The hope of immunotherapy against chronic hepatitis B, which afflicts over 300 million people worldwide and is among the primary risk factors for liver cirrhosis and liver cancer. The first tests in the world were conducted on preclinical models by a group of researchers from the Irccs San Raffaele hospital in Milan and the Vita-Salute San Raffaele university, in collaboration with the American start-up Asher Biotherapeutics. The results, published in 'Science Translational Medicine', open the way to the treatment of HBV infection thanks to a molecule – interleukin-2 – capable of reactivating the immune system against the disease. In fact, in patients with chronic hepatitis B, the natural defenses are unable to eradicate the virus responsible for the pathology, which continues to survive and reproduce inside the liver cells.
HBV – they recall from San Raffaele – is transmitted through contact with infected blood, sexually or from mother to child during childbirth. Unlike what happens when an adult contracts the virus, over 90% of children infected at birth develop the chronic form of hepatitis B. Today there is a preventive vaccine against the infection, but patients who have already contracted it do not have it can benefit. For them, a possible turning point comes from the study coordinated by Matteo Iannacone, director of the Division of Immunology, Transplants and Infectious Diseases of the Irccs San Raffaele hospital, who returned to Italy after a long experience in the United States thanks to the Career Development Award of the Armenise-Harvard Foundation . Iannacone's research, in synergy with the unit directed by Luca Guidotti, deputy scientific director of San Raffaele, has contributed in recent years to developing some of the antivirals commonly used to treat hepatitis B in its chronic form.
Already in 2019, with some data published in 'Nature', through a molecular analysis carried out thanks to intravital microscopy techniques, scholars had demonstrated that T lymphocytes are unable to eradicate Hbv infection and are dysfunctional since their activation. The characterization of dysfunctional T lymphocytes had also allowed the San Raffaele researchers to identify the most suitable and effective molecules for reawakening these cells. One is interleukin-2 (Il-2), a messenger molecule of the immune system, which acts as a sort of immunotherapy and has already been successfully tested both in cultured cells obtained from patient samples and in animal models. However, Il-2, when administered systemically, produces serious side effects, increasing the permeability of blood vessels and causing severe edema. This happens because the molecule not only acts on T lymphocytes, but also on Natural killer cells that induce toxicity, as well as on regulatory cells that inhibit the immune response. The new study bypasses these obstacles.
Thanks to the collaboration with Asher Biotherapeutics which produces interleukin-2 – explains a note – the researchers were able to experiment with this molecule by developing a so-called 'cis-targeting' approach: Il-2, conjugated with a specific antibody, can to target only T lymphocytes, activating them correctly against the disease.
“We have seen, in mouse models of the disease – reports Iannacone – that by administering this type of immunotherapy the T lymphocytes expand in number and increase their function, that is, they release cytokines capable of inhibiting viral replication and eliminate the infected cells, breaking down made the virus.” The results demonstrated, in preclinical models of hepatitis B, but also in the blood of healthy people, the safety, low toxicity and therapeutic efficacy of this innovative approach. “In addition to antiviral approaches – comments Iannacone – it is possible to finally think of an immunotherapy strategy” against chronic hepatitis B. “The next step is to test this approach in humans, in combination with antivirals.”
The research was supported by the European Research Council (ERC), the Airc Foundation for cancer research, the Ministry of Health and the Ministry of University and Research.