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Exhaustion-resistant CAR-T cells for the treatment of 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.

Field of science

  • /medical and health sciences/clinical medicine/oncology/cancer
  • /natural sciences/biological sciences/genetics and heredity/genome
  • /medical and health sciences/clinical medicine/oncology/leukemia

Call for proposal

H2020-MSCA-IF-2018
See other projects for this call

Funding Scheme

MSCA-IF-EF-RI - RI – Reintegration panel

Coordinator

CONSORCI INSTITUT D'INVESTIGACIONS BIOMEDIQUES AUGUST PI I SUNYER
Address
Calle Rossello 149 Puerta Bjs
08036 Barcelona
Spain
Activity type
Other
EU contribution
€ 160 932,48