2 research outputs found
Metabolic instruction of the graft-versus-leukemia immunity
Allogeneic hematopoietic cell transplantation (allo-HCT) is frequently performed to cure hematological malignancies, such as acute myeloid leukemia (AML), through the graft-versus-leukemia (GVL) effect. In this immunological process, donor immune cells eliminate residual cancer cells in the patient and exert tumor control through immunosurveillance. However, GVL failure and subsequent leukemia relapse are frequent and associated with a dismal prognosis. A better understanding of the mechanisms underlying AML immune evasion is essential for developing novel therapeutic strategies to boost the GVL effect. Cellular metabolism has emerged as an essential regulator of survival and cell fate for both cancer and immune cells. Leukemia and T cells utilize specific metabolic programs, including the orchestrated use of glucose, amino acids, and fatty acids, to support their growth and function. Besides regulating cell-intrinsic processes, metabolism shapes the extracellular environment and plays an important role in cell-cell communication. This review focuses on recent advances in the understanding of how metabolism might affect the anti-leukemia immune response. First, we provide a general overview of the mechanisms of immune escape after allo-HCT and an introduction to leukemia and T cell metabolism. Further, we discuss how leukemia and myeloid cell metabolism contribute to an altered microenvironment that impairs T cell function. Next, we review the literature linking metabolic processes in AML cells with their inhibitory checkpoint ligand expression. Finally, we focus on recent findings concerning the role of systemic metabolism in sustained GVL efficacy. While the majority of evidence in the field still stems from basic and preclinical studies, we discuss translational findings and propose further avenues for bridging the gap between bench and bedside
Phase II trial of hypomethylating agent combined with nivolumab for acute myeloid leukaemia relapse after allogeneic haematopoietic cell transplantationâImmune signature correlates with response
SummaryAcute myeloid leukaemia (AML) relapse after allogeneic haematopoietic cell transplantation (alloâHCT) is often driven by immuneârelated mechanisms and associated with poor prognosis. Immune checkpoint inhibitors combined with hypomethylating agents (HMA) may restore or enhance the graftâversusâleukaemia effect. Still, data about using this combination regimen after alloâHCT are limited. We conducted a prospective, phase II, openâlabel, singleâarm study in which we treated patients with haematological AML relapse after alloâHCT with HMA plus the antiâPDâ1 antibody nivolumab. The response was correlated with DNAâ, RNAâ and proteinâbased singleâcell technology assessments to identify biomarkers associated with therapeutic efficacy. Sixteen patients received a median number of 2 (range 1â7) nivolumab applications. The overall response rate (CR/PR) at day 42 was 25%, and another 25% of the patients achieved stable disease. The median overall survival was 15.6âmonths. Highâparametric cytometry documented a higher frequency of activated (ICOS, HLAâDR), low senescence (KLRG1, CD57) CD8 effector T cells in responders. We confirmed these findings in a preclinical model. Singleâcell transcriptomics revealed a proâinflammatory rewiring of the expression profile of T and myeloid cells in responders. In summary, the study indicates that the postâalloâHCT HMA/nivolumab combination induces antiâAML immune responses in selected patients and could be considered as a bridging approach to a second alloâHCT. Trialâregistration: EudraCTâNo. 2017â002194â18