A Phase I Clinical Trial of Ad5.SSTR/TK.RGD, a Novel Infectivity-Enhanced Bicistronic Adenovirus, in Patients with Recurrent Gynecologic Cancer

Abstract

Purpose Ad5.SSTR/TK.RGD is an infectivity-enhanced adenovirus expressing a therapeutic thymidine kinase suicide gene and a somatostatin receptor that allows for noninvasive gene transfer imaging. The purpose of this study was to identify the MTD, toxicities, clinical efficacy and biologic effects of Ad5.SSTR/TK.RGD in patients with recurrent gynecologic cancer. Experimental Design Eligible patients were treated intraperitoneally (IP) for 3 days with 1×109 to 1×1012 vp/dose of Ad5.SSTR/TK.RGD followed by intravenous ganciclovir for 14 days. Toxicity and clinical efficacy were assessed utilizing CTC Adverse Events grading and RECIST criteria. Imaging utilizing In-111 pentetreotide was obtained before and after treatment. Tissue samples were obtained to evaluate for gene transfer, generation of wild-type virus, viral shedding and antibody response. Results Twelve patients were treated in three cohorts. The most common vector-related clinical toxicities were grade 1–2 constitutional or pain symptoms, experienced most often in patients treated at the highest dose. MTD was not identified. Five patients demonstrated stable disease; all others experienced progressive disease. One patient with stable disease experienced complete resolution of disease and normalization of CA125 on further follow-up. Imaging detected increased In-111 pentetreotide retention in patients treated at the highest dose. Ancillary studies demonstrated presence of Ad5.SSTR/TK.RGD virus and HSV1-tk expression in ascites samples collected at various time points in most patients treated within the higher dose cohorts. Conclusions This study demonstrates the safety, potential efficacy, and possible gene transfer imaging capacity of Ad5.SSTR/TK.RGD in patients with recurrent gynecologic cancer. Further development of this novel gene therapeutic appears to be warranted.

Pulsed Versus Continuous Application of the Prodrug 5-Fluorocytosine to Enhance the Oncolytic Effectiveness of a Measles Vaccine Virus Armed with a Suicide Gene

“…In a phase 1 trial on hepatocellular carcinoma (NCT00844623) five consecutive cohorts of two patients received increasing doses of an HSV-TK suicide gene-encoding adenoviral vector by intratumoral injection; subsequently, equal doses of either intravenous ganciclovir (GCV) or oral vGCV were applied; no specific information on dosages or duration of prodrug therapies were provided. In a further phase 1 study on ovarian cancer (NCT00964756) patients were treated intraperitoneally for 3 days with an HSV-TK suicide geneencoding adenoviral vector followed by intravenous application of GCV (5 mg/kg twice daily; at a constant rate for more than 1 hour) for 14 days (Kim et al, 2012). In another phase 1 study in patients with head and neck cancer and other malignant tumors, single intratumoral injections of an adenoviral vector encoding HSV-TK were performed on day 1 followed by systemic (intravenous) administration of GCV (50 mg/kg twice daily) from days 2 to 15 (Xu et al, 2009).…”

Progress and problems with the use of suicide genes for targeted cancer therapy

“…The pros and cons of these molecules is beyond the scope of this review and the reader is invited to refer to the most updated review paper by Verheije and Rottier [80]. In a recent phase I clinical study by Kim et al (2012), the application of this technique has been demonstrated by using a tropism modified adenovirus carrying RGD sequence in the fiber knob[81]. As a result, the transfection of adenovirus depended on integrin receptors rather than CAR.…”

Combination of vaccine-strain measles and mumps virus synergistically kills a wide range of human hematological cancer cells: Special focus on acute myeloid leukemia

“…Currently, numerous OLVs, including adenovirus [1][2][3], reovirus [4], measles virus [5], Newcastle disease virus [6], Seneca Valley virus [7], retrovirus [8], vaccinia virus [9], herpes simplex virus [10] and Coxsackie virus A21 [10] are in or have completed clinical trials for a variety of solid malignancies with encouraging results.…”