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

Introduction

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.

Proposed Solution

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.

System Overview

This innovative system will incorporate a dual synthetic locus control region (sLCR) reporter, with:

1. One sLCR reporter indicating T cells in a potent "serial killer" mode.
2. Another sLCR reporter representing T cell dysfunction.

Objectives

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.
• Generate and validate a synthetic reporter of CAR T cell products' function and dysfunction.
• Produce a media supplement that promotes ACT products' functions.