Journal Article

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

Presser, Aaron, Sonabend, Adam M, Lesniak, Maciej S, Arrieta, Victor A, Gottschalk, Stephen, Lee-Chang, Catalina, Seblani, Maggie, Duffy, Joseph T, Miska, Jason, Zannikou, Markella, Horbinski, Craig M, Chen, Christopher J, Levine, Rebecca N, Balyasnikova, Irina V, Liu, Qianli

2023

Overview

IntroductionThe 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 of IL15 is one attractive strategy to modulate the TME. However, at present, it is unclear if IL15 could be used to directly target myeloid-derived suppressor cells (MDSCs), a major cellular component of the GBM TME. Here, we explored if MDSC express IL15Rα and the feasibility of exploiting its expression as an immunotherapeutic target.MethodsRNA-seq, RT-qPCR, and flow cytometry were used to determine IL15Rα expression in paired peripheral and tumor-infiltrating immune cells of GBM patients and two syngeneic murine GBM models. We generated murine T cells expressing IL13Rα2-CARs and secretory IL15 (CAR.IL15s) or IL13Rα2-CARs in which IL15 was fused to the CAR to serve as an IL15Rα-targeting moiety (CAR.IL15f), and characterized their effector function in vitro and in syngeneic IL13Rα2+glioma models.ResultsIL15Rα was preferentially expressed in myeloid, B, and dendritic cells in patients’ and syngeneic GBMs. In vitro, CAR.IL15s and CAR.IL15f T cells depleted MDSC and decreased their secretion of immunosuppressive molecules with CAR.IL15f T cells being more efficacious. Similarly, CAR.IL15f T cells significantly improved the survival of mice in two GBM models. TME analysis showed that treatment with CAR.IL15f T cells resulted in higher frequencies of CD8+T cells, NK, and B cells, but a decrease in CD11b+cells in tumors compared with therapy with CAR T cells.ConclusionsWe demonstrate that MDSC of the glioma TME express IL15Ra and that these cells can be targeted with secretory IL15 or an IL15Rα-targeting moiety incorporated into the CAR. Thus, IL15-modified CAR T cells act as a dual targeting agent against tumor cells and MDSC in GBM, warranting their future evaluation in early-phase clinical studies.

• Publisher: BMJ Publishing Group Ltd,BMJ Publishing Group LTD,BMJ Publishing Group
• Subject: Animals / Antigens / Brain cancer / Brain Neoplasms / Cancer / Cell Engineering / Cytokines / Experiments / Flow cytometry / Genomes / Glioblastoma / Glioma / Glioma - drug therapy / Immune Cell Therapies and Immune Cell Engineering / Immunotherapy / Immunotherapy, Adoptive / Interleukin-13 Receptor alpha2 Subunit - therapeutic use / Interleukin-15 / Lymphocytes / Mice / Myeloid-Derived Suppressor Cells / Myeloid-Derived Suppressor Cells - metabolism / Patients / T-Lymphocytes / Tumor Microenvironment / Tumors