TArgeting acute myeloid Leukemia immunosuppressive microEnvironment by combined IDO1 inhibiTion and PD-1 blockadE
Background, rationale: Survival of Acute Myeloid Leukemia (AML) is poor. To improve patients’ outcomes, immunotherapy is a promising strategy. The causative role of immunosuppressive bone marrow (BM) microenvironment, where overexpression of immune checkpoint (IC) receptors, such as PD-1 and tryptophan degradation via indoleamine 2,3-dioxygenase (IDO)1 mediate immune-tolerance, is emerging. However, an early translation of IDO1 and IC inhibitors in AML has provided modest clinical results. Hypothesis: IDO-1-based microenvironment mechanisms of resistance hamper AML immunotherapy Aims: To explore TRANSCAN-3 AIM1, the following objectives will be addressed: 1. To decipher the composition of the BM microenvironment 2. To unravel the contribution of the microenvironment to resistance mechanisms 3. To functionally validate ex-vivo data by in vitro modeling Methods: BM samples will be collected from a cohort of AML patients prospectively enrolled in Phase 1-2 immunotherapy clinical trial with Azacitidine, anti-IDO1 (Epacadostat), and anti-PD1 (INCMGA00012). The project activities will be structured in 4 interconnected and integrated work packages. WP1: Project Management, Ethics, Dissemination, and Training, capacity building activity. WP2: Characterization of BM microenvironment: mass cytometry, single-cell RNA-seq, immunometabolism, and epigenetics (multi-omics). WP3: Experimental in vitro modeling to validate mechanisms of resistance (co-cultures, cell interactions). WP4: Methodology, Biostatistics, and Bioinformatics: integrated analysis of clinical and multi-omics data. Expected results and potential impact: The expected discovery of microenvironment-based mechanisms of resistance and the identification of biomarkers associated with response will affect clinical practice by improving patients’ selection. The expected development of a novel platform for BM microenvironment investigation will impact technology transfer by providing advanced diagnostic tools.
Funded by the European Union under the Horizon Europe Framework Programme - Grant Agreement Nº: 101095654. Views and opinions expressed are however those of the author(s) only and do not necessarily reflect those of the European Union or European Health and Digital Executive Agency (HADEA). Neither the European Union nor the granting authority can be held responsible for them.