Allogeneic hematopoietic stem cell transplant (allo-HCT) is known to be effective in the treatment of acute myeloid leukemia (AML); however, many patients relapse after transplantation, and prognosis is poor in this subpopulation. Findings from a study recently published in Science Translational Medicine shed light on the mechanisms of relapse, which is associated with leukemia cell production of lactic acid, a process that blocks the antitumor activity of donor T cells. Sodium bicarbonate may reprogram the metabolism of the donor T cells, and could therefore be a pharmacological strategy to overcome this immunosuppressive effect, according to the study data.
Sodium bicarbonate’s metabolic effect was demonstrated in both patient-derived cells and mouse models. After assessing sodium bicarbonate’s efficacy in AML-transplanted mouse models, the investigators tested sodium bicarbonate in 10 patients with AML, all of whom had relapsed after allo-HCT. After treatment, CD8-positive T cells that were isolated from the patients showed a promising increase in metabolic activity.
“We showed in mice and in humans that we can reverse the detrimental effect of lactic acid and rescue the T cells,” said Robert Zeiser, MD, of the University of Freiburg, Germany.
Leukemia cells release a chemical factor that neutralizes the graft-versus-leukemia (GVL) activity of the transplanted cells. The investigators used mass spectrometry to measure the different metabolites produced by the leukemia cells and identified lactic acid as the chemical responsible for stopping T cell activity, leading to subsequent relapse due to the T cells’ impaired ability to eradicate leukemia cells.
Nearly 100 years ago, German physician Otto Warburg showed that tumor metabolism differs from that of healthy cells. Even when plenty of oxygen is available, cancer cells use fermentation of glucose to meet their energy needs, generating lactic acid. The new results show that this lactic acid performs an important role in keeping T cells at bay.
“In fact, lactic acid is not just a ‘waste product’; it is a bioactive molecule, and in recent years, its immunosuppressive properties limiting intrinsic and therapeutic anti-tumor immunity have become evident,” Dimitrios Mougiakakos, MD, of the Friedrich-Alexander University in Erlangen, Germany, told Cancer Therapy Advisor. “As professor Zeiser elegantly shows, this enhanced glucose metabolism of relapsing AML blasts impedes T-cell function, thus limiting GVL activity.”
By lowering the pH inside the T cells, lactic acid reduced glycolytic activity and oxidative phosphorylation. Transcriptome analysis revealed that the gene sets involved in these processes were downregulated.
To counteract the effect of lactic acid and restore T cell function, Zeiser and his colleagues turned to sodium bicarbonate, which is commonly used to neutralize stomach acid and to treat metabolic acidosis, a systemic excess of acid. The researchers first showed that sodium bicarbonate could reverse the effects of lactic acid on metabolism in isolated T cells.
Treatment with sodium bicarbonate not only reversed the metabolic shutdown induced by lactic acid, but also enabled the cells to take in the extracellular lactic acid and use it for fuel. “The lactic acid is internalized in the so-called TCA cycle, or tricarboxylic acid cycle, and it’s used as an energy source,” Dr Zeiser said. “That is a very good situation, because then the lactic acid is gone, and the leukemia cannot paralyze the T cells anymore.”