Feasibility of Adenovirus-Mediated hNIS Gene Transfer and 131I Radioiodine Therapy as a Definitive Treatment for Localized Prostate Cancer

Abstract

We have developed a replication-competent adenovirus (Ad5-yCD/mutTK(SR39)rep-hNIS) armed with two suicide genes and the human sodium iodide symporter (hNIS) gene. In this context, hNIS can be used as a reporter gene in conjunction with nuclear imaging and as a potentially therapeutic gene when combined with (131)I radioiodine therapy. Here, we quantified the volume and magnitude of hNIS gene expression in the human prostate following injection of a high Ad5-yCD/mutTK(SR39)rep-hNIS dose using a standardized injection algorithm, and estimated the radiation dose that would be delivered to the prostate had men been administered (131)I with curative intent. Six men with clinically localized prostate cancer received an intraprostatic injection of Ad5-yCD/mutTK(SR39)rep-hNIS under transrectal ultrasound guidance. All men received 2 × 0.5 ml deposits (5 × 10(11) vp/deposit) in each of the four base and midgland sextants and 2 × 0.25 ml deposits (2.5 × 10(11) vp/deposit) in each of the two apex sextants for a total of 12 deposits (5 × 10(12) vp) in 5 ml. On multiple days after the adenovirus injection, men were administered sodium pertechnetate (Na(99m)TcO(4)) and hNIS gene expression in the prostate was quantified by single photon emission computed tomography (SPECT). hNIS gene expression was detected in the prostate of six of six (100%) men. On average, 45% (range 18-83%) of the prostate volume was covered with gene expression. Had men been administered 200 mCi (131)I, we estimate that the mean absorbed dose to the prostate would be 7.2 ± 4.8 Gy (range 2.1-13.3 Gy), well below that needed to sterilize the prostate. We discuss the obstacles that must be overcome before adenovirus-mediated hNIS gene transfer and (131)I radioiodine therapy can be used as a definitive treatment for localized prostate cancer.

Viral dose, radioiodide uptake, and delayed efflux in adenovirus-mediated NIS radiovirotherapy correlates with treatment efficacy

“…The data presented here corroborate this issue. But our findings also address a recent report from a clinical trials of a NIS expressing adenovirus that produced poor results with respect to uptake of radioiodine 26 . Barton et al observed that the mean absorbed dose from administration of their vector into recurrent prostate cancers was well below the dose needed for a favorable therapeutic outcome.…”

HSV-NIS, an oncolytic herpes simplex virus type 1 encoding human sodium iodide symporter for preclinical prostate cancer radiovirotherapy

“…3, 45, 46 Previously, an oncolytic adenovirus-expressing NIS was shown by 99m TcO 4 -based SPECT/CT imaging to concentrate iodide in the virus-injected tumors of patients with prostate cancer. 4 Although the adenovirus used in this published clinical trial did not mediate tumor regressions, 47 the study did serve to establish the feasibility of exploiting NIS as a reporter gene for human oncolytic applications. We are hopeful that HSV will be able to replicate and spread faster than an oncolytic adenovirus in human prostate cancer.…”

Radioiodine therapy for castration-resistant prostate cancer following prostate-specific membrane antigen promoter-mediated transfer of the human sodium iodide symporter

“…hNIS has been demonstrated to be a potentially therapeutic gene for human PC 23. Six men had clinically localised PCa and received an intraprostatic injection of Ad5-yCD/mutTK (SR39) rep -hNIS under transrectal ultrasound guidance.…”