Personalized virotherapy in cancer

adenocarcinoma (PDAC) remains a highly lethal disease with a median survival time that does not exceed 6.5 months [1]. Since more than 80% of patients present with advanced metastatic disease, systemic chemotherapy remains the only treatment. The high resistance to conventional and targeted therapies in PDAC as in other desmoplastic tumors of adults is largely due to the dense extracellular matrix (ECM). The ECM distorts blood and lymphatic vessels structure that hampers the possibility of systemically delivered therapies to reach the tumor mass [2]. The use of engineered oncolytic viruses (OVs) is a promising new therapy for cancer treatment. Different OVs have been engineered to express immune stimulatory molecules indicating that OVs can act at two levels, by directly killing malignant cells in concurrence with the simultaneous activation of the host anti-tumor immunity. OVs can be also combined with chemotherapeutic agents providing an aggressive platform for cancer attack. One of these OVs, a Herpes Simplex virus named T-VEC armed with GM-CSF has just completed a phase III trial in advanced melanoma with promising results and might reach the clinic after FDA approval (Clinical Trials.gov Identifier NCT01740297). Conditionally Replicative Adenoviruses are oncolytic adenoviruses (OAV) engineered to selectively replicate within and kill tumor cells. Selectivity is obtained through the use of ''cancer cell''-specific promoters (CCSP) that are selected to replace viral promoters and drive the expression of genes essential for OAV replication. OAVs replicate essentially in malignant cells with positive expression of the gene from which the CCSP was selected. OAVs efficacy can be also improved through the exchange of the capsid fiber of the virus or addition of specific moieties that will retarget vectors to enter the cell through alternative receptors [3]. As for other therapeutic modalities, viral spread and therapeutic efficacy is hampered by the ECM barrier. With this in mind, we started engineering OAVs whose replication was driven by CCSPs active both in the stroma and in the malignant compartment of the tumor mass. The OAV AdF512 retargeted to bind to an alternative cell surface receptor and carrying DNA Editorial elements responsive to hypoxia and inflammation exhibited enhanced efficacy on melanoma xenografts made of human melanoma cells mixed with human fibroblasts [4]. AdF512v1 was also able to lyse fresh samples obtained from ovary cancer patients including samples refractory to chemotherapy [5]. More recently we have shown that the OAV AV25CDC combined with gemcitabine exhibited a large efficacy and complete …