Deciphering cellular signalling to cure graft-versus-host disease (GVHD) and leukemia relapse

Introduction

Acute graft-versus-host disease (GVHD) and leukemia relapse cause 75% of the mortality of patients having undergone allogeneic hematopoietic cell transplantation (allo-HCT). A better understanding of signalling in immune cells, tissue-specific cell types, and leukemia cells is key to developing novel therapies against GVHD and leukemia relapse.

Overall Goal

The ambitious overall goal of AlloCure is to identify the pathogenic events that initiate GVHD, maintain therapy-refractory GVHD, and mediate immune escape causing leukemia relapse. Specifically, we aim to address the following high-risk/high-gain questions:

1. Initiation of GVHD: I hypothesize that a loss of to date unexplored intestinal enteroendocrine cells promotes GVHD initiation. To study these small cell subsets, we will use reporter genes and novel imaging methods to systematically evaluate their fate and signalling during intestinal GVHD.

2. Refractory GVHD: Signalling propagating refractory GVHD is not well understood. Our phospho-proteomics data set from corticosteroid- and ruxolitinib-refractory GVHD patients will instruct selective analysis of kinase activation in immune cells and enterocytes by using genetic Cre-lox-based and pharmacological approaches.

3. Leukemia Relapse: I have shown that leukemia-derived lactic acid inhibits glycolysis and MEK/ERK signalling in T cells, thereby impairing graft-versus-leukemia (GVL) effects. Here, I will decipher which other leukemia-derived metabolites mediate pathogenic signalling in immune cells and test if oncogenic signalling in leukemia cells drives immunosuppressive metabolite production.

Strategy for Enhancement

To enhance GVL, we will inhibit pathogenic kinase activation in leukemia cells and myeloid suppressor cells. Using high-risk/high-gain approaches in a combination of murine and human studies, AlloCure aims to develop individualized therapeutic strategies to interfere with pathogenic signalling responsible for GVHD or leukemia relapse to reduce the mortality rate of patients undergoing allo-HCT.