Abstract 4715: Depletion of mMDSCs using a CCR2-directed cytotoxicity targeting chimera (CyTAC) leads to remodeling of the tumor microenvironment and immune mediated tumor regression

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Abstract mMDSCs (monocytic myeloid derived suppressor cells) are recruited to solid tumors and serve as potent inhibitors of T-cell mediated antitumor immunity. Therapeutic depletion of mMDSCs presents an exciting opportunity to increase the frequency and durability of anti-tumor clinical responses achieved with immune checkpoint inhibition. Currently, no marketed or investigational agents function by specific mMDSC depletion and no specific markers for therapeutic targeting of these cells have been clinically validated. We demonstrate that mMDSCs express high and homogeneous levels of the chemokine receptor CCR2. Because of this, we have developed a CCR2 targeting Cytotoxicity Targeting Chimera, which potently binds CCR2 on cells, and when combined with the CyTAC platform antibody, eliminates target cells via enhanced effector mediated killing. We demonstrate that the CCR2 CyTAC can deplete CCR2+ monocytes and mMDSCs from the periphery and intratumorally both ex vivo and in vivo. In the MC38 syngeneic tumor model this depletion leads to T-cell dependent anti-tumor activity and increases the levels of CD8 T-cells within the tumor microenvironment. We show across multiple additional syngeneic tumor models that depletion of CCR2+ cells remodels the tumor microenvironment causing an increase in tumor infiltrating CD8 T-Cells and a decrease in regulatory T-cells and mMDSCs. These PD changes were observed in both responding and non-responding tumor models where response can be enhanced with anti-PD1. Significance: We have applied our CyTAC technology to specifically target CCR2 expressing cells and depletion of mMDSCs and demonstrate that this can lead to remodeling of the tumor microenvironment from a pro-tumor to pro-inflammatory phenotype. This agent has potential for treating tumors with high mMDSC content regardless of tumor type. Note: Human biological samples were sourced ethically, and their research use was in accord with the terms of the informed consents under an IRB/REC approved protocol. 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: Brandon J. Turunen, Beth Knapp-Reed, Craig Leach, Peiling Chen, Matthew Sender, Joseph Marino, Cunyu Zhang, Yao Chen. Depletion of mMDSCs using a CCR2-directed cytotoxicity targeting chimera (CyTAC) leads to remodeling of the tumor microenvironment and immune mediated tumor regression [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 4715.

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