyme prostaglandin reductase 1 (PTGR1). RNAseq analysis of cancer cells exposed to LP-184 revealed activation of the STING pathway. A link between replication stress response (RSR) defect signature and enhancement of anti-PD1 activity in mouse models implicated certain DNA Damage Repair (DDR) targeting agents in induction of RSR defects and modulation of response to immuno-oncology (IO) agents. Assessing the effect of LP-184 on potentiating anti-PD1-driven immune checkpoint blockade in triple-negative breast cancer (TNBC) in a syngeneic mouse model showed that LP-184 combined with an anti-PD1 agent elicited a greater anti-tumor response than monotherapies in mouse TNBC tumors that are non-hypermutated and IO resistant. Investigation of effects of LP-184 on immune factor modulation in the tumor microenvironment (TME) with and without co-treatment with anti-PD-1 agent by fluorescence-activated cell sorting demonstrated that LP-184 plus anti-PD1 led to a larger T cell population in the TME along with higher activity of T cells. Flow cytometry based cell cycle analysis in TNBC cells revealed that LP-184 treatment created RSR defects comparable to that induced by CHK1 inhibitor Prexasertib, a promising agent in TNBC, often characterized by high levels of genomic instability and concomitant addiction to the RSR pathway involving ATR/CHK1. Results suggest that LP-184 can synergize with an anti-PD1 agent in a TNBC mouse model potentially via reshaping the TME by decreasing M2 macrophages, increasing T cell infiltration, and enhancing individual T cell function when combined with ICB therapy. Potential mechanisms of LP-184-driven M2 macrophage reduction could include decreased M2 macrophage polarization via tumor cell death or specific targeting of this PTGR1-expressing immunosuppressive cell type. LP-184, currently in a monotherapy Phase 1 dose finding/optimization safety study, thus exhibits potential to sensitize tumors non-responsive to anti-PD-1 therapy. Furthermore, single-cell RNA sequencing was performed on tumor samples from mice treated with control, LP-184, anti-PD1, and their combination. Clustering and differential expression analysis uncovered treatment-responsive cell populations and genes. Enrichment analysis highlighted key pathways affected by each treatment, focusing on immune-related pathways, cytokines, and chemokines. This proved to be a powerful approach that provides insights into immune-tumor cell interactions modulated by LP-184 and anti-PD1 within the TME. Next steps include testing whether LP-184 treatment elevates cytoplasmic ssDNA or dsRNA, activates the STING pathway, induces immunogenic cell death, and increases the expression of immunostimulatory cytokines. Citation Format: Yong Du, Aditya Kulkarni, Jianli Zhou, Hui Dai, Kishor Bhatia, Shiaw-Yih Lin. LP-184, a Novel Acylfulvene, Sensitizes Immuno-refractory Triple-Negative Breast Cancers (TNBCs) To Anti-PD1 Therapy by Affecting the Tumor Microenvironment [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr A044.