The IgG4 hinge with CD28 transmembrane domain improves V<sub>H</sub>H-based CAR T cells targeting a membrane-distal epitope of GPC1 in pancreatic cancer.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 37031249.
- Also identified by DOI 10.1038/s41467-023-37616-4 and PMC identifier 10082787.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
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 V<sub>H</sub>H 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 V<sub>H</sub>H-based CAR T for pancreatic cancer therapy and provides an engineering strategy for developing potent CAR T cells targeting membrane-distal epitopes.
Medical subject headings
- CD28 Antigens
- Pancreatic Neoplasms