July 12, 2019 — Mesothelioma is a deadly cancer mainly caused by exposure to asbestos or other toxic mineral fibers. Currently, there is no effective cure against this disease and life expectancy of patients with mesothelioma remains very low. Virotherapy, which is based on the use of viruses to fight cancer cells, has long been investigated as a possible antitumoral strategy. Oncolytic viruses, in particular, have the ability to lyse tumor cells and spread the infection locally. The recent approval by the Food & Drug Administration of an oncolytic virus for the treatment of melanoma, in 2015, has sparked a renewed interest in the field. Indeed, many pre-clinical and clinical studies are evaluating viral-based strategies against mesothelioma. Mesothelioma is particularly amenable to virotherapy because the pleural cavity provides an easy route to direct intratumoral injection eluding viral inactivation in the bloodstream and limiting off-target infection.
A new collaborative study from researchers of the National Cancer Institute of Naples, ‘Pascale Foundation’, Italy; the University of Naples 'Federico II'; the University of Siena; and the Sbarro Institute for Cancer Research and Molecular Medicine in Philadelphia, PA, USA, explored the possible use of dl922-945, an adenovirus engineered to infect and replicate selectively in cancer cells, against mesothelioma. Adenovirus, a non-enveloped virus with a linear DNA genome, is among the oncolytic viruses most studied for therapeutic approaches. Adenovirus causes the common cold in humans or other diseases that are self-limited in immunocompetent hosts. It has a stable genome that does not mess up with the host genome and is able to self-replicate in the infected cells achieving a local high titer.
In this new study, published in Frontiers in Oncology, an open access peer-reviewed scientific journal, the authors showed that dl922-945 is able to infect and self-amplify within human mesothelioma cells, subverting their cell cycle features and inducing cancer cell death, an effect that is similarly triggered also in other cancer cell lines, such as those of the aggressive thyroid anaplastic carcinomas. The molecular mechanisms underlying dl922-945-induced cell demise, however, are still only partially characterized. In this study the authors showed that dl922-945 infection induces the exposure of calreticulin (an endoplasmic reticulum chaperone) on the surface of dying cells and the release of ATP and HMGB1, three hallmarks of the so called ‘immunogenic cell death’. In fact, the release of these molecules, along with tumor antigens from lysed cells, is crucial to activate a robust anti-tumoral immune response, so that dl922-945 has the potential to act as an in situ cancer vaccine against mesothelioma.
The authors also showed that dl922-947 infection reduces the production of two pro-angiogenic factors that contribute to tumor development, interleukin 8 and the vascular endothelial growth factor A, thereby further shaping the tumor microenvironment towards an antitumoral background.
“Virotherapy through dl922-947 synergized with the chemotherapy drug cisplatin in mesothelioma cell lines, suggesting that this approach could function along with the mainstay of treatment in the clinical setting,” says Carmelina A. Iannuzzi of the Pascale Foundation, who carried out this work as a PhD student at the University of Siena.
“dl922-947 treatment proved effective also in vivo, inhibiting the growth of mesothelioma xenografts, leading to complete tumor shrinkage in some mice and reducing the formation of intratumoral microvessels,” states Sarah Di Somma, co-first author of the study from the University of Naples.
“The ability of oncolytic viruses to reverse the tumor-induced immune tolerance through such modifications of the tumoral microenvironment is a major goal of current cancer therapies and yet another advantage of this class of antitumoral agents,” says Giuseppe Portella, virologist at the University of Naples who has characterized dl922-947 effects also in other tumor types.
“The next step will consist in assessing the potential of virotherapy in combination with the recently developed immune targeted therapies and translate these approaches to the clinical practice upon rigorous clinical trial testing,” says Francesca Pentimalli co-lead author of the study from the National Cancer Institute of Naples, which is under the Scientific Direction of Gerardo Botti, a renowned pathologist who is also a co-author of the study.
“Some studies predict an increase in the incidence of mesothelioma in some areas and therefore new therapeutic strategies able to cure or at least chronicize the disease are urgently needed,” concludes Antonio Giordano, Director and Founder of the Sbarro Institute who has devoted a great part of his latest efforts in findings novel approaches against mesothelioma, establishing dedicated research groups working in network across Naples, Siena, and Philadelphia.
About the Sbarro Health Research Organization
The Sbarro Health Research Organization (SHRO) is non-profit charity committed to funding excellence in basic genetic research to cure and diagnose cancer, cardiovascular diseases, diabetes and other chronic illnesses and to foster the training of young doctors in a spirit of professionalism and humanism. To learn more about the SHRO please visit www.shro.org