Cancer imaging and therapy utilizing a novel NIS-expressing adenovirus: The role of adenovirus death protein deletion

Abstract

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.

Emulating interactions between microorganisms and tumor microenvironment to develop cancer theranostics

“…Compared to large viruses, they are safer carriers for both in vitro and in vivo cell transfection 132 . Besides, many monitoring systems, including bioluminescence imaging, fluorescence imaging, and nuclear medicine-based imaging, are widely applied both experimentally and clinically, which is based on the backbones of oncolytic viruses (Adenovirus 133 - 135 , HSV-1 136 , measles virus 137 , Newcastle disease virus 53 , parvovirus 138 , vaccinia virus 139 and VSV 140 - 142 ) or the genes armed on them 51 . For instance, engineered oncolytic measles virus (MV-GFP-HSNS-scEGFRvIII and MV-GFP-HAA-scEGFRvIII) can not only induce GFP expression for imaging the EGFRvIII-expressing glioma lines and xenografts but also present an antitumor activity 49 .…”

“…For instance, engineered oncolytic measles virus (MV-GFP-HSNS-scEGFRvIII and MV-GFP-HAA-scEGFRvIII) can not only induce GFP expression for imaging the EGFRvIII-expressing glioma lines and xenografts but also present an antitumor activity 49 . Oncolytic adenoviruses not only can be armed with luciferase cDNA 133 , green fluorescent protein (GFP) 134 , and sodium/iodide symporter (NIS) (Figure 7 ) 135 for tumor imaging but also serve as vectors for the treatment of head-and-neck cancer 52 . In addition, engineered adenovirus evades innate immunity in vivo , decreases tumor growth, and prolongs survival of lung cancer-bearing mice (Figure 8 ) 143 .…”

“… Oncolytic NIS-expressing adenovirus enhances cancer imaging in pancreatic cancer models. Adapted with permission from 135 , Copyright 2021, Elsevier, CC BY-NC-ND 4.0. …”

Adenovirus Type 6: Subtle Structural Distinctions from Adenovirus Type 5 Result in Essential Differences in Properties and Perspectives for Gene Therapy

“…Thus, incorporation of an RGD-4C motif into the HI loop of the Ad fiber knob allows the virus to bind to αvβ-class integrins, while replacement of the fiber knob of Ad type 5 with that of type 3 retargets these chimeric viruses (Ad5/3) to the Ad3 receptor desmoglein-2, which is highly expressed in cancer cells [35,[40][41][42][43][44]. RGD and Ad5/3 modifications of the fiber remarkably increase the oncolytic efficacy of Ad-vectors in many tumor types, including brain, ovarian, pancreatic, colon cancers, not only in vitro and in vivo but also in clinical application [10,35,36,[38][39][40][41]43,[45][46][47]. The above approaches for fiber modifications for Ad vector retargeting to a receptor other than CAR can be beneficial for Ad6-based oncolytics as well.…”

“…Third, Ads can be efficiently produced at high titer, and its manufacturing is well-established [6,8]. Fourth, Ads have a comparatively large packaging capacity, allowing insertion of a variety of therapeutic and imaging transgenes [9,10]. Furthermore, the Ad genome and its replication machinery have been highly characterized, which allows fine-tuning of purpose-built Ad vectors.…”