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Un bénéfices supplémentaire du bicarbonate?

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Un bénéfices supplémentaire du bicarbonate?

Messagepar Nutrimuscle-Conseils » 6 Jan 2021 01:47

Could Baking Soda Fight Leukemia Relapse After Stem Cell Transplant?
Tracy Hampton, JAMA. 2021;325(1):19.

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.

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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.
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Re: Un bénéfices supplémentaire du bicarbonate?

Messagepar Nutrimuscle-Conseils » 6 Jan 2021 01:49

Metabolic reprogramming of donor T cells enhances graft-versus-leukemia effects in mice and humans
Franziska M. Uhl Science Translational Medicine 28 Oct 2020:Vol. 12, Issue 567

A basic treatment for leukemia
For patients with acute myeloid leukemia, hematopoietic stem cell transplant offers a chance of curing the underlying cancer, in part because of the graft-versus-leukemia effect, or anticancer activity of transplanted T cells. Unfortunately, this does not always work, and engrafted T cells often fail to control the leukemia. By studying patients with acute myeloid leukemia who relapsed after hematopoietic stem cell transplant, Uhl et al. found that lactic acid produced by leukemic cells specifically interfered with T cell activity. The detrimental effects of lactic acid could be overcome with sodium bicarbonate, which improved T cell metabolic fitness in both mouse models and human patients.

Abstract
Acute myeloid leukemia (AML) relapse after allogeneic hematopoietic cell transplantation (allo-HCT) has a dismal prognosis. We found that T cells of patients relapsing with AML after allo-HCT exhibited reduced glycolysis and interferon-γ production. Functional studies in multiple mouse models of leukemia showed that leukemia-derived lactic acid (LA) interfered with T cell glycolysis and proliferation. Mechanistically, LA reduced intracellular pH in T cells, led to lower transcription of glycolysis-related enzymes, and decreased activity of essential metabolic pathways. Metabolic reprogramming by sodium bicarbonate (NaBi) reversed the LA-induced low intracellular pH, restored metabolite concentrations, led to incorporation of LA into the tricarboxylic acid cycle as an additional energy source, and enhanced graft-versus-leukemia activity of murine and human T cells. NaBi treatment of post–allo-HCT patients with relapsed AML improved metabolic fitness and interferon-γ production in T cells. Overall, we show that metabolic reprogramming of donor T cells is a pharmacological strategy for patients with relapsed AML after allo-HCT.
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Re: Un bénéfices supplémentaire du bicarbonate?

Messagepar Nutrimuscle-Diététique » 6 Jan 2021 17:14

Traduction de l'étude :wink:

La reprogrammation métabolique des cellules T du donneur améliore les effets du greffon contre la leucémie chez les souris et les humains
Franziska M. Uhl Science Translational Medicine 28 octobre 2020: Vol. 12, Numéro 567

Un traitement de base pour la leucémie
Pour les patients atteints de leucémie myéloïde aiguë, la greffe de cellules souches hématopoïétiques offre une chance de guérir le cancer sous-jacent, en partie à cause de l'effet du greffon contre la leucémie ou de l'activité anticancéreuse des cellules T transplantées. Malheureusement, cela ne fonctionne pas toujours et les cellules T greffées ne parviennent souvent pas à contrôler la leucémie. En étudiant des patients atteints de leucémie myéloïde aiguë qui ont rechuté après une greffe de cellules souches hématopoïétiques, Uhl et al. ont découvert que l'acide lactique produit par les cellules leucémiques interférait spécifiquement avec l'activité des cellules T. Les effets néfastes de l'acide lactique pourraient être surmontés avec du bicarbonate de sodium, qui a amélioré la capacité métabolique des cellules T chez les modèles murins et les patients humains.

Abstrait
La rechute de leucémie myéloïde aiguë (LMA) après une greffe allogénique de cellules hématopoïétiques (allo-HCT) a un pronostic sombre. Nous avons constaté que les cellules T de patients rechutant avec la LMA après l'allo-HCT présentaient une glycolyse et une production d'interféron-γ réduites. Des études fonctionnelles dans plusieurs modèles murins de leucémie ont montré que l'acide lactique dérivé de la leucémie (LA) interférait avec la glycolyse et la prolifération des lymphocytes T. Mécaniquement, l'AL a réduit le pH intracellulaire dans les cellules T, a conduit à une transcription plus faible des enzymes liées à la glycolyse et à une diminution de l'activité des voies métaboliques essentielles. La reprogrammation métabolique par le bicarbonate de sodium (NaBi) a inversé le faible pH intracellulaire induit par LA, restauré les concentrations de métabolites, conduit à l'incorporation de LA dans le cycle de l'acide tricarboxylique en tant que source d'énergie supplémentaire, et amélioré l'activité du greffon contre la leucémie de T murin et humain cellules. Le traitement NaBi des patients post-allo-HCT atteints de LAM récidivante a amélioré la capacité métabolique et la production d'interféron-γ dans les cellules T. Dans l'ensemble, nous montrons que la reprogrammation métabolique des cellules T du donneur est une stratégie pharmacologique pour les patients atteints de LAM récidivante après allo-HCT.
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