Development of novel oncolytic Paroviruses with ability to silence the TRAF3IP2 Gene as novel therapeutics against Glioblastoma

H-1PV (PV) is not pathogenic for humans and possesses oncolytic and onco-suppressive properties in a number of in vitro and in vivo models. Phase I/IIa clinical trial in patients with glioblastoma showed that virus treatment is safe, well tolerated and associated with first evidence of efficacy. However, the wild type virus at the regimes used was unable to eradicate the tumour indicating that further development is necessary to improve clinical outcome. In a proof of concept study, we demonstrated that it is possible to enhance the anticancer potential of H-1PV by inserting a shRNA expression cassette into the H-1PV genome allowing the virus to transduce shRNAs and thereby efficiently knockdown the expression of oncogenes or other genes involved in carcinogenesis. In this study we plan to use this innovative platform for the silencing of the TRAF3IP2 gene (encoding the Act-1 protein), a central upstream regulator of more than 1400 genes, including the NF-kB pathway, whose activity is dysregulated in glioblastoma. Silencing of TRAF3IP2 by means of a lentivirus vector, has been recently shown to arrest tumor growth in a xenograft (U87) rat model of human glioma. The natural oncotropism of H-1PV should restrict the expression of the shRNAs targeting TRAF3IP2 specifically in cancer cells. The shRNAs on the other hand should empower H-1PV in killing cancer cells more efficiently (also those eventually less susceptible or resistant to virus oncolysis) and support the virus in reshaping the tumour microenvironment through the silencing of TRAF3IP2 and induce more robust anticancer immune responses.
Our final goal is to produce preclinical proof of concept of the superior anticancer activity of the novel H-1PV expressing shRNA against TRAF3IP2 as a prerequisite to move this novel therapy into first clinical application for treatment of patients with glioblastoma.