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Researchers from Cima and the University Clinic of Navarra manage to enhance the function of the cells responsible for eliminating tumors, T-type lymphocytes. Through genetic modification, they obtain cells capable of adapting to the adverse tumor microenvironment and enhancing their proliferative activity and antitumor. With this cell therapy strategy, they have managed to delay the growth of the disease and increase survival in mice with melanoma and hepatocarcinoma.
The results of this study have been published in the latest issue of the scientific journal Oncoimmunology.
Complexity of the tumor environment
The tumor microenvironment is a complex and changing environment in which malignant cells coexist with immune cells. It is characterized by being an acidic environment, with a very low pH.
“When the pH drops, the lymphocytes become acidic and ‘turn off’, they are not able to carry out their function. So, we noticed that some tumor cells they do survive in that environment because they express proteins that allow them to modulate their intracellular pH, achieving an advantage over lymphocytes”, points out Juan José Lasarte, director of the Cima Immunology and Immunotherapy Program. Analyzing this concept, we looked for a way to modulate the pH of the lymphocytes so that they do not acidify and thus increase their proliferative capacity”, adds Lasarte.
New strategy to improve current immunotherapy
Adoptive cell therapy is a type of immunotherapy based on administering T lymphocytes to the patient to help him fight his disease. It is a personalized medicine therapy, since they are extracted the patient’s own T cells, are multiplied in the laboratory and infused back into it. Sometimes these cells are modified in the laboratory to improve their ability to recognize the tumor and kill it, as is the case with CAR-T cells. Another adoptive cell therapy is therapy with infiltrating lymphocytes tumor cells, immune cells found naturally in the patient’s tumor.
They are currently testing experimental therapies to try to neutralize the acidic pH of the tumor, but these treatments affect the entire body, not being very effective. «In our research we look for a more focused alternative and we focus on enhance immune cells so that they could survive in the acidic tumor environment, ”says Lasarte.
Specifically, Flor Navarro, researcher at Cima and first author of the study, points out: “in the laboratory we genetically modified the T lymphocytes by adding ‘transporters’ to their membrane that enable them to expel from their interior the protons that infiltrated from the tumor medium and caused its acidification. With this modification, we ensure that the lymphocyte does not ‘turn off’ in this adverse acid environment and can exert its antitumor activity».
The work has been carried out in studies in-vitro and in-vivo in mice with melanoma and hepatocarcinoma. Using various immunotherapy strategies, they have managed to “significantly delay tumor growth and increase survival,” confirms Navarro. “Clinical trials with CAR-T for the treatment of hepatocarcinoma are currently underway. With our research we have verified that we could enhance that available CAR-T therapy with our ‘carrier’. Thus, the results of this work suggest that overcoming ‘the barrier’ of the pH acidity of the tumor environment with T-lymphocytes modified with the ‘transporter’ could enhance the efficacy of existing combined immunotherapies”, points out the researcher.
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