Abstract 6380: PLX-4545, a selective IKZF2 degrader, reprograms suppressive Tregs leading to tumor growth inhibition and combination benefit with immune checkpoint therapy

Abstract Background: Checkpoint inhibitors (CPI) have significantly advanced cancer treatment; however, responses are limited to patient subsets. Tumors avoid immunosurveillance by recruiting suppressive regulatory T-cells (Treg) limiting the activation and expansion of tumor effector T-cells (Teff). The transcription factor IKZF2 (Helios) is required to maintain a suppressive Treg phenotype in the inflammatory tumor microenvironment and is also implicated in dysregulated tumor CD8 T-cells. PLX-4545 is a potent and selective IKZF2 degrader, that depletes IKZF2 and converts suppressive Tregs into effector-like T-cells leading to antitumor immunity. Results: Immune profiling of PBMCs identified significant increases in IKZF2+CD25+FOXP3+ Tregs in cancer patients relative to healthy donors; IKZF2 expression was further increased in tumor Tregs. IKZF2 expression in CD8 T-cells was also significantly increased in tumor infiltrating lymphocytes (TILs) and was associated with an exhausted phenotype (high TIGIT, low Granzyme B, low IL-2). In vitro, treatment of PBMCs with PLX-4545 lead to rapid and complete degradation of IKZF2, conversion of suppressive Tregs into effector-like T-cells through reduction of CD25 and FOXP3 expression, and increased proliferation of Teff cells. In vivo efficacy studies with oral administration of PLX-4545 resulted in dose dependent depletion of IKZF2 and single agent antitumor activity. Immune profiling confirmed that IKZF2 is more highly expressed in tumor Tregs relative to circulating Tregs. Degradation of IKZF2 upon PLX-4545 treatment preferentially converted tumor Tregs into effector-like T-cells through decreased CD25 expression and increased production of effector cytokines (IL2, IFNγ), resulting in increased infiltration of CD4/8 Teff cells into tumor tissue. Combination of PLX-4545 with anti-PD1 significantly increased the proliferation of Teff cells and inhibition of tumor growth in vivo. Bioinformatics analysis of TCGA gene expression identified tumor types with elevated IKZF2 expression that correlated with immune gene signatures enabling prioritization of tumor types. An immunohistochemistry biomarker was developed to evaluate IKZF2 expression in tumor resident immune cells. Conclusion: PLX-4545, a selective IKZF2 degrader, preferentially converts tumor Tregs into effector-like T-cells, enhances CD8 T-cell response and shifts Teff:Treg balance in favor of anti-tumor activity, resulting in single agent activity and combination benefit with CPI. IKZF2 expression is elevated in cancer patient subsets, particularly in tumor Tregs and dysregulated CD8 TILs. PLX-4545 provides the potential to overcome immune resistance and broaden clinical response to CPI. PLX-4545 is currently in a Phase I clinical trial to evaluate safety, pharmacokinetics and pharmacodynamic response. Citation Format: Yujun Huang, Susan Song, Linette Yang, Jianguo Ma, Jay Chung, Alejandro Dearie, Stephen Chien, Quinn Spalding, Sean Choi, Gabrielle Blanco, Julia Toth, Xiaoming Li, Gregory S. Parker, Peggy A. Thompson. PLX-4545, a selective IKZF2 degrader, reprograms suppressive Tregs leading to tumor growth inhibition and combination benefit with immune checkpoint therapy [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 6380.