Abstract 2254: Therapeutic depletion of FR-β-positive M2 macrophages in solid tumor indications: A novel IO strategy

Abstract Traditional IO therapy has primarily focused on T cell checkpoints, however macrophages typically represent the largest immune population present within tumors and can constitute up to 50% of total tumor mass. Macrophages are implicated in both immune mediated control of tumors as well as tumor progression depending on the phenotype of macrophages in the tumor microenvironment (TME). Immune suppressive M2-like tumor associated macrophages (TAMs) release immuno-suppressive cytokines such as IL-10 and TGF-β which promote regulatory T cells, angiogenesis, metastasis, and tumor progression correlating with a poor prognosis in several solid tumor indications including breast, bladder, ovarian, gastric, prostate, RCC, melanoma, and lung cancers. Folate Receptor beta (FRβ) expression is associated specifically with M2-like immune suppressive macrophages and is not observed on proinflammatory M1-like macrophages. FRβ expression correlates with poor prognosis across lung cancer indications. Depletion of FRβ macrophages by natural killer (NK) cells using an Fc enhanced monoclonal antibody (mAb) to drive antibody-dependent cellular cytotoxicity (ADCC), is proposed as a therapeutic modality, by removing M2-like immunosuppressive macrophages from the TME, while preserving anti-tumorigenic M1-like macrophages. Modified Fc enhanced human FRβ targeting tool mAb M909 results in M2 specific ADCC activity in human monocyte derived macrophage populations in vitro. A single dose of modified Fc enhanced murine FRβ targeting tool mAb CL10 results in depletion of murine FRβ+ myeloid cells from MC38 tumors in vivo for up to 6 days. To guide patient stratification in lieu of highly invasive biopsy sampling, a soluble biomarker that can be assessed in peripheral blood and correlates to tumor FRβ expression is highly desirable. In patient matched peripheral blood and non-small cell lung cancer (NSCLC) tumor biopsy samples, peripheral blood FRβ+ nonclassical monocytes correlated with FRβ+ TAMs and CX3CR1+ cells which are known to drive macrophage recruitment to the TME. Interestingly, prevalence of NK cell marker NKG2D in peripheral blood also correlated to FRβ+ TAMs. Taken together, the data suggest further exploration of a depleting anti-FRβ+ Fc enhanced mAb as a therapeutic strategy for certain solid tumor indications is merited. All studies conducted according to GSK's Policy on the Care, Welfare and Treatment of Lab Animals and reviewed by the Institutional Animal Care and Use Committee at GSK or by the ethical review process at the institution where the work was performed. Citation Format: Michael Adam, R. Paul Wilson, Helen Sanderson, Chris Hopson, Julie Krueger, Veronica Herrera, Heidi Emerich, Andrew Sanderson, Carol Harris, James Smothers. Therapeutic depletion of FR-β-positive M2 macrophages in solid tumor indications: A novel IO strategy [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 2254.