Leveraging the impact of gut microbes to advance the efficacy of CAR-T cell immunotherapy.

T cell therapy with chimeric antigen receptor (CAR)-T cells is a curative-intent, transformative treatment aimed to boost antitumor abilities of host T cells against refractory/relapsed B cell malignancies and, recently, against refractory/relapsed myeloma.

Major challenges of current CAR-T cell immunotherapies are the loss of long-term efficacy, the occurrence of toxicities including infections, and a lack of personalized patient strategies including biomarkers for response prediction and interventions to enhance CAR-T cell efficacy.

This proposal builds on our first evidence for a major role of the gut microbiome in CAR-T cell therapy, and addresses these challenges by presenting a translational research strategy aimed to dissect and leverage the impact of gut microbes in its antitumor efficacy.In Aim 1, we will investigate the hypothesis that gut and intratumoral microbiome configurations and its metabolites are associated with clinical response of CD19-CAR-T cells in lymphoma, with immunophenotypes of these engineered T cells and the tumor immune microenvironment.

We will examine the effects of nutrition and antimicrobial drugs on microbiome features to identify potential mechanisms and therapeutic levers.

In Aim 2, we will address the biology of microbiome-CAR-T cell interactions through experimental gut microbiome modulations, and humanizing mice with patient-derived microbial ecologies and individual species and strains in preclinical research models.

In Aim 3, we will assess potential therapeutic interventions to increase CAR-T efficacy by investigating the action of microbiome-derived metabolites on CAR-T cells and studying phage- and diet-based interventions to mitigate antibiotic-induced gut microbiome dysbiosis.Characterising the function of the microbiome and its products in CAR-T immunotherapy harbours an enormous potential to improve current and future T cell transfer therapies for numerous patients suffering from cancer.