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

Introduction

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.

Challenges in CAR-T Cell Therapy

Major challenges of current CAR-T cell immunotherapies include:

• Loss of long-term efficacy
• Occurrence of toxicities, including infections
• 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.

Research Aims

Aim 1: Investigating Microbiome Configurations

In Aim 1, we will investigate the hypothesis that gut and intratumoral microbiome configurations and their metabolites are associated with the clinical response of CD19-CAR-T cells in lymphoma. We will also examine the immunophenotypes of these engineered T cells and the tumor immune microenvironment.

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

Aim 2: Exploring Microbiome-CAR-T Cell Interactions

In Aim 2, we will address the biology of microbiome-CAR-T cell interactions through:

1. Experimental gut microbiome modulations
2. Humanizing mice with patient-derived microbial ecologies
3. Individual species and strains in preclinical research models

Aim 3: Assessing Therapeutic Interventions

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
• Phage- and diet-based interventions to mitigate antibiotic-induced gut microbiome dysbiosis

Conclusion

Characterizing the function of the microbiome and its products in CAR-T immunotherapy harbors enormous potential to improve current and future T cell transfer therapies for numerous patients suffering from cancer.