Decoding the immuno-regulatory functions of the human bone marrow niche upon cancer cellular therapy

Objective

ImmunhOss proposes the personalized modelling of cellular immunotherapies towards improving their efficacy in leukemia context. Cellular immunotherapies hold great clinical promises after demonstrating spectacular success in lymphomas and multiple myeloma, through the pioneering Chimeric Antigen Receptor T cells (CAR-Tc) strategy. However, the outcome remains poor for acute myeloid leukemia (AML) which accounts for the majority and most lethal adult leukemia. Pre-clinical successes were not followed by clinical efficacy, pointing at the substantial discrepancy between mouse models and patient response. In AML, evidence suggest a key role of the human bone marrow microenvironment, capable of acting both as a pro-inflammatory and immuno-suppressive unit. Towards decoding the bone marrow functions in AML, my laboratory has successfully developed humanized ossicles (hOss), as miniaturized bone organs forming ectopically in mice. Those were shown to reconstitute the patient bone marrow microenvironment, leading to the superior AML engraftment and the individualized recapitulation of chemotherapy responses. ImmunhOss builds on the unique hOss technology to uncover the immuno-regulatory roles of the human bone marrow upon CAR-Tc therapy. By detailed and interaction mapping between immune, bone marrow and AML cells (WP 1), I will validate the existence and composition of immuno-regulatory niches. Temporal modelling of CAR-Tc therapy in hOss will reveal potential changes in these niches and uncover mechanisms of AML resistance (WP 2). Finally, I propose using hOss to test strategies for enhancing CAR-Tc effectiveness by targeting identified bone marrow immune niches (WP 3). By integrating cancer immunology and personalized tissue engineering, ImmunhOss is particularly timely as addressing the critical need for highly relevant tools capable of modelling immunotherapy response.