Published on December 12, 2025
Targeting the Extracellular Matrix With Tenascin-C-Specific CAR T Cells Extends Survival in Preclinical Models of Glioblastoma
by Alex Kadhim
Researchers at the University of Geneva have found that engineering CAR T cells to target Tenascin-C (TNC), an extracellular matrix protein enriched in glioblastoma, can shrink tumors and prolong survival in preclinical brain tumor models while sparing healthy tissue. The study, published in the Journal for ImmunoTherapy of Cancer, found that focusing CAR T cells on a GBM-restricted splice variant of TNC (the FNIII-D domain) yields potent antitumor activity, including bystander killing of nearby antigen-negative cells, with a positive preclinical safety profile.
Glioblastoma remains one of the most lethal human cancers, with median survival around 15 months and no major therapeutic advances in two decades. A key challenge is that GBM expresses few truly tumor-specific antigens, causing CAR T-cell approaches to lose effectiveness. In addition, because the brain is highly sensitive to inflammation, any off tumor targeting carries substantial risk. Therefore, existing immunotherapies such as checkpoint inhibitors, vaccines, and oncolytic viruses have shown minimal benefit in phase III trials. Recently, TNC has emerged as an appealing alternative target as it is a developmentally regulated ECM protein re-expressed in GBM, highly enriched in the tumor microenvironment, and implicated in invasion, angiogenesis, and immune evasion. Importantly, the FNIII-D splice domain is absent from healthy adult brain but strongly expressed in GBM. In this study, the authors created a second-generation FNIII-D–specific CAR (TNC_28z) using an R6N-derived single-chain antibody and tested it across in vitro, ex vivo, and in vivo models.
TNC-CAR T cells demonstrated TNC-dependent activation (CD25/CD69), selective proliferation against TNC-positive GBM lines, and potent cytotoxicity marked by high secretion of IFN-γ, TNF-α, IL-6, granzyme B, and perforin. Bystander killing of TNC-negative cells increased significantly when recombinant TNC (1–5 µg/mL) was added (p<0.05). In mice implanted with 2.5×10⁴ patient-derived Ge518 GBM cells, a single intracranial dose of 1×10⁶ TNC-CAR T cells produced marked tumor regression and significantly prolonged survival compared with non-transduced or CD19-CAR controls (log-rank p<0.01), without weight loss or off-tumor toxicity. Combining TNC-CAR T cells with anti-PD-1, anti-TIM-3, and anti-LAG-3 further extended survival. Ex vivo, TNC-CAR T cells were activated by 10/13 GBM samples but not by AVM, epilepsy, or autopsy brain tissue. These findings demonstrate that targeting a tumor-restricted ECM splice variant can overcome antigen heterogeneity and support the development of next-generation CAR T-cell therapies for GBM and other solid tumors.
Reference:
de Sostoa J, Marinari E, Pedard M, et al. Targeting the extracellular matrix with Tenascin-C-specific CAR T cells extends survival in preclinical models of glioblastoma. J Immunother Cancer. 2025;13(11):e011382. Published 2025 Nov 4.
http://doi.org/10.1136/jitc-2024-011382
![]()