Despite the expanding interest in immunotherapy (IMT), only a minority of patients experience substantial benefits, highlighting the need for predictive biomarkers and combinatorial strategies. Radiotherapy may exert synergstic effect by priming the tumour microenvironment. However, RT may influence the tumour microenvironment (TME) through both immunostimulatory and immunosuppressive pathways. Thus, for RT and IMT to be optimally integrated into a multimodal approach, it is crucial to understand RT-induced immunological changes in TME, identify synergistic and predictive strategies and establish effective RT schedule.
METRICs aims to unravel the determinants of the response to IMT and IMT/RT combinations that are related to the host (gut microbiome and systemic metabolic landscape) as well as to the distinct metabolic profile of tumours, with the goal of designing and testing metabolism/microbiome-based interventional strategies for enhancing the RT-IMT combinations. We hypothesize that metabolome landscape, gut microbiome and cancer cell’s metabolic profile may serve as predictive biomarkers of IMR-RT combinations and offer caveats for further interventions.
Both IMT and RT are tightly linked to metabolic alterations. Our preliminary data implicates crucial roles for host’s metabolome landscape as well as for cancer cell’s specific metabolic program in determining the response to immunotherapy with T Cell-based therapies.
Another important determinant is the gut microbiota. We performed gut microbiota metagenomic analyses and plasma metabolic analyses on stool and blood of cancer patients at different time points after CAR T cell infusion, as well as tumour and bone marrow biopsies. A specific gut microbiota composition (abundance of Akkermansia muciniphila) and decrease in the indole metabolic pathway were observed in responding patients. Combined treatment with CAR T cells and Akkermansia spp supplementation improved tumour control and survival in a mouse model of a high-grade B cell lymphoma.
We will apply a holistic approach exploiting our complementary expertise. We aim to collect in 3 centres tumour and sequential blood and stool samples from 400 cancer patients (161 already biobanked) treated with different combinations of IMT-RT and, as comparators, with other IMT combinations +/- chemotherapy and with single-agent IMT or RT. We will perform metabolomics and metagenomics analyses to identify the perturbations associated with response. We will then devise strategies to sensitize to the combination and validate in 2D, patient-derived 3D and animal models. Furthermore, different RT regimens will be tested to determine the optimal combination protocol. Finally, the impact of cancer cell’s metabolic profile on the response to the combination will be dissected
METRICs begins with clinical observations and multi-omics analyses of human samples, follows to preclinical studies and finally produce strategies ready for clinical testing