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For patients with leukemia and other hematological malignancies, donor hematopoietic stem cells can recognize and attack remaining cancer cells after chemotherapy. But residual cancer cells’ immune-suppressing effects can thwart these transplants and lead to eventual relapse, requiring a donor lymphocyte infusion. A new study suggests that a treatment as simple as sodium bicarbonate—better known as baking soda—can potentially boost donor lymphocytes’ ability to overcome relapse after stem cell transplants.
In a previous study, the same research team found that T cells from hematopoietic stem cell transplants among patients with acute myeloid leukemia (AML) possess different metabolic properties depending on their treatment response. In their latest work, published in Science Translational Medicine, the investigators compared T cells at the time of AML diagnosis, during remission after stem cell transplant, and at relapse.
“We conducted this study to better understand how leukemia cells manage to escape the immune system after stem cell transplantation and if metabolic changes play a role that can be antagonized by the intake of certain nutrients or medication,” senior author Robert Zeiser, MD, head of tumor immunology and immune modulation at the University of Freiburg in Germany, said by email.
Following relapse, patients’ killer T cells exhibited reduced glycolysis and production of interferon-γ, a cytotoxicity marker—signs that their metabolism and cancer-killing ability were compromised. To analyze the mechanisms behind these changes, the team injected differently exposed killer T cells into mice with AML. T cells that were not previously exposed to AML cells exhibited an anti–cancer “graft-vs-leukemia” effect, but exposed T cells did not. Therefore, the researchers concluded, AML cells likely release factors that inhibit T cells’ ability to fight leukemia.
The researchers went on to show that sodium bicarbonate counteracts one of those factors: lactic acid. German physiologist and physician Otto Warburg, MD, PhD, first demonstrated that malignant cells produce lactic acid almost a century ago. Since then, “it’s becoming increasingly clear that it’s not simply a waste product, but rather is a bioactive molecule with immunosuppressive properties,” Dimitrios Mougiakakos, MD, a professor of tumor immunology at the University of Erlangen-Nuremberg, who was not involved with the recent study, noted by email.
In mouse and cell experiments, Zeiser’s team found that AML-derived lactic acid interfered with T cell glycolysis, proliferation, and graft-vs-leukemia effect. It did so by lowering the immune cells’ internal pH, which reduced glycolysis-related gene expression and decreased the activity of essential metabolic pathways.
Stored patient blood samples had a much lower lactic acid concentration at AML diagnosis than they did after relapse, suggesting that stem cell transplants themselves increase lactic acid production. “We hypothesize that the immune pressure after transplantation leads to the emergence of leukemic clones that produce high amounts of lactic acid,” Zeiser said.
In further experiments, bicaNorm, an oral sodium bicarbonate medication used to treat metabolic acidosis, reverted T cells’ intracellular pH back to normal and restored their metabolism and proliferation. Adding bicaNorm to the drinking water of mice with AML that received stem cell transplants prolonged the animals’ survival.
The experiments “provide a great deal of mechanistic information about how lactic acid can impair T cell function and how this can be coopted by AML as an immune evasion strategy,” Paul Armistead, MD, PhD, of the University of North Carolina Lineberger Comprehensive Cancer Center, who was not involved with the research, said in an email. “However,” he cautioned, “it should be noted that actual T cell–mediated cytotoxicity against AML was not evaluated to the same degree as other T cell functions.” Considering the urgent need for more effective therapies for relapsed AML, trials that examine current treatments plus bicaNorm—which is safe, inexpensive, and easy to administer—are warranted, he said.
Zeiser’s team reported preliminary trial results in their recent article. Combining a week-long course of bicaNorm with donor lymphocyte infusions following stem cell transplants improved T cell metabolism and interferon-γ production among 10 patients with relapsed AML. But a true test of sodium bicarbonate’s potential will require a larger prospective clinical trial assessing whether the therapy prolongs survival in patients with leukemia relapse.
Mougiakakos said he wants to see well-controlled trials using bicaNorm to treat relapse after allogeneic hematopoietic stem cell transplant, or even to prevent relapse before it happens. “Moreover, bicaNorm could represent a partner with verified low toxicity for other approaches aiming to harness graft-versus-leukemia effects,” he said.
Zeiser noted that the work may have broader applications, as it draws on 2 increasingly promising areas of cancer-related research: immunotherapy and cancer immunometabolism, the metabolic interplay between host immune cells and cancer. “We hope, by connecting the 2, to get a powerful new toolbox for the clinic,” he said.
Hampton T. Could Baking Soda Fight Leukemia Relapse After Stem Cell Transplant? JAMA. 2021;325(1):19. doi:10.1001/jama.2020.24504
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