SynNotch CAR T cells for better prostate cancer treatment

There are currently no curative treatments available for patients with advanced metastatic prostate cancer, highlighting the urgent need for the development of additional therapies.

Although chimeric antigen receptor (CAR) T cells are emerging as a highly successful therapeutic approach against B-cell-derived cancers, they are not able to efficiently kill solid tumors, like prostate cancer.

The project aims to address current challenges for CAR T cells in solid tumors, such as antigen heterogeneity, poor CAR T cell persistence, and immunosuppressive tumor microenvironment, with the purpose of generating more effective and safer CAR T cells for prostate cancer treatment.

To achieve this goal, we will engineer CAR T cells with novel SynNotch circuits to enhance their ability to kill prostate cancer cells.

Briefly, we will use SynNotch CAR circuits to overcome the tumor antigen heterogeneity and to avoid “on target, off tumor” toxicity, and an additional SynNotch IL-2 circuit will be added to boost the infiltration of CAR T cells into solid tumors.

We will use CRISPR to both insert SynNotch-CAR circuits and to improve T cell responses by inactivating T cell exhaustion genes.

To understand the mechanisms of action of SynNotch CAR T cells, we will analyze the tumor microenvironment by flow cytometry and spatial transcriptomics.

The project is planned to run over three years, and the work will be done by the applicant Yunbing Shen under the mentorship of Prof. Alan Ashworth.