Abstract B019: CCR5 inhibition with leronlimab is associated with enhanced PD-L1 expression, ICI response, and long-term survival in metastatic TNBC.

Abstract Introduction: CCR5 is overexpressed in ∼95% of triple-negative breast cancer (TNBC) and is associated with resistance to PD-1/PD-L1 checkpoint inhibitors. CCR5 inhibition reduces graft vs. host disease and tumor metastasis in animal models. Recent clinical observations suggest that combining the CCR5-blocking antibody leronlimab with immunotherapy (immune checkpoint inhibitor) (ICI) may significantly improve survival in metastatic TNBC (mTNBC). The current studies were conducted to identify the molecular mechanisms by which leronlimab governs PD-L1 expression and ICI responses. Methods: Analysis of patient gene expression, tumor histology, cancer-associated macrophage/circulating tumor cells (CAML/CTC) from the clinical studies, and tissue culture analysis of TNBC were conducted. Findings: Clinical outcomes: In a retrospective post hoc analysis, data were pooled from 28 patients with mTNBC from three clinical trials (NCT03838367 [N=10]; NCT04313075 [N=16]; NCT04504942 [N=2]). Leronlimab was well tolerated, with no patients withdrawing due to leronlimab-related adverse events and no dose-limiting toxicities. Survival outcomes: Of the patients (median age, 48.5 years (32-83; N=28), prior lines of therapy in the metastatic setting (median=2), visceral metastases (64% (N=18)), of which (N=8) had brain metastases, and non-visceral metastases (36% (N=10)), ∼18% of heavily pretreated mTNBC patients are currently alive after median >60 months. (1 year survival 35.7%; 2 year survival 21.4%; 3 and 4 year survival 17.9%). Clinical correlates: Higher leronlimab dose (550–700 mg once weekly), induction of PD-L1, and the formation of CCR5 dots in CAML/CTC and treatment with an ICI were associated with improved survival. In large TNBC cohorts (N=1,214), CCR5 expression correlated strongly with ICI-resistance signatures, IFNγ and MHC I/II antigen presentation, and T-cell expansion. CCR5 correlated with ICI resistance in validation cohorts. Cellular effects: CCR5 expression suppressed glycosylated PD-L1; CCR5 inhibition increased total PD-L1 and reduced acidic environment-driven AMPKThr172 activation in TNBC cells. Proteomic findings: CCR5 activity induced sB7H3 ((CD276) member of the immune checkpoint) and sTyro3 (linked to ferroptosis inhibition) and the Tyro3 ligand Pros1. Both CD276 and Tyro3 are associated with ICI resistance, and the abundance of both was attenuated by CCR5 blockade. Conclusions: CCR5 may promote ICI resistance in TNBC by upregulating immune checkpoints (sB7H3) and sTyro3. ∼18% of patients with mTNBC treated with leronlimab in combination, or subsequently, with (ICI are currently alive (median >60 months). Leronlimab is well tolerated and induces PD-L1 expression on CAML/CTC, which may prime tumors for successful PD-L1 blockade. The encouraging long-term survival justifies further evaluation of leronlimab in combination with ICIs. Reference: 369P Pestell, RG., et al., V 10, ESMO Open 2025/5/1 Citation Format: Richard G. Pestell, Zhiping Li, Ritika Harish, Xuanmao Jiao, Rui Hallgeir, Massimo Cristofanilli, Daniel L. Adams, Max Lataillade, Neil E. Buss, Denis R. Burger, Cyrus A. Arman, Jacob P. Lalezari. CCR5 inhibition with leronlimab is associated with enhanced PD-L1 expression, ICI response, and long-term survival in metastatic TNBC [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Mechanisms of Cancer Immunity and Cancer-related Autoimmunity; 2025 Sep 24-27; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(9 Suppl):Abstract nr B019.