Journal
SCIENCE
Volume 371, Issue 6534, Pages 1166-+Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.abc1855
Keywords
-
Categories
Funding
- NIH [P50GM081879, U54CA244438, R01 CA196277]
- Howard Hughes Medical Institute
- UCSF Center for Cellular Construction [DBI-1548297]
- NSF Science and Technology Center
- Cancer Research Institute
Ask authors/readers for more resources
The study engineered a two-step positive-feedback circuit that enables human cytotoxic T cells to discriminate targets based on a sigmoidal antigen-density threshold. This circuit involves a low-affinity synthetic Notch receptor controlling the expression of a high-affinity CAR, leading to sharp discrimination between cancer cells and normal cells based on antigen density.
Overexpressed tumor-associated antigens [for example, epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2)] are attractive targets for therapeutic T cells, but toxic off-tumor cross-reaction with normal tissues that express low levels of target antigen can occur with chimeric antigen receptor (CAR)-T cells. Inspired by natural ultrasensitive response circuits, we engineered a two-step positive-feedback circuit that allows human cytotoxic T cells to discriminate targets on the basis of a sigmoidal antigen-density threshold. In this circuit, a low-affinity synthetic Notch receptor for HER2 controls the expression of a high-affinity CAR for HER2. Increasing HER2 density thus has cooperative effects on T cells-it increases both CAR expression and activation-leading to a sigmoidal response. T cells with this circuit show sharp discrimination between target cells expressing normal amounts of HER2 and cancer cells expressing 100 times as much HER2, both in vitro and in vivo.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available