Abstract 5925: A novel oncolytic adenovirus for radioiodine therapy and imaging

• Published in: Cancer research (Chicago, Ill.) Ill.), 2018-07, Vol.78 (13_Supplement), p.5925-5925
• Main Authors: Koodie, Lisa, Kawakami, Eriko Iguchi, Jacobsen, Kari, Cayci, Zuzan, Taylor, Andrew, Greeno, Edward W., Schumacher, Robert J., Morris, John C., Fernandez-Zapico, Martin E., Davydova, Julia
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2018-5925

Recently, the use of oncolytic viruses encoding the sodium-iodide symporter (NIS) has become an attractive approach to achieve radionuclide imaging of cancer. However, the potential of virus-induced NIS expression to facilitate therapy with radioactive 131I has not been fully explored. We designed a tumor-selective, infectivity-improved oncolytic adenovirus (Ad5/3-Cox2-NIS-ADP) modified to express high quantities of NIS. This virus induced radioisotope uptake in prostate and lung cancer cells and facilitated SPECT/CT imaging, but more importantly, supported the effective therapy with 131I. In our original vector, enhanced oncolysis was mediated by overexpression of adenoviral death protein (ADP). Although this structure was operative in detection and therapeutic regimens, we were concerned that the cytolytic effect of ADP may affect NIS membrane localization, and diminish its effectiveness as a theranostic tool. We therefore designed an identical Ad5/3-Cox2-NIS-ADP-deleted virus {ADP(-)} and assessed the impact of ADP on NIS expression and radioisotope uptake. Western blot and immunocytochemical analyses of pancreatic cancer cells infected with ADP(-) demonstrated higher NIS levels when compared to the ADP(+) counterpart. This correlated with an improved 125I uptake in vitro. SPECT/CT imaging studies assessing 99mTcO4- accumulation in mice to visualize pancreatic adenocarcinoma (PDAC) using patient-derived xenografts (PDX) showed that a single dose of ADP(-) accumulated far greater levels of 99mTcO4- when compared to ADP(+). Remarkably, ADP(-) produced stronger signal that was maintained up until day 32, and this outlasted ADP(+) and the control vector, replication-deficient AdCMV-NIS, currently employed in a clinical trial. Notably, within the PDAC, ADP(-) showed a distinct NIS cell membrane distribution pattern as it co-localized with cell membrane bound-cytokeratin-4. Unlike ADP(-), ADP(+) produced a punctate NIS staining pattern, with little to no cell membrane localization. These results support our hypothesis that ADP-cytolytic effect reduces NIS membrane localization, subsequently affecting radionuclide uptake. To evaluate the therapeutic potential of NIS-based radiotherapy, we treated mice bearing PDAC tumors with virotherapy alone or in combination with 131I. NIS-expressing OAds in combination with 131I significantly reduced tumor growth when compared to viro- or radiotherapy alone. The therapeutic effect in mice treated with ADP(-) combined with