Scientists headed by a team at the University of Freiburg have discovered that the antacid sodium bicarbonate (NaBi)—also known as baking soda or bicarbonate of soda—can metabolically reprogram T cells in leukemia patients to resist the immune-suppressing effects of cancer cells that can drive leukemia relapse after stem cell transplants. By studying both mouse models of leukemia and T cells from patients before and after transplantation, Franziska Uhl, PhD, and colleagues found that acute myeloid leukemia (AML) cells suppressed the metabolic activities and the spread of donated T cells by secreting lactic acid (LA).
The studies showed that treating cells with sodium bicarbonate reversed the effects of lactic acid, and boosted the graft-versus-leukemia (GVL) activity of both mouse and human T cells. The work helps to clarify why patients frequently relapse after allogeneic hematopoietic cell transplantation (allo-HCT), and lays the foundation for a clinical trial that could test whether sodium bicarbonate could represent a safe and simple therapy to reduce relapse rates and improve treatment outcomes for AML patients.
Reporting on their studies in Science Translational Medicine, first author Uhl, and colleagues, concluded, “Overall, we show that metabolic reprogramming of donor T cells is a pharmacological strategy for patients with relapsed AML after allo-HCT … Together, these findings demonstrate the mechanism of metabolic evasion of the immune cells by LA production in aggressive blood cancers and pave the way for a clinical trial to combine T-cell transfer with bicarbonate for AML relapse treatment.” Their paper is titled, “Metabolic reprogramming of donor T cells enhances graft-versus leukemia effects in mice and humans.”
Allogeneic hematopoietic cell transplantation is a form of stem cell transplant that can sometimes cure people with blood cancers such as AML. However, complete response rates can be as low as 17% after 100 days, largely because the leukemia will frequently return. Relapse after allo-HCT has a “dismal” prognosis, the authors noted. “The major cause of death after allogeneic hematopoietic cell transplantation … is relapse of the underlying hematological malignancies,” they wrote.
There is a pressing need for methods that can boost the anticancer effects of stem cell transplants, but researchers haven’t fully understood why donated T cells often fail to finish off tumors. One possibility is that the leukemia cells play a role in this suppression of cancer-killing T-cell activity. “The failure of the T cells in the allo-HCT recipient to prevent the relapse and the inability of the T cells contained in DLI [donor lymphocyte infusion] to eliminate leukemia cells may be related to leukemia cells that impair activation and metabolic activity of T cells,” the scientists suggested.
Through their experiments in mouse models of leukemia and studies using T cells from AML patients both before and after transplantation, Uhl and colleagues found that leukemia cells secreted lactic acid, which changed the pH of the cellular environment, impacted on T cell metabolic activities, and interfered with T cell glucose metabolism, which inhibited proliferation. “Overall, our findings show that AML cells reduce glycolytic activity of T cells in patients and mice,” the team noted. “Mechanistically, we demonstrated that this was mediated by LA release reducing intracellular pH in T cells, which changed the transcriptional profile leading to metabolic and proliferative dysfunction. Their findings were relevant to T cells isolated from patients relapsing with AML after allo-HCT, which displayed reduced glycolytic activity and oxidative phosphorylation, when compared with T cells harvested from the same patients at an earlier time point before relapse, when the AML was still in remission. Studies in mouse models confirmed that lactic acid impaired the proliferative capacity and antitumor activity of T cells.
The changes in metabolic fitness of T cells correlated with increased abundance of lactic acid in the serum of patients. “We observed that LA increased in patients with AML relapse after allo-HCT but not in patients with AML who were in remission after allo-HCT, supporting the concept that LA release is relevant for immune escape in the presence of allogeneic immune pressure,” the authors noted.
Searching for therapies, the team turned to the antacid sodium bicarbonate, a compound that is already used to counteract metabolic acidosis in patients. “… we investigated whether exogenous NaBi could help to overcome the metabolic CD8+ inhibition of T cells caused by LA.” They found that a clinical formulation named bicaNorm reversed the suppressive metabolic changes and antiproliferative effects of LA on T cells in vitro, and in live AML-bearing mice. “When T cells were given to AML-bearing mice, the animals survived longer when treated with NaBi,” the team noted.
Encouraged by the preclinical results, the researchers then prescribed bicaNorm for one week to 10 AML patients who had a relapse after allo-HCT, and received DLIs. The results showed that the patients’ T cells received “a metabolic boost,” and exhibited an enhanced immune profile. “The rescue of metabolic activity was accompanied by increased IFN-γ and TNFα production,” the authors noted. “Our findings provide a pharmacological strategy to overcome metabolic reprogramming of transferred T cells to enhance GVL effects in patients relapsing after allo-HCT.”
They acknowledge a limitation of their study, in that most of the functional results were derived from tests in a mouse model. “ … only correlative studies were performed with human cells,” the scientists noted. To find whether NaBi improves GVL effects in humans will need a prospective clinical study. As the researchers concluded, “Our findings provide a scientific rationale for a combination of DLI and NaBi in patients relapsing with AML after allo-HCT, in particular when increased LA concentrations are detected as observed in the patients with AML relapse whom we had studied.”