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Pancreatic cancer, Italian study opens up new scenarios on resistance to immunotherapy

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Pancreatic cancer, Italian study opens up new scenarios on resistance to immunotherapy

The research, published in Science Translational Medicine, is coordinated by the Veneto Oncological Institute and the University of Verona.

Il cancro al pancreas is one of the most resistant oncological diseasesimmunotherapy. A new study, coordinated by theVeneto Oncological Institute and fromUniversity of Veronatrace a new path to try to overcome this resistance, by modifying the tumor microenvironment. The research, published in the scientific journal Science Translational Medicine, was funded by the Cancer Research Institute, the Cariverona Foundation, the AIRC, the Ministry of Health, the Ministry of Education and Merit and EuroNanoMed.


The authors analyzed a mechanism of evasion from the immunological control implemented by pancreatic cancer. They did this by integrating functional, phenotypic and molecular data, and by developing a combined immunotherapy, effective in preclinical models in which the human immune system has been reconstructed. In patients with pancreatic cancer i neutrophils, cells of the immune system circulating in the blood, are activated by factors produced by the neoplastic cells. These cells release, spontaneously and in an uncontrolled way, complex molecular structures, called NET.

These structures, which resemble a real network (for which they take the name NET), are mainly made up of genetic material (DNA) and proteins. Among the latter the enzyme arginase 1 (ARG1)which, activated inside the NETs, ​​generates some molecular forms that cause the excessive consumption of an amino acid essential to the antitumor activity of T lymphocytes. The immune response towards the tumor is, therefore, hindered.

To counter the functional block of the T lymphocytes the study group generated a new antibody capable of recognizing and neutralizing the human ARG1 enzyme. Through functional and biochemical analyses, experts have demonstrated that the function of T lymphocytes is restored with the help ofanticorpo mAb 1.10while chemical inhibitors of the enzyme are not effective in blocking the molecular forms activated in cancer patients.

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In humanized preclinical models of pancreatic cancer, the administration of mAb 1.10 increases the efficacy of immunotherapy based both on the use of immunological checkpoint inhibitors both on the transfer of cytotoxic lymphocytes specific for telomerase tumor antigen. These data are also confirmed by biopsies of pancreatic tumors exposed in vitro to the anti-ARG1 antibody.

The study proposes a new key to understanding the immunoregulatory function of the ARG1 enzyme and tumor-negative neutrophils. Above all, the work suggests that, by reprogramming the tumor microenvironment, even a tumor known to be refractory to immunotherapy such as pancreatic cancer can become sensitive and responsive.

“This study opens up new scenarios in tumors showing intrinsic and primary resistance to immunotherapy – comments the professor Vincent Brontelead study coordinator –. The work continues a research path started more than ten years ago by my group. Research continues, aiming to obtain fully human antibodies to the ARG1 enzyme, to be used in therapy and diagnostics. This will apply to many cancers, not just pancreatic cancer.”.

Nurse Times editorial team

Fonte: Italian Medical News

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