Abstract A092: A novel bispecific antibody reprograms the immune suppressive TME and sensitize GBM for immune checkpoint inhibitors

Abstract GBM (glioblastoma) is the most common and aggressive primary brain tumor in adults. Unfortunately, despite aggressive treatments, the median survival is 15.4 months, with less than 5% of patients surviving > 5 year. Therefore, there is urgent need to develop more effective treatments for GBM patients. In theory, immunotherapies are ideal for treating GBM since immune cells can cross the blood brain barrier (BBB), track infiltrating glioma cells, and selectively kill cancer cells while sparing normal brain cells. Unfortunately, most GBM immunotherapy trials, including vaccines, adoptive cellular therapy, CAR-T cells, and immune checkpoint blockade, have provided only modest benefit to GBM patients thus far. A significant barrier that limits efficacy of immunotherapy in GBM and other cancers 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 immune landscape to more pro-inflammatory state. We recently defined the molecular heterogeneity of glioma and immune cells in human GBM at the single cell level by analyzing >210,000 cells from 44 samples. A major observation from this analysis was that S100A4 is a critical regulator of immune suppressive myeloid and T cells in GBM. Deleting S100a4 in immune cells only was sufficient to reprogram the tumor micronenvironment and significantly extend survival of mice bearing tumors from multiple glioma models. In other cancers, high levels of S100A4 expression is predictive of worse survival and increased metastasis, indicating that S100A4 is a promising immunotherapy target. Based on this and other unpublished results from the lab, we developed a blocking antibody against human S100A4 protein. While we successfully developed antibodies that blocked breast cancer metastases to the lung, our lead antibody did not cross the BBB efficiently to affect glioma growth. To overcome this well-established challenge, we generated a BBB-penetrant bispecific S100A4-TfR antibody that accumulates at therapeutic doses in gliomas. Preliminary results suggest that bispecific antibody (BsA) treatment alone significant extends survival and is associated with increased T cell infiltration and immune remodeling. When combined with anti-PD1 treatment, the median survival nearly doubles in the combination treated mice, compared to IgG control. We are currently performing single cell RNA-sequencing to elucidate molecular and cellular changes induced by the BsA treatment in different cell types and how it synergizes with anti-PD1 treatment in gliomas. Citation Format: Thomas Wong, Jia-Shiun Leu, Xuejun Fan, Reece Kang, Nourhan Abdelfattah, Fransisca Leonard, Ningyan Zhang, Kyuson Yun. A novel bispecific antibody reprograms the immune suppressive TME and sensitize GBM for immune checkpoint inhibitors [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr A092.