Abstract LB213: Heterogeneous expression of IL13Ra2 in melanoma patient-derived xenograft models and targeting with bispecific T cell engager for melanoma therapy

Melanoma is a highly aggressive skin cancer, especially diagnosed in advanced stages. While current treatments such as targeted therapies and immunotherapies have made promising progress, challenges like drug resistance and limited effectiveness in some patients persist. Therefore, ongoing development of novel therapies, particularly for late-stage melanoma, is crucial. In this study, we explored the expression of interleukin-13 receptor subunit alpha-2 (IL13Rα2) in melanoma patient-derived xenograft (PDX) models. Our findings revealed heterogeneous expression of IL13Rα2, particularly in samples from advanced stages of melanoma. Then we investigated IL13Rα2 as a potential target for melanoma treatment by employing an IL13Rα2-CD3 bispecific T cell engager (BTE). We tested the effect of IL13Rα2-CD3 BTE to T cells activity by flow cytometry. The IL13Rα2-CD3 BTE facilitated T-cell activation and proliferation by bridging melanoma cells and T-cells. We studied the potency of IL13Rα2-CD3 BTE in tumor killing assay in vitro. We also observed the ability of IL13Rα2-CD3 BTE to direct T cells to kill multiple melanoma patient-derived cell lines through xCELLigence assay in vitro, including those with various mutations associated with late-stage metastatic melanoma. For in vivo studies, we administered DNA expression constructs encoding IL13Rα2-CD3 BTE (IL13Rα2-CD3 dBTE) into immunodeficient mice for direct in vivo expression. The mice were challenged with A375 cells and then treated with IL13Rα2-CD3 dBTE versus control and reconstituted with human PBMCs or T cells. Tumor development was monitored, and T cells infiltration in tumor was analyzed through flow cytometry. IL13Rα2-CD3 dBTE expressed in vivo led to notable tumor regression through inducing increased T-cell infiltration and activation within the tumor microenvironment. These promising findings underscore the potential of targeting IL13Rα2 as a relevant target for the development of biologics including dBTE aimed at treating specific subsets of melanoma. Citation Format: Shushu Zhao, Yeqing Chen, Pratik S. Bhojnagarwala, Cory Livingston, Joshua Jose, Yangcheng Gao, Daniel Park, Meenhard Herlyn, David B. Weiner. Heterogeneous expression of IL13Ra2 in melanoma patient-derived xenograft models and targeting with bispecific T cell engager for melanoma therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited s); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2): nr LB213.