Genotypic, metabolic and immunophenotypic characterization of Early T-cell Precursor (ETP) Acute Lymphoblastic Leukemia (ALL) for the preclinical development of CAR-T cells

Early precursor T-cell (ETP) acute lymphoblastic leukemia (ALL) is a rare hematologic malignancy, characterized by an uncontrolled expansion of immature T cells and distinctive immunophenotypic and genetic profile. ETP-ALL has high levels of minimal residual disease (MRD) as compared with other T-ALL subtypes and poor response to chemotherapy. Refractoriness and relapses are presumably due to ineffective targeting of leukemia initiating cells (LICs) that are described as more resistant to standard chemotherapy. Currently, the expansion of adoptive immunotherapy has allowed the development of an innovative anticancer therapy approach, based on the ability of chimeric antigen receptor (CAR)-modified T cells to turn on the endogenous immune response against the antigen-presenting cells. Despite various promising results in this field, a successful CAR-based therapy needs to be developed for ETP-ALL. The overall goals of this project will be to reveal the genotypic, metabolic and immunophenotypic profile of human ETP-ALL in order to identify circadian pathway-dependent cellular targets of LIC-enriched subsets and to develop CAR-engineered T cells targeting these tumor populations resistant to conventional treatments as more effective and less-invasive treatments for ETP-ALL patients.