304 glioblastoma transfer miRNAs into microglial cells through extracellular vesicles

304 Glioblastoma Transfer miRNAs into Microglial Cells through Extracellular Vesicles Molecular Therapy Volume 21, Supplement 1, May 2013 Copyright © The American Society of Gene & Cell Therapy S116 C[.]

CANCER-TARGETED GENE & CELL THERAPY 302 Myeloid Suppressor Cell Blockade Potentiates Anti-Tumor Responses of Adoptive T Cell Transfer Therapy Steven Mok,1 Christopher Tsui,1 Thinle Chodon,1 Antoni Ribas,1 Richard C Koya.1 UCLA, Los Angeles Adoptive cell transfer (ACT) of anti-cancer reactive T lymphocytes can induce long lasting clinical responses in metastatic melanoma patients, though the number of responders is low Tumors can escape immune responses by inducing an inflammatory milieu that recruits and supports tumor-infiltrating myeloid cells (TIMs) with immune suppressive functions, such as myeloid derived suppressor cells (MDSC) and M2-polarized macrophages Therapies that block recruitment of suppressor TIMs have the potential to enhance adoptive T cell-based immunotherapies, providing a rationale for this combined approach We established a BRAFV600E mutant murine melanoma cell line (SM1) for which ACT of melanoma-targeted T cells induced anti-tumor responses, but not a complete eradication in vivo Through gene expression profiling and single-nucleotide polymorphism (SNP) arrays, we found that, out of 108 identified cytokines produced by SM1, colony stimulating factor (CSF1) was highly expressed CSF1 induces proliferation of immune suppressors Gr-1(+) CD11b(+) MDSC and F4/80(+) CD11b(+) macrophages In order to block the recruitment of TIMs, we tested a potent CSF1R inhibitor, PLX3397 Cultured primary murine T cells exposed to PLX3397 with a broad range of concentrations (0.1 to 50 M) showed no evidence of cytotoxicity by MTS assay We then tested the combination of PLX3397 and ACT in vivo using two models In the first one, SM1 cells stably expressing the chicken ovalbumin (OVA) antigen were implanted in C57BL/6 mice Daily oral gavage with PLX3397 (50 mg/ kg) combined with ACT of OVA-specific TCR transgenic cells (OT- 1) demonstrated superior effects of the combined treatment (tumor size on day 14: vehicle: 1611.2±22.5 mm2, PLX3397: 1028.0±24.0 mm2, OT-1: 1112.5±35.7 mm2, combined PLX3397+OT-1: 347.3±15.5 mm2, p