Project description
A Trojan horse against cancer
Chimeric antigen receptor T cells (CAR Ts) constitute a powerful new approach for instructing the immune system to fight cancer. Despite their great promise, CAR T cell clinical success against solid tumours has been hampered by toxicity and immunosuppression. To overcome these limitations, the EU-funded TRAP-CART project proposes to induce a supportive tumour microenvironment for CAR T function. The rationale is to engineer haematopoietic stem cells to produce progeny that can deliver inflammatory and CAR T activation signals in the immediate vicinity of the tumour. This strategy can employ rather inert CAR Ts that become armed in the tumour microenvironment, thereby avoiding off-target effects.
Objective
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 TME
2)Induce a CAR T-supportive TME that activates programmable CAR T-cells in situ
Fields of science
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CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques.
Keywords
Programme(s)
Funding Scheme
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinator
1090 Wien
Austria