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

Jorge Ibanez¹, Nikhil Hebbar¹, Unmesha Thanekar¹

¹Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.

Cell Reports. Medicine

|November 22, 2023

Summary

Chimeric antigen receptor (CAR) T-cell therapy shows promise for targeting cancer. Researchers identified cell surface Glucose-regulated protein 78 (GRP78) as a viable target for CAR T-cells against various tumors.

Keywords:

CAR T cells ER stress GRP78 brain tumors immune synapse immunotherapy solid tumors

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Area of Science:

Oncology
Immunology
Molecular Biology

Background:

T-cell based immunotherapies face limitations due to a lack of targetable antigens.
The unfolded protein response (UPR) pathway is crucial for cancer cell survival, proliferation, and metastasis.
Glucose-regulated protein 78 (GRP78), a key UPR regulator, is overexpressed and present on the cell surface of many cancers.

Purpose of the Study:

To evaluate cell surface GRP78 as a target for chimeric antigen receptor (CAR) T-cell immunotherapy.
To assess the efficacy of GRP78-specific CAR T-cells against solid and brain tumors.

Main Methods:

Characterization of GRP78 expression on various solid and brain tumor cell lines.
Development and testing of GRP78-specific CAR T-cells in vitro and in vivo models.
Analysis of GRP78 expression dynamics on CAR T-cells post-activation.

Main Results:

Cell surface GRP78 is highly expressed across multiple solid and brain tumors.
GRP78-CAR T-cells effectively recognized and eliminated GRP78-positive tumors in vitro and in vivo.
GRP78 upregulation on CAR T-cells post-activation was observed, but this was tumor-cell-line specific.

Conclusions:

Cell surface GRP78 is a promising target for developing novel CAR T-cell therapies for various cancers.
GRP78-CAR T-cells demonstrate therapeutic potential against GRP78-expressing tumors.
Tumor-specific heterogeneity in GRP78 expression may influence CAR T-cell therapeutic response.