Abstract 2711: A novel bispecific antibody to reprogram the immune suppressive GBM TME

Abstract

Abstract GBM (glioblastoma) is the most common and aggressive primary brain tumor in adults. Immunotherapy is an emerging and promising treatment modality for GBM. Unfortunately, most immunotherapy trials have provided only modest benefit to GBM patients thus far. A significant barrier that limits efficacy of immunotherapy in GBM is the paucity of tumor infiltrating lymphocytes and abundance of immune suppressive myeloid cells. A critical step in enhancing the efficacy of immunotherapy for GBM requires approaches that enhance T cell infiltration and reprogram the myeloid cells to a more pro-inflammatory state. S100A4 is a major regulator of stemness, epithelial-mesenchymal transition, and immunosuppression in glioma stem cells and a critical regulator of immune suppressive myeloid and T cell phenotypes in GBM. Targeting S100A4 in either glioma cells or stromal cells is sufficient to reprogram the tumor immune landscape and extend survival of glioma bearing mice, indicating that S100A4 is a promising immunotherapy target. Since S100A4 has both intracellular and extracellular function as well as cytokine-like function, we developed a S100A4 blocking antibody. While the anti-S100A4 antibody blocks breast cancer metastasis efficiently, it did not cross the BBB. Hence, we generated a bispecific S100A4-TfR antibody (BsA) that allows robust BBB penetration. Using ELISA, confocal immunofluorescent microscopy, and multiplexed flow cytometry, our preliminary results suggest that systemic administration of the S100A4-TfR BsA results in accumulation of BsA in the brain and glioma tissue, increased T cell infiltration and immune remodeling. Furthermore, the BsA is taken up by glioma cells and accumulates intracellularly, which is correlated with decreased nuclear SOX2 expression. These results suggest that S100A4-TfR BsA is a promising agent to treat GBM to reprogram the GBM immune landscape and reduce stemness. We are currently performing single cell RNA-sequencing to elucidate molecular and cellular changes induced by the bispecific antibody treatment in different cell types and performing long term survival analyses to evaluate its therapeutic potential. Citation Format: Thomas Wong, Jia-Shiun Leu, Xuejun Fan, Reece Kang, Nourhan Abdelfattah, Fransisca Leonard, Ningyan Zhang, Kyuson Yun. A novel bispecific antibody to reprogram the immune suppressive GBM TME [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2711.