320. Adenovirus Expansion of Radioiodine Therapy to Non-Thyroid Cancer Treatment and Diagnostics

Abstract

Radioiodine therapy has successfully treated and diagnosed cancers over the last 50 years. The clinical scope of radioiodine is limited in thyroid cancers because of restricted iodine uptake. Our lab proposes to expand the clinical use of radioiodine into non-thyroid cancer theranostics by targeting cancers (e.g. pancreatic and prostate) with oncolytic adenovirus to over express the human sodium iodine symporter (NIS). The adenovirus expression of the symporter allows iodine to concentrate into the targeted cancer cells providing diagnostic imaging with I123 and therapy with I131.We designed infectivity-enhanced oncolytic Adenoviruses (NIS-OAd), Ad5/3_TSP_E3_ADP_NIS, to express NIS and adenovirus death protein (ADP) from the E3 region. The Ad5/3 fiber modification enables the infection of CAR negative cells. Vector replication is controlled through a tumor specific promoter (TSP, e.g. COX2 in pancreatic and Pb in prostate cancer). We have shown the specificity of our viruses with TSPs in vitro with multiple pancreatic and prostate cancer cell lines. The expression of ADP resulted in an increase in oncolytic activity and transgene expression. The functionality of NIS-OAds was tested with in vitro radioiodine uptake assay and showed up to a 10-fold increase in radioiodine uptake in prostate and pancreatic cancer cell lines. This endorses that oncolytic viruses increase functional NIS expression in tumors.Our animal model experiments included nude mice xenographs to evaluate therapeutic and imaging affects with i.v. injections of NIS-OAds in A549 lung and LnCap prostate cancer cells. In A549 models, the combination of NIS-OAds and I131 had an increase in therapeutic effect over virus alone signifying functional NIS expression in solid tumors. LnCap xenographs had SPECT/CT images taken after NIS-OAds and non-replicating virus administration with I123. NIS-OAds had the highest tumor specific signal confirming that NIS-OAds can be diagnostic in tumors.Viral functionality in human tissue was evaluated by PCR in ex vivo tissue slices showing that virus replication was specific to cancerous tissues and did not occur in normal tissue. This study supports the high-level replication control of NIS-OAds in non-thyroid cancer tissues. A related non-replicating NIS expressing Ad is also being evaluated in prostate cancer by Dr. Morris, our collaborator, in a stage I clinical trial. Together the virus specificity, imaging, and therapeutic data support the potential of NIS-OAds as cancer theranostics.In sum, this data provides key functionality and safety support of NIS expressing Ad use in humans. Current projects include therapeutic and imaging animal studies with radioiodine in pancreatic cancer immuno-competent Syrian hamsters, and human xenographs in nude mice. Further studies will evaluate the distribution of NIS expression in vivo and cytotoxicity of virus with radiation. Ultimately the goal of our research is to form a multimodal therapy with radiation and oncolytic virus for diagnosis and therapy of cancers.