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IL7 and IL7 Flt3L co-expressing CAR T cells improve therapeutic efficacy in mouse EGFRvIII heterogeneous glioblastoma

Authors :
Sheridan L. Swan
Nalini Mehta
Ekaterina Ilich
Steven H. Shen
Daniel S. Wilkinson
Alexa R. Anderson
Tatiana Segura
Luis Sanchez-Perez
John H. Sampson
Ravi V. Bellamkonda
Source :
Frontiers in Immunology. 14
Publication Year :
2023
Publisher :
Frontiers Media SA, 2023.

Abstract

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.

Subjects

Subjects :
Immunology
Immunology and Allergy

Details

Language :
English
ISSN :
16643224
Volume :
14
Database :
OpenAIRE
Journal :
Frontiers in Immunology
Accession number :
edsair.doi.dedup.....512d6bdd6324dfcfb4a4750add1f8df8
Full Text :
https://doi.org/10.3389/fimmu.2023.1085547