IL15 modification enables CAR T cells to act as a dual targeting agent against tumor cells and myeloid-derived suppressor cells in GBM

• DOI: 10.1136/jitc-2022-006239
• Publication Date: 2023-02-09T15:01:08Z
• Authors: Markella Zannikou; Joseph T Duffy; Rebecca N Levine; Maggie Seblani; Qianli Liu; Aaron Presser; Victor A Arrieta; Christopher J Chen; Adam M Sonabend; Craig M Horbinski; Catalina Lee-Chang; Jason Miska; Maciej S Lesniak; Stephen Gottschalk; Irina V Balyasnikova
• Keywords: Myeloid-derived Suppressor Cell

Introduction The immunosuppressive tumor microenvironment (TME) is a major barrier to the efficacy of chimeric antigen receptor T cells (CAR-T cells) in glioblastoma (GBM). Transgenic expression IL15 one attractive strategy modulate TME. However, at present, it unclear if could be used directly target myeloid-derived suppressor (MDSCs), cellular component GBM Here, we explored MDSC express IL15Rα and feasibility exploiting its as an immunotherapeutic target. Methods RNA-seq, RT-qPCR, flow cytometry were determine paired peripheral tumor-infiltrating immune patients two syngeneic murine models. We generated expressing IL13Rα2-CARs secretory (CAR.IL15s) or which was fused CAR serve IL15Rα-targeting moiety (CAR.IL15f), characterized their effector function vitro IL13Rα2+glioma Results preferentially expressed myeloid, B, dendritic patients’ GBMs. In vitro, CAR.IL15s CAR.IL15f depleted decreased secretion molecules with being more efficacious. Similarly, significantly improved survival mice TME analysis showed that treatment resulted higher frequencies CD8+T cells, NK, B but decrease CD11b+cells tumors compared therapy cells. Conclusions demonstrate glioma IL15Ra these can targeted incorporated into CAR. Thus, IL15-modified act dual targeting agent against GBM, warranting future evaluation early-phase clinical studies.