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

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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

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 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. Methods RNA-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. Results IL15Rα 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. Conclusions We 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.

Original languageEnglish (US)
Article numbere006239
JournalJournal for immunotherapy of cancer
Volume11
Issue number2
DOIs
StatePublished - Feb 9 2023

Keywords

  • Brain Neoplasms
  • Cell Engineering
  • Immunotherapy, Adoptive
  • Myeloid-Derived Suppressor Cells
  • T-Lymphocytes

ASJC Scopus subject areas

  • Molecular Medicine
  • Oncology
  • Cancer Research
  • Immunology and Allergy
  • Pharmacology
  • Immunology

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