Project overview Joint Funding
BITe-AML (Boost Immuno-Therapy for AML)
Program: CI Funding Line: INNOVATION Project type: research project Entity: blood cancer Status: current
Acute myeloid leukemia (AML) is a life-threatening blood cancer characterized by the expansion of immature myeloid blasts in the bone marrow and poor outcome. Understanding molecular causes of the disease, such as genetic alterations of the FLT3 gene, as well as the development of targeted inhibitors against such targets, has paved the way for the development of targeted drugs that improve patient outcome. Despite these advances, genetic alterations of the FLT3 gene remain a negative prognostic marker, and the vast majority of patients with FLT3-mutated AML still rely on allogeneic stem cell transplantation (allo-HSCT) for long-term disease control. This procedure introduces a new, foreign immune system that is able to recognize and eliminate leukemic cells (graft-versus-leukemia effect, GvL). However, this new immune system also introduces significant risks: The immune response is not targeted, and the anti-leukemic immunity is largely unpredictable, meaning that stem cell transplantation is associated with treatment-related morbidity and mortality. To this day, it is not possible to induce a selective GvL effect, which carries a substantial risk of immune-mediated side effects (such as acute and chronic graft-versus-host disease, GvHD). Other immunotherapies, such as genetically modified T-cells, have not yet contributed to improving survival for AML patients, unlike in lymphoid malignancies. Therefore, there is an urgent need for innovative strategies to enhance immunotherapy in AML patients.
The Joined Funding project Boost Immunotherapy for AML (BITeAML) aims to advance the treatment of acute myeloid leukemia (AML) by exploring and optimizing innovative immunotherapeutic strategies for enhancing the graft-versus-leukemia effect after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Given the poor long-term prognosis for many AML patients, even after intensive chemotherapy and allo-HSCT, there is a critical need for new therapy approaches. The starting point of the project is a multi-omic analysis of patient samples from the prospective SORMAIN study. This study demonstrated the clinical efficacy of Sorafenib, a tyrosine kinase inhibitor with activity against FLT3, which was able to reduce relapse risk and prolong survival of patients with FLT3-mutated AML when given as post-allo-HSCT maintenance therapy.
Our initial studies suggest that this effect is driven by rewiring of the bone marrow immune microenvironment. The BITEAML consortium will uncover the mechanisms driving sorafenib-based immune modulation post-allo-HSCT in patients by combining clinical proteomics, metabolomics and advanced (single cell) sequencing technologies. This in-depth characterization of cellular and molecular immune rewiring in patients will be complemented by mechanistic studies in suitable AML models exploring the synergy between molecular drugs and alloreactive T-cells to further enhance the graft-versus-leukemia effect. Finally, the development of new T-cell receptor-based therapies against leukemia-specific surface proteins, identified through immunopeptidome profiling and T-cell receptor sequencing, will be pursued. The results obtained in this project will provide a molecular and immunological rationale for a future clinical trial aiming at a further enhancement of the graft-versus-leukemia effect in AML patients to improve their outcome.
Involved Partnersites
Berlin, Frankfurt/Mainz, Freiburg, TubingenCoordinators
