341. Targeting The CSF1/CSF1R Axis is an Effective Treatment Strategy for Malignant Meningiomas
Features NREF-funded Author
Authors: Jacky Yeung, MD; Danielle Miyagishima, BS; Miguel Sanmamed, MD, PhD; Ti Badri, MS; Jennifer Moliterno, MD; Joseph Piepmeier, MD; Murat Gunel, MD; Lieping Chen, MD, PhD (New Haven, CT)
While most meningiomas are benign and surgical resection can be curative, there are a small group of patients with recurrent and malignant forms of the tumor that have limited surgical and chemotherapeutic options. Our initial results using RNA deconvolution revealed M2 immunosuppressive macrophages as the most prevalent immune cell type in human meningiomas. We hypothesized that targeting macrophages in meningiomas would be an effective treatment strategy.
We targeted the CSF1/CSF1R axis, an important regulator of macrophage phenotype, using a pre-clinical immunocompetent murine model for malignant meningioma (Yale/INSERM collaboration). FVB Mice were injected in the flank subcutaneously with 106 tumor cells. The mice were treated with 200 µg of monoclonal antibodies targeting CSF1 or CSF1R i.p. twice weekly at 1 week post-implantation. Immunohistochemistry were used to analyze the immune cell infiltration. RNA-seq was performed to identify changes in gene expression in the tumor microenvironment after treatment.
Immunohistochemistry identified an abundance of myeloid cells, a paucity of T cells, and low PD-L1 expression in our model of murine meningiomas. We found that anti-CSF1 antibody (5A1) treatment significantly abrogates the growth of murine meningiomas and increased T cell infiltration into the tumor microenvironment. Similarly, anti-CSF1R antibody (AFS98) treatment exerted significant CD8-dependent anti-tumor effect in vivo without changing F4/80+ tissue macrophage abundance. Treatment with anti-CSF1R antibody, but not anti-PD-1 antibody, effectively slowed the growths of early (day 7) and late (day 30) meningiomas. GO analysis using RNA-seq data revealed differentially expressed gene sets related to immune and inflammatory responses.
Our findings demonstrate that anti-CSF1/CSF1R antibody treatment effectively suppresses tumor growth in a preclinical murine malignant meningioma model that is resistant to anti-PD-1 antibody therapy. The current data provides strong rationale for future human clinical trial.