Dissertation committee:
1.Αθανάσιος Α.Γ. Τζιόυφας, Καθηγητής, Ιατρική, ΕΚΠΑ
2.Νικόλαος Τσαβαρής, Καθηγητής, Ιατρική, ΕΚΠΑ
3.Ιωάννης Ρούτσιας, Επίκουρος Καθηγητής, Ιατρική, ΕΚΠΑ
4.Βασίλης Γοργούλης, Καθηγητής, Ιατρική, ΕΚΠΑ
5.Παναγιώτης Βλαχογιαννόπουλος, Καθηγητής, Ιατρική, ΕΚΠΑ
6.Μιχάλης Κουτσιλιέρης, Καθηγητής, Ιατρική, ΕΚΠΑ
7.Ευσταθία Καψογεώργου, Επίκουρη Καθηγήτρια, Ιατρική, ΕΚΠΑ
Summary:
The results of the described research projects support that the oncolytic virus VSV.IFN-β manifests remarkable anticancer effects against mesothelioma cancer cells and this is mediated not only through direct lysis of cancer cells, but also through the induction of CD8+ T-cell mediated anticancer immunity. Furthermore, immunocompetent mice that were cured and remained cancer free for more than 6 months after treatment of heterotopic subcutaneous mouse mesothelioma flank tumors with VSV.mIFN-β did not develop new flank tumors after reexposure to subcutaneous injections with the same mouse mesothelioma cells, indicating the development of anticancer “immune memory”. These results support the translation of VSV.IFN-β in clinical trials as a novel therapeutic approach for patients with malignant pleural mesothelioma.
However, the efficacy of VSV.IFN-β depends on the functionality of the type I IFN pathways, an observation which was expected if one considers the exquisite sensitivity of VSV to the antiviral functions of type I IFNs. Although a large percentage of cancer cells have evolutionarily favored the deactivation of type I IFN pathways due to their antiproliferative effects in cancer growth, the presence of some cancer cells with “active” type I IFN pathways pose an inherent mechanism of resistance to the oncolytic effects of VSV. With this in mind, it is necessary to develop personalized therapeutic strategies, i.e. immunohistochemistry for biomarkers indicative of “active” or “inactive” type I IFN pathways, in order to select patients who have higher chances of responding to the oncolytic effects of VSV.
One of the main reasons for the genetic engineering of VSV to express IFN-β is the improved safety of it in case of infection of normal cells by tes virus; in this case, the expression of IFN-β would be expected to enhance the antiviral response of normal cells to the virus, preventing the replication of the virus and thus cell death. Although VSV.mIFN-β did not induce significant side effects and was very well tolerated at the treatment doses administered to immunocompetent mice, neurotoxic complications were observed in the immunodeficient mice treated with VSV.hIFN-β and VSV.GFP. Other studies have also demonstrated neurotoxicity of wild-type VSV in mice. These observations have raised doubts about the safety of the administration of this virus in patients with malignant pleural mesothelioma who could become immunosuppressed in the context of their malignancy or their treatment with chemotherapy. Hence, for the therapeutic administration of this virus the use of modified, nontoxic, attenuated viral strains is necessary or one should consider the local rather than systemic administration of this virus.
Another very important obstacle in the clinical application of VSV, as well as of other oncolytic viruses, is the induction of neutralizing antibodies that inactivate the virus, especially after its systemic administration. Strategies that could be applied to reduce the immunogenicity of this virus include the modification of its immunogenic viral epitopes, the coating of the virus with polymers that “hide” these epitopes and prevent their recognition by the immune system, and systemic immunosuppression. However, the latter approach could increase the risk of side effects by rendering normal cells more succeptible to viral attack, while VSV’s anticancer effect could be significantly hampered, as this is not only mediated by oncolysis of cancer cells, but also through induction of adaptive anticacer immune response.
Furthermore, the intravenous administration of VSV is followed by its uptake by hepatocytes, limiting its access to the systemic circulation and thus to the tumor’s microenvironment. Thus, strategies to improve the access of systemically administered VSV to the tumor microenvironment are also important for the improvement of the efficacy of oncolytic virotherapy; one such approach is the induction of local tumor inflammation which is currently under investigation. Finally, the incorporation of oncolytic virotherapy with other clinically approved therapeutic strategies for malignant pleural mesothelioma, as well as other cancer types, is of major importance and merits further investigation, as the concurrent or successive application of such therapeutic approaches may have a synergistic effect with better results compared to the application of each therapeutic approach separately.
Despite these difficulties that generally concern most types of oncolytic viruses, oncolytic virotherapy is a groundbreaking, novel therapeutic strategy which is being actively investigated in clinical trials. There are at least 15 different types of oncolytic viruses (genetically modified adenoviruses, herpesviruses, retroviruses, vaccinia, Coxsackie and measles viruses) under clinical trials for various cancer types, such as glioblastoma multiforme, pancreatic, lung, colon, renal cell and head and neck cancer. For malignant pleural mesothelioma, a phase I clinical trial is currently investigating a viral strain of the oncolytic measles virus expressing the sodium iodide symporter (MV.NIS), while VSV.hIFN-β.NIS is currently being investigated in patients with multiple myeloma, acute lymphoblastic leukemia, T-cell lymphoma and endometrial cancer (NCT03017820).
Keywords:
Viral vectors, Cancer gene therapy, Oncolytic virotherapy, Malignant mesothelioma, Vesicular stomatitis virus
