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  • br outlier situations Nevertheless there were

    2019-10-21


    outlier situations. Nevertheless, there were observed mice in all HT29 treatment groups with tumor regression. HCT116-derived xenografts demonstrated more uniform tumor formation and more uniform tumor regression following viral infection (Figure 5). Immunohisto-chemical examination of tumors demonstrates abrogation of tumor cell division in virus-treated groups with substantial inflammatory infiltrate around tumor N-octanoyl-L-Homoserine lactone that is not present in untreated xeno-grafts (Figure 5). Finally, upon immunohistochemical analysis at 10 days following viral injection, only tumor sections demonstrated positive staining for virus (Figure S2).
    CF33-hNIS Infection Is Synergistic with I-131 Radioisotope and Induces Sustained Tumor Growth Abrogation in HCT116 Xenografts
    To explore whether expression of hNIS by infected tumor cells could lead to synergistic tumor destruction using CF33-hNIS in combina-tion with I-131, mice bearing bilateral flank xenografts established with HCT116 or HT29 colorectal cancer cells were treated with uni-lateral intra-tumoral injections with: (1) PBS alone, (2) I-131 alone, (3) CF33-hNIS alone, or (4) CF33-hNIS + I-131. It should be noted 
    that in order to adequately evaluate synergy, a lower dose of virus (1 104 PFU) was used than was employed in tumor regression experiments (1 105 PFU). Mice treated with PBS or I-131 alone showed unrestrained tumor growth and had to be euthanized by day 30 upon reaching predetermined tumor size limits (Figures 6A and 6B). Single treatment with intravenous (i.v.) I-131 did promote some reduction in tumor growth compared with control in HCT116-derived tumors (Figure 6A), but not in HT29-derived tumors (Figure 6B). Although intratumoral CF33-hNIS treatment alone showed expected tumor growth abrogation (Figure 5), the combination of i.v. I-131 plus intratumoral CF33-hNIS demonstrated superior tumor growth abrogation and regression in HCT116 xeno-grafts (Figure 6A). Importantly, this observed tumor regression was sustained over time during the study period (Figure 6A). Immunohis-tochemical examination of tumors demonstrates an absence of tumor cells in combination-treated tumors along with a sizable inflamma-tory infiltrate (Figure 6B). In the HT29 xenografts group, statistical significance was not achieved between virus alone and virus plus I-131 groups prior to euthanasia, which was required secondary to growth of non-injected tumors on contralateral flanks.
    Molecular Therapy: Oncolytics
    DISCUSSION
    This study reports that our novel chimeric orthopoxvirus CF33-hNIS is able to infect, replicate in, and kill colon cancer cells, and induce sustained regression of tumor in vivo. Herein, we further confirm our hypothesis that the addition of hNIS to the viral genome results in infected cancer cell expression of functional hNIS that in turn al-lows for uptake of radioisotope. This enables real-time imaging of vir-ally infected cells via PET imaging of I-124 uptake along with synergy with therapeutic radioiodine (I-131), which facilitates ablation of sur-rounding cells. The in vivo findings of tumor regression occur at doses 1–4 logs lower than those used by other groups with vaccinia-based vectors in similar experiments.18,19 Moreover, this work demonstrates that the synergistic addition of radioiodine ablation to oncolytic viral infection sustains oncolytic virus-induced tumor regression. Thus, an oncolytic virus (OV) carrying hNIS permits local radiotherapy by eliciting a high concentration of radioisotope, which may be used clinically to decrease undesired side effects and enhance viral efficacy at lower, less toxic, less expensive doses. As a well-known theranostic tool, it also holds promise for direct noninvasive scintigraphy and PET imaging to allow both evaluation of viral biodistribution and dosimetric calculations as a prerequisite for planning therapy studies with higher doses of radioisotopes like Re-188 and I-131.20–24