Cima scientists 'boost' immune cells to fight cancer

Researchers at Cima and Clínica Universidad de Navarra have genetically modified T-lymphocytes to adapt to the tumor microenvironment and improve their antitumor activity. This cell therapy with lymphocytes, tested in different immunotherapy strategies, delays tumor growth and increases survival in mice.

Front row Juan José Lasarte and Flor Navarro, together with the Cima research team.

June 14, 2022

Researchers at Cima and Clínica Universidad de Navarra have enhanced the function of the cells responsible for eliminating tumors, the T-type lymphocytes. Through genetic modification, they have obtained cells capable of adapting to the adverse tumor micro-environment and improving their proliferative and antitumor activity. 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

The 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 as an acidic environment with a very low pH. "When the pH drops, the lymphocytes become acidified and 'shut down'; they cannot exert their function. But, we noticed that some tumor cells survive in this environment. It is because they express proteins that allow them to modulate their intracellular pH and give them an advantage over lymphocytes," says Juan José Lasarte, director of the Immunology and Immunotherapy Program at Cima. "Analyzing this concept, we looked for a way to modulate the pH of the lymphocytes so that they would not become acid 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 T cells are extracted from the patient, multiplied in the laboratory, and re-infused into the patient. Sometimes these cells are modified in the laboratory to improve their ability to recognize and destroy the tumor, as is the case with CAR-T cells. Another adoptive cell therapy is therapy with tumor-infiltrating lymphocytes, immune cells naturally found in the patient's tumor. 

Experimental therapies are currently being tested to try to neutralize the acidic pH of the tumor, but these treatments affect the whole body, not being very effective. "In our research, we are looking for a more focused alternative, and we focus on improving the immune cells so that they can survive in the acidic tumor environment," says Lasarte.

Specifically, says Flor Navarro, Cima researcher and first author of the study: "in the laboratory, we genetically modified the T lymphocytes by adding 'transporters' to their membrane. That enables them to expel from their interior the protons that infiltrate from the tumor environment and cause its acidification. With this modification, we managed to prevent the lymphocyte from 'shutting down' in this adverse acidic environment and allow it to exert its antitumor activity".
The work has been carried out in in-vitro and in-vivo studies in mice with melanoma and hepatocarcinoma. Using various immunotherapy strategies, researchers have managed to "significantly delay tumor growth and increase survival," confirms Navarro.

"Clinical trials are currently underway with CAR-T for the treatment of hepatocarcinoma. With our research, we have proven that we could potentiate this available CAR-T therapy with our 'transporter.' Thus, the results of this work suggest that overcoming the 'barrier' of the acidity of the pH of the tumor environment with T-lymphocytes modified with the 'transporter,' could enhance the efficacy of existing combined immunotherapies," the researcher points out.

The work is part of the Navarra Health Research Institute. It has received funding from the Government of Navarra (Project DESCARTHeS), the Ministries of Education and Science (Project AutoCAR), Science and Innovation (CARPanTu project), and the European Union's Next Generation and Horizon 2020 grants. It has also received support from the Ramón Areces Foundation and the Paula & Rodger Riney Foundation.