EXTH-71. CHEMOTACTIC RECOMBINANT ADENO-ASSOCIATED VIRUS (RAAV) VIROTHERAPY IMPROVES LYMPHOCYTE RECRUITMENT IN GLIOBLASTOMA (GBM)

Abstract BACKGROUND Although immunotherapy holds promise for producing durable outcomes in GBM, a major obstacle is the limited ability of cytotoxic T lymphocytes (CTLs) to home tumor. CTLs are recruited via long-range signaling mediated by diffusion chemokines present inflammatory environments. During glioma formation, tumors manufacture immune-suppressive and cytokines that co-opt resident cells, resulting preferential recruitment immune suppressor cells from periphery. We explored novel strategy selectively reprogram tumor microenvironment (TME) using focal delivery rAAV encoding powerful call-and-receive chemokine CTLs: CXCL9. HYPOTHESIS: transduction GBM TME express CXCL9 (rAAV6-CXCL9) will enhance CTL infiltration improve responsiveness immunotherapy. METHODS Proteomic arrays were used identify absent human glioma. 3D immunohistochemistry flow cytometry was evaluate geospatial transgene expression lymphocyte trafficking vitro vivo. Survival studies rAAV6-CXCL9 alone combination with anti-PD-1 checkpoint blockade performed preclinical models GBM. Tumor immunogenicity following treatment evaluated scRNAseq proteomic analysis. RESULTS rAAV6 as reliable capsid transducing murine tumor-reactive astrocytes. Transgene single intra-tumor injection focal, stable, results high levels production. effective at promoting T-cell chemotaxis sensitizes PD-1 blockade, improving survival two distinct syngeneic models- an effect largely dependent on CD8 T-cells. CONCLUSIONS combine excellent safety profile delivery, enhancing exposure within compartment mitigating systemic toxicities seen conventional therapies. therapy successful stimulating intended biological response our encoded (CXCL9): increased recruitment. This has far-reaching potential across other platforms.