MICROBOTS – Unravel the power of MICRObial metaBOliTeS to prevent graft versus host disease and cure leukemia relapse

Introduction

Allogeneic stem cell transplantation (allo-SCT) is the most common cellular immunotherapy for hematologic malignancies. However, beneficial outcomes are limited by severe morbidity and mortality due to graft-vs.-host disease (GVHD) and relapse as a consequence of insufficient antitumor immune response (graft-vs-leukemia, GVL).

Gut Microbiome and Clinical Outcomes

In allo-SCT patients, a diverse gut microbiome is associated with beneficial clinical outcomes. Fecal microbiota transplantation (FMT) emerges as a promising therapeutic option for acute gastrointestinal GVHD patients. Yet, how the gut and tissue-associated microbiome governs immune function and tissue homeostasis remains poorly understood.

Microbial Signatures

We identified microbial signatures—i.e., configurations of microbial communities and their associated immune-modulatory metabolites—in allo-SCT patients that:

1. Favourably associate with clinical outcomes,
2. Can engage an Interferon (IFN)-I inducing pathway to induce tissue regeneration, and
3. Protect mice from immune-mediated tissue damage.

Hypothesis and Objectives

We therefore hypothesize that gut and tissue-associated microbial consortia and their immune-modulatory metabolites serve as a game changer for allo-SCT. “MICROBOTS” will test this by:

1. Providing a thorough characterization of microbiome/metabolome-host interaction at the epithelial interface in allo-SCT patients with or without GVHD, relapse, and undergoing FMT.
2. Evaluating the functional impact of identified microbial signatures in advanced preclinical models of GVL and GVHD.

Expected Outcomes

These novel insights will provide a template for the design of a Precision FMT approach with defined microbial-metabolite cocktails aimed to achieve robust and durable antitumor responses in allo-SCT patients. Additionally, this approach seeks to improve tissue regeneration and minimize immune-mediated side effects (GVHD).

Potential Impact

This may induce a paradigm shift in clinical allo-SCT protocols and potentially other T cell transfer therapies (CAR/TCR T cells) in cancer treatment as a whole.