PV-701(Wellstat Biologics Corp.)

We are very pleased and proud to be able to publish this special issue of Current Cancer Drug Targets devoted to oncolytic virus therapy covering basic and clinical research on adenovirus, vaccinia virus, herpes virus, and Newcastle disease virus. In these papers, we welcome the world's top authorities in the field who have generously contributed their latest review articles for exclusive publication in this special issue. Moreover, this issue also includes a range of opinion from government drug organizations. Here we simply wish to bring together the newest knowledge and experience in the field of cutting-edge oncolytic virus therapy for researchers and every kind of cancer therapist. The Foreword presents a historical perspective on the development of oncolytic virus together with the encouraging results of recent clinical trials (e.g., H101 has been tested in clinical trial of nearly 250 patients and approved for human use by the Chinese FDA, while PV701 has been tried in over 110 patients, as described in our special issue).

Purpose: Previous phase 1 trials of i.v.-administered PV701 have shown this virus to be well-tolerated with toxicity primarily associated with the first dose. Our hypothesis, based on preclinical evidence, was that patient tolerability could be improved by slowing the i.v. infusion rate, and that this approach would allow for the safe administration of higher doses. Additionally, this phase 1 trial was the first to measure PV701 clearance.Experimental Design: For the first dose, a 3-h infusion was used compared with the 10- and 30-min infusions administered in the two previous trials. Subsequent doses were infused over 1 h. Six doses were given per 3-week cycle. Escalation of the first dose was done separately from the escalation of doses 2 to 6. Viral clearance was determined using whole blood reverse transcription-PCR.Results: Eighteen patients with advanced chemorefractory cancer were enrolled. The first dose was safely escalated to 24 × 109 plaque-forming units/m2 and doses 2 to 6 were safely escalated to 120 × 109 plaque-forming units/m2. Tolerability was improved compared with the rapid bolus dosing used previously with the elimination of severe flu-like symptoms. Furthermore, infusion reactions were markedly decreased in this trial compared with previous PV701 trials. The presence of neutralizing antibodies did not significantly affect PV701 clearance. Four major and two minor tumor responses were observed.Conclusions: Using slow infusion, patient tolerability was improved, while the first dose was safely escalated relative to two previous PV701 trials. Based on improved tolerability and encouraging signs of activity, this slow infusion regimen was selected for further PV701 clinical development.