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Updated: Oct 18, 2025
Generation of CAR T Cells for Adoptive Therapy in the Context of Glioblastoma Standard of Care
Published on: February 16, 2015
Fn14-targeted BiTE and CAR-T cells demonstrate potent preclinical activity against glioblastoma
Gaowei Li1, Zongliang Zhang2, Linjun Cai3
1Department of Neurosurgery, West China Hospital, West China School of Medicine, Sichuan University, Chengdu, Sichuan Province, People's Republic of China.
Abstract:
T cell-engaging therapies involving bispecific T cell engager (BiTE) and chimeric antigen receptor T (CAR-T) cells have achieved great success in the treatment of hematological tumors. However, the paucity of ideal cell surface molecules that can be targeted on glioblastoma (GBM) partially reduces the immunotherapeutic efficacy. Recently, high expression of Fn14 has been reported in several solid tumors, so the strategy of exploiting this specific antigen for GBM immunotherapy is worth studying. Consequently, we constructed Fn14× CD3 BiTE and Fn14-specific CAR-T cells and investigated their cytotoxic activity against GBM in vitro and in vivo. First, expression of Fn14 was confirmed in glioma tissues and GBM cells. Then, we designed Fn14-specific BiTE and CAR-T cells and tested their cytotoxicity in GBM cell cultures and mouse models of GBM. Fn14 was highly expressed in GBM tissues and cell lines, while it was undetectable in normal brain samples. Fn14× CD3 BiTE, Fn14 CAR-T cells and Fn14 CAR-T/IL-15 cells were antigen-specific and highly cytotoxic, showing good antitumor activity in vitro and causing significant regression of established solid tumors in xenograft models. However, the xenografts treated with Fn14 CAR-T cells regrew, whereas xenografts treated with Fn14 CAR-T/IL-15 cells did not. IL-15 engineering augmented the antitumor activity of Fn14 CAR-T cells and resulted in significant antitumor effects similar to those of Fn14× CD3 BiTE. Our results suggest that Fn14 is an appropriate target for GBM. Anti-Fn14 BiTE and Fn14-specific CAR-T/IL-15 cells may be exciting immunotherapeutic options for malignant brain cancer.
Insights
Targeting Fn14 shows promise for glioblastoma (GBM) immunotherapy. Fn14-specific bispecific T cell engager (BiTE) and engineered CAR-T cells demonstrated significant anti-GBM activity in preclinical models.
Area of Science:
- Immunotherapy
- Oncology
- Molecular Biology
Background:
- T cell-engaging therapies like bispecific T cell engager (BiTE) and chimeric antigen receptor T (CAR-T) cells are effective against hematological tumors.
- Glioblastoma (GBM) treatment is limited by a lack of suitable cell surface targets for immunotherapy.
- Fn14 is a potential target antigen highly expressed in solid tumors, including GBM.
Purpose of the Study:
- To investigate the potential of Fn14 as a target for GBM immunotherapy.
- To construct and evaluate the efficacy of Fn14-specific BiTE and CAR-T cells against GBM.
Main Methods:
- Confirmed Fn14 expression in glioma tissues and GBM cell lines, with minimal expression in normal brain tissue.
- Developed and tested Fn14×CD3 BiTE and Fn14-specific CAR-T cells (including IL-15 engineered variants) for GBM cytotoxicity in vitro and in vivo xenograft models.
Main Results:
- Fn14 was highly expressed in GBM but not normal brain tissue, validating it as a target.
- Fn14×CD3 BiTE and Fn14 CAR-T cells exhibited antigen-specific cytotoxicity and antitumor activity against GBM.
- IL-15 engineered Fn14 CAR-T cells demonstrated enhanced and sustained antitumor effects compared to non-engineered CAR-T cells, similar to BiTE efficacy.
Conclusions:
- Fn14 is a suitable and specific target for GBM immunotherapy.
- Anti-Fn14 BiTE and IL-15 augmented Fn14 CAR-T cells represent promising therapeutic strategies for malignant brain cancers.
