ProjektPowerMiT – Leveraging the impact of gut microbes to advance the efficacy of CAR-T cell immunotherapy.
Grunddaten
Akronym:
PowerMiT
Titel:
Leveraging the impact of gut microbes to advance the efficacy of CAR-T cell immunotherapy.
Laufzeit:
01.03.2024 bis 28.02.2029
Abstract / Kurz- beschreibung:
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.
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.
Schlüsselwörter:
Haematopoiesis and blood diseases
Microbiome and host physiology
Innovative immunological tools and approaches, including therapies
CAR-T cell therapy; hematologic malignancy; metabolome; gnotobiotics
Beteiligte Mitarbeiter/innen
Leiter/innen
Medizinische Fakultät
Universität Tübingen
Universität Tübingen
Exzellenzcluster: Kontrolle von Mikroorganismen zur Bekämpfung von Infektionen (CMFI)
Zentren oder interfakultäre wissenschaftliche Einrichtungen
Zentren oder interfakultäre wissenschaftliche Einrichtungen
Lokale Einrichtungen
Universität Tübingen
Geldgeber
Brüssel, Belgien