Generation, validation and use of a synthetic reporter of CAR T cell products function and dysfunction

Cell-based immunotherapy, particularly adoptive cell transfer (ACT) using engineered T cells, holds great promise as a therapeutic strategy for cancer treatment.

However, challenges such as the manufacturing process, excessive antigen exposure, and the hostile tumor microenvironment often lead to dysfunctional T cell products, limiting their effectiveness in treating both blood cancers and solid tumors.

We propose a novel tool to define in vitro conditions to enhance T cell product fitness through the development of a synthetic reporter system for detecting T cell dysfunction states, referred to as SynT.

This innovative system will incorporate a dual synthetic locus control region (sLCR) reporter, with one sLCR reporter indicating T cells in a potent ""serial killer"" mode and another sLCR reporter representing T cell dysfunction.

By using SynT, we aim to screen for external signaling and pharmacological modulators that can enrich and reverse the dysfunctional state in CAR T cells. we will generate and validate a synthetic reporter of CAR T cell products function and dysfunction, and produce a media supplement that promotes ACT products functions.