Project description
Overcoming poor CAR-T cell activity in solid tumours
T lymphocytes engineered to express chimeric antigen receptors (CAR) have shown promising results as an anti-cancer strategy against haematological malignancies. However, results against solid tumours are not satisfactory even though CAR-T cells infiltrate tumours efficiently. The EU-funded Exh-Res-CART project is examining the hypothesis that poor CAR-T cell activity in solid tumors is due to cell exhaustion in the tumour microenvironment. Using cutting-edge technologies, scientists will determine the mechanisms responsible for CAR-T cell unresponsiveness and design approaches to enhance the persistence and function of these cells in solid tumours.
Objective
Adoptive transfer of T-cells collected from patient’s blood and engineered to express chimeric antigen receptors (CARs) has produced unprecedented clinical responses in patients with cancer. CAR-T cells targeting CD19 were recently approved by the US food and drug administration (FDA) and the European Commission (EC) for the treatment of leukemia and lymphoma, heralding a new era for cancer treatment. However, despite the stunning results of CAR-T cells in patients with hematologic malignancies, results with CAR-T cells in patients with solid tumors are far from expected. Although CAR-T cells are able to infiltrate solid tumors and exert antigen directed activity, observed responses in patients with solid tumors have been minor and transient. But what are the mechanisms behind the poor T-cell activity in solid tumors? Are CAR-T cells susceptible to dysfunction in a similar way as the endogenous tumor-specific T cells that fail to eliminate the tumors in treatment-naïve cancer patients?
My central hypothesis is that CAR-T cells become exhausted in the tumor microenvironment mainly due to continuous antigen encounter, and that this process can be prevented or delayed. My general aim for this project is to enhance the persistence and function of CAR-T cells by overcoming T-cell dysfunction while promoting T-cell stemness. By using animal models and a combination of innovative technologies, including next-generation sequencing and genome editing I will: 1) elucidate the T-cell intrinsic mechanisms by which CAR-T cells become unresponsive to solid tumors, 2) design new approaches to enable infused T cells to overcome dysfunction and persist within the tumor microenvironment.
Fields of science
Programme(s)
Funding Scheme
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinator
08036 Barcelona
Spain