GRP78-CAR T cell effector function against solid and brain tumors is controlled by GRP78 expression on T cells

Sep 24, 2026

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Ibanez and colleagues investigate whether GRP78-CAR T cells provide an effective, low-toxicity therapy for pediatric solid and brain tumors in pre-clinical models. They show that antitumor activity depends on cell-surface GRP78 (csGRP78) levels on tumor cells and on activation-induced csGRP78 on T cells. GRP78 is highly expressed on the surfaces of multiple tumor types, enabling CAR T recognition and killing in vitro and in vivo, while tumor-type-specific csGRP78 upregulation contributes to heterogeneous responses and efficacy.

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CategoryHealthcare

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GRP78 is expressed on the cell surface of solid and brain tumors

Article GRP78-CART cell effector function against solid and brain tumors is controlled by GRP78 expression on T cells Authors Jorge Ibanez, Nikhil Hebbar, Unmesha Thanekar, ..., Jason Chiang, M. Paulina Velasquez, Giedre Krenciute Correspondence [paulina.velasquez@stjude.org](paulina.velasquez@stjude.org) (M.P.V.), [giedre.krenciute@stjude.org](giedre.krenciute@stjude.org) (G.K.) In brief Ibanez et al. describe that GRP78-CART cell therapy is a suitable option for pediatric solid and brain tumors with no toxicity in pre-clinical models. The antitumor activity of GRP78-CAR T cells is impacted by csGRP78 levels on tumorsand by activation-induced csGRP78 on T cells. d GRP78 is expressed among different pediatric solid and brain tumors d GRP78-CAR T cells recognize and kill GRP78+ tumors d Efﬁcacy of GRP78-CAR T cells is mediated by GRP78 levelson tumor cells and T cells d csGRP78 upregulation on CAR T cells is tumor-type dependent Ibanez et al., 2023, Cell Reports Medicine 4, 101297 November 21, 2023 ª 2023 The Author(s) . [https://doi.org/10.1016/j.xcrm.2023.101297](https://doi.org/10.1016/j.xcrm.2023.101297) ll ll OPEN ACCESS Article GRP78-CAR T cell effector function against solid and brain tumors is controlled by GRP78 expression on T cells Jorge Ibanez,1 Nikhil Hebbar,1 Unmesha Thanekar,1 Zhongzhen Yi,1 Haley Houke,1 Meghan Ward,1 Chris Nevitt,1 Liqing Tian,1 Stephen C. Mack,2 Heather Sheppard,3 Jason Chiang,3 M. Paulina Velasquez,1,* and Giedre Krenciute1,4,* 1Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA 2Department of Developmental Neurobiology, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA 3Department of Pathology, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA 4Lead contact *Correspondence: [paulina.velasquez@stjude.org](paulina.velasquez@stjude.org) (M.P.V.), [giedre.krenciute@stjude.org](giedre.krenciute@stjude.org) (G.K.) [https://doi.org/10.1016/j.xcrm.2023.101297](https://doi.org/10.1016/j.xcrm.2023.101297) SUMMARY Lack of targetable antigens isa key limitation for developing successful T cell-based immunotherapies. Members of the unfolded protein response (UPR) represent ideal immunotherapy targets because the UPR regulates the ability of cancer cells to resist cell death, sustain proliferation, and metastasize. Glucose-regulated protein 78 (GRP78) is a key UPR regulator that is overexpressed and translocated to the cell surface of a wide variety of cancers in response to elevated endoplasmic reticulum (ER) stress. We show that GRP78 is highly expressed on the cell surface of multiple solid and brain tumors, making cell surface GRP78 a promising chimeric antigen receptor (CAR) T cell target. We demonstrate that GRP78-CAR T cells can recognize and kill GRP78+ brain and solid tumors in vitro and in vivo. Additionally, our ﬁndings demonstrate that GRP78 is upregulated on CAR T cells upon T cell activation; however, this expression is tumor-cell-line speciﬁcand results in heterogeneous GRP78-CAR T cell therapeutic response. INTRODUCTION The anti-tumor activity of chimeric antigen receptor (CAR) T cells for solid and brain tumors is hampered by several factors including limited CAR T cell expansion and persistence, the immunosuppressive tumor microenvironment (TME), and heterogeneous expression of a limited array of targetable tumor antigens.1 ,2 These factors have impacted the limited success of clinical trials for glioblastoma multiforme (GBM) and solid tumors.3–7 Additionally, on-target/off-cancer toxicities have been observed in pre-clinical and clinical studies,8 ,9 highlighting the need to identify tumor-speciﬁc antigens expressed on a broad range of tumors. To achieve this, we set out to explore targeting cell surface glucose-regulated protein 78 (csGRP78) as a CAR T cell

FAQs

What controls the effector function of GRP78-CAR T cells against solid and brain tumors?

The study finds that GRP78-CAR T antitumor function is controlled by GRP78 expression on T cells and csGRP78 levels on tumors, including activation-induced csGRP78 in T cells.

Why is GRP78 considered a promising CAR T target?

GRP78 is a key unfolded protein response regulator that is overexpressed and translocated to the tumor cell surface under ER stress, and its essentiality lowers the likelihood of antigen loss.

What do the authors observe about therapeutic response across different tumors?

The results indicate heterogeneous GRP78-CAR T efficacy across tumor types, linked to tumor-type-dependent csGRP78 upregulation on CAR T cells.

Sep 24, 2026

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