The IgG4 hinge with CD28 transmembrane domain improves VHH-based CAR T cells targeting a membrane-distal epitope of GPC1 in pancreatic cancer

Nan Li, Alex Quan, Dan Li, Jiajia Pan, Hua Ren, Gerard Hoeltzel, Natalia Val, Dana Ashworth, Weiming Ni, Jing Zhou, Sean Mackay, Stephen M. Hewitt, Raul Cachau and Mitchell Ho ()
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Nan Li: National Institutes of Health
Alex Quan: National Institutes of Health
Dan Li: National Institutes of Health
Jiajia Pan: National Institutes of Health
Hua Ren: National Institutes of Health
Gerard Hoeltzel: National Institutes of Health
Natalia Val: National Institutes of Health
Dana Ashworth: IsoPlexis Corporation
Weiming Ni: IsoPlexis Corporation
Jing Zhou: IsoPlexis Corporation
Sean Mackay: IsoPlexis Corporation
Stephen M. Hewitt: National Institutes of Health
Raul Cachau: National Institutes of Health
Mitchell Ho: National Institutes of Health

Nature Communications, 2023, vol. 14, issue 1, 1-19

Abstract: Abstract Heterogeneous antigen expression is a key barrier influencing the activity of chimeric antigen receptor (CAR) T cells in solid tumors. Here, we develop CAR T cells targeting glypican-1 (GPC1), an oncofetal antigen expressed in pancreatic cancer. We report the generation of dromedary camel VHH nanobody (D4)-based CAR T cells targeting GPC1 and the optimization of the hinge (H) and transmembrane domain (TM) to improve activity. We find that a structurally rigid IgG4H and CD28TM domain brings the two D4 fragments in proximity, driving CAR dimerization and leading to enhanced T-cell signaling and tumor regression in pancreatic cancer models with low antigen density in female mice. Furthermore, single-cell-based proteomic and transcriptomic analysis of D4-IgG4H-CD28TM CAR T cells reveals specific genes (e.g., HMGB1) associated with high T-cell polyfunctionality. This study demonstrates the potential of VHH-based CAR T for pancreatic cancer therapy and provides an engineering strategy for developing potent CAR T cells targeting membrane-distal epitopes.

Date: 2023
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DOI: 10.1038/s41467-023-37616-4

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