Tumor targeting through a TME-specific regulatory code and programmable CAR T cells

Two major issues hamper successful treatment of solid cancers with CAR T cells. First, immunosuppression imposed by the tumor microenvironment (TME) can compromise CAR T cell function.

Second, CAR T cells require specific antigens for precise tumor recognition to limit/avoid toxicities associated with on-target/off-tumor activity. Initial attempts to overcome these challenges included immune checkpoint blockade and tunable CAR T cells.

Here, we propose to develop a conceptually new framework for solid tumor therapy that introduces genetically modified, blood-derived TME cells as Trojan horses to deliver inflammation and broadcast “intratumor” signals that activate programmable CAR T cells.

Overall, we will design a hematopoietic stem cell (HSC)-directed strategy for Tumor microenvironment-Regulated Activation of Programmable CAR T (TRAP-CART).

This project builds on the host lab’s expertise in high-throughput genomics, bioinformatics, and CAR T cells, and on my own background in HSC engineering.Through epigenome/transcriptome profiling, we will systematically identify gene-regulatory elements that are specific to blood-derived cells in the TME.

We will use such regulatory sequences for HSC-directed gene therapy, such that their progeny will express a programmed transgene only in the immediate vicinity of tumor cells.

This TME-regulated transgene will induce inflammation (to help overcome the hostile immune environment of many solid tumors) and/or release localized activatory signals for CAR T-cells (making it possible to use weakly specific CARs while avoiding on-target/off-tumor activity elsewhere in the body).

We will focus on melanoma as our “model cancer”, which has a high mutational burden, good mouse models and is widely used for testing cutting-edge immunotherapies.

Specific Objectives:1)Develop a promoter/enhancer toolbox for HSC gene therapy targeting the TME2)Induce a CAR T-supportive TME that activates programmable CAR T-cells in situ