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Published on: February 24, 2023
Targeting IL13Rα2 in melanoma with a bispecific T-cell engager: expression profiling and preclinical evaluation
Shushu Zhao1, Yeqing Chen1, Pratik S Bhojnagarwala1
1Wistar Institute of Anatomy and Biology, Philadelphia, Pennsylvania, USA.
Background:
Melanoma is a highly aggressive skin cancer, especially in advanced stages. While current treatments such as targeted therapies and immunotherapies have made significant 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.
Methods:
In this study, we explored the expression of interleukin-13 receptor subunit alpha-2 (IL13Rα2) in melanoma patient-derived xenograft models. 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 on T cell activity by flow cytometry. We studied the potency of IL13Rα2-CD3 BTE in tumor killing assay in vitro. For in vivo studies, we administered DNA expression cassettes encoding IL13Rα2-CD3 BTE (IL13Rα2-CD3 DNA encoding BTE (dBTE)) into immunodeficient mice for direct in vivo expression. The mice were challenged with A375 cells and then treated with IL-13Rα2-CD3 dBTE versus control and reconstituted with human peripheral blood mononuclear cells (PBMCs) or T cells. Tumor development was monitored, and T cell infiltration in the tumor was analyzed throughflow cytometry.
Results:
Our findings revealed heterogeneous expression of IL-13Rα2, particularly in samples from advanced stages of melanoma. The IL13Rα2-CD3 BTE facilitated T-cell activation and proliferation by bridging melanoma cells and T cells. 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. IL13Rα2-CD3 dBTE expressed in vivo led to notable tumor regression through inducing increased T-cell infiltration and activation within the tumor microenvironment.
Conclusions:
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.
Insights
Targeting interleukin-13 receptor subunit alpha-2 (IL13Rα2) with bispecific T-cell engagers (BTEs) shows promise for advanced melanoma. This approach activates T cells to effectively kill melanoma cells, leading to significant tumor regression in preclinical models.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Melanoma is an aggressive skin cancer with unmet needs in advanced stages.
- Current therapies face challenges like drug resistance and limited efficacy.
- Novel therapeutic strategies are critical for improving outcomes in late-stage melanoma.
Purpose of the Study:
- To investigate interleukin-13 receptor subunit alpha-2 (IL13Rα2) as a therapeutic target in melanoma.
- To evaluate the efficacy of an IL13Rα2-CD3 bispecific T-cell engager (BTE) in preclinical melanoma models.
Main Methods:
- Explored IL13Rα2 expression in melanoma patient-derived xenografts.
- Assessed IL13Rα2-CD3 BTE activity on T cells using flow cytometry and in vitro tumor killing assays.
- Administered DNA encoding IL13Rα2-CD3 BTE (dBTE) in vivo and monitored tumor development and T cell infiltration.
Main Results:
- Heterogeneous IL13Rα2 expression was observed, particularly in advanced melanoma.
- IL13Rα2-CD3 BTE effectively activated T cells and mediated melanoma cell killing in vitro.
- In vivo administration of IL13Rα2-CD3 dBTE resulted in significant tumor regression and increased T cell infiltration.
Conclusions:
- IL13Rα2 is a viable target for novel melanoma biologics.
- IL13Rα2-targeted bispecific T-cell engagers demonstrate potent anti-melanoma activity.
- These findings support the development of IL13Rα2-based therapies for specific melanoma subsets.
