431. Efficient Systemic Treatment with Fiber-Redesigned Oncolytic Adenovirus in Pancreatic Cancer In Vivo Model
Authors: Mizuho Sato, Yoshiaki Miura, Julia Davydova, Masato Yamamoto
Journal: Molecular Therapy (2015)

Oncolytic virus has high potential for systemic cancer therapy because it does not require high initial intratumoral concentration for antitumor effect, and adenovirus (Ad) has been one of frequently-used platforms for oncolytic virus. However, its efficacy upon systemic application has been quite limited to date. Unlike loco-regional therapy, systemic application of cancer gene therapy mandates different level of selectivity of delivery, and lack of tumor selectivity at the stage of infection has hampered the in vivo efficacy of systemic therapy. The improvement of vector distribution and cancer selective transduction would overcome the obstacles for systemic delivery and enable efficient systemic treatment of cancer with oncolytic Ad. AdML-VTIN was identified as a mesothelin (MSLN) targeted Ad by high-throughput screening of Ad-fiber library. This AB-loop-redesigned Ad yielded a potent and selective infectivity to MSLN-positive pancreatic cancer (Panc-1) in vitro. Moreover, intra-tumor (i.t.) injection of AdML-VTIN (1010 vp/tumor) showed selective and powerful anti-tumor effect against Panc-1 tumors. In order to assess the potential of AdML-VTIN for systemic application, we compared organ distribution after intravenous (i.v.) injection to the nude mice with Panc-1 tumors between AdML-VTIN and AdML-5WT (wild type Ad5 fiber). The liver sequestration of AdML-VTIN was lowered more than one order of magnitude compared to AdML-5WT at both 1 hr and 48 hrs after injection. At day 7, the viral copy number of AdML-VTIN in the tumor was more than 3 orders of magnitude higher that those with AdML-5WT. Next, systemic therapeutic effect against Panc-1 tumors was compared with between AdML-VTIN and AdML-5WT with the low-dose single i.v. injection (109 vp/mouse). Tumor significantly shrunk only in AdML-VTIN treated group while AdML-5WT didn't show any growth suppression. Four out of ten tumors were eliminated at 15 days after the injection. Six out of ten AdML-VTIN treated tumors showed the regrowth, and these tumors were treated with multiple i.v. injections (day 47, 61, 68, and 75) of AdML-VTIN. Even though the multiple i.v. treatment was started after tumor volume reached 500 mm3, all mice survived until the end of experiment and four out of six regrown tumors showed remission. When therapeutic effect of AdML-VTIN was assessed with i.v. (systemic) and i.t. (local) injections, the tumor volume significant decreased in both groups. The anti-tumor effect of systemic i.v. injection group was similar to that of i.t. injection group at day 24 although the viral particle in the tumor with i.v. injection was about half of that with i.t. injection at day 1. In this study, systemic i.v. injection of the fiber-redesigned oncolytic Ad showed significantly lower liver sequestration and better tumor accumulation. More importantly, both systemic and intratumoral injections resulted in remarkable anti-tumor effect at low dose. An impressive anti-tumor effect of systemic administration indicated that targeted-oncolytic Ad may embody efficient treatment for cancers which are mostly found with spread or metastatic lesions.