IL7 and IL7 Flt3L co-expressing CAR T cells improve therapeutic efficacy in mouse EGFRvIII heterogeneous glioblastoma.
Journal Article (Journal Article)
Chimeric antigen receptor (CAR) T cell therapy in glioblastoma faces many challenges including insufficient CAR T cell abundance and antigen-negative tumor cells evading targeting. Unfortunately, preclinical studies evaluating CAR T cells in glioblastoma focus on tumor models that express a single antigen, use immunocompromised animals, and/or pre-treat with lymphodepleting agents. While lymphodepletion enhances CAR T cell efficacy, it diminishes the endogenous immune system that has the potential for tumor eradication. Here, we engineered CAR T cells to express IL7 and/or Flt3L in 50% EGFRvIII-positive and -negative orthotopic tumors pre-conditioned with non-lymphodepleting irradiation. IL7 and IL7 Flt3L CAR T cells increased intratumoral CAR T cell abundance seven days after treatment. IL7 co-expression with Flt3L modestly increased conventional dendritic cells as well as the CD103+XCR1+ population known to have migratory and antigen cross-presenting capabilities. Treatment with IL7 or IL7 Flt3L CAR T cells improved overall survival to 67% and 50%, respectively, compared to 9% survival with conventional or Flt3L CAR T cells. We concluded that CAR T cells modified to express IL7 enhanced CAR T cell abundance and improved overall survival in EGFRvIII heterogeneous tumors pre-conditioned with non-lymphodepleting irradiation. Potentially IL7 or IL7 Flt3L CAR T cells can provide new opportunities to combine CAR T cells with other immunotherapies for the treatment of glioblastoma.
Full Text
Duke Authors
Cited Authors
- Swan, SL; Mehta, N; Ilich, E; Shen, SH; Wilkinson, DS; Anderson, AR; Segura, T; Sanchez-Perez, L; Sampson, JH; Bellamkonda, RV
Published Date
- January 2023
Published In
Volume / Issue
- 14 /
Start / End Page
- 1085547 -
PubMed ID
- 36817432
Pubmed Central ID
- PMC9936235
Electronic International Standard Serial Number (EISSN)
- 1664-3224
International Standard Serial Number (ISSN)
- 1664-3224
Digital Object Identifier (DOI)
- 10.3389/fimmu.2023.1085547
Language
- eng