Encoding the sodium iodide symporter (NIS) by an adenovirus (Ad) is a promising strategy to facilitate non-invasive imaging and radiotherapy of pancreatic cancer. However, insufficient levels of NIS expression in tumor cells have limited its clinical translation. To optimize Ad-based radiotherapy and imaging, we investigated the effect of Ad death protein (ADP) deletion on NIS expression. We cloned two sets of oncolytic NIS-expressing Ads that differed only in the presence or absence of ADP. We found that ADP expression negatively affected NIS membrane localization and inhibited radiotracer uptake. ADP deletion significantly improved NIS-based imaging in pancreatic cancer models including patient-derived xenografts, where effective imaging was possible for up to 6 weeks after a single virus injection. This study demonstrates that improved oncolysis may hinder the therapeutic effect of oncolytic viruses designed to express NIS. In vivo studies in combination with 131 I showed potential for effective radiotherapy. This also highlights the need for further investigation into optimal timing of 131 I administration and suggests that repeated doses of 131 I should be considered to improve efficacy in clinical trials. We conclude that ADP deletion is essential for effective NIS-based theranostics in cancer.

Background: Gastrointestinal (GI) malignancies represent a heterogeneous group of diseases. Traditional tumor markers, though part of standard-of-care, lack sensitivity and specificity. Tumor-informed circulating tumor DNA (ctDNA) assay-based molecular residual disease assessment as well as recurrence and treatment response monitoring can serve as a robust tool in patients with wide range of GI malignancies and ethnicities.Methods: A personalized, tumor-informed multiplex PCR-NGS assay (Signatera TM ) was used for the detection and quantification of ctDNA in 258 plasma samples from 198 patients with GI cancers at two institutions. Serial time-points were collected on a subset of patients (n=64) to monitor their ctDNA levels in response to treatment. Chi-square test was used to compare ctDNA-positivity rates in different cohorts. Results:The study included stage I-IV patients with a median age of 62 years (61% females and 49% ethnic minorities); 92% had surgical resection, 83% received systemic treatment. ctDNA-positivity was significantly associated with advanced stage (P=0.004), and presence/extent of metastases (P<0.00003). Serial time-point analysis showed that 22% (14/64) patients cleared ctDNA following treatment. ctDNA was detected in all patients who recurred (4/4; 100% sensitivity).Conclusions: Serial monitoring of ctDNA using a tumor-informed ctDNA assay can be prognostic and predictive in advanced GI malignancies in adjuvant setting.

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