A phase I trial of intratumoral administration of recombinant oncolytic adenovirus overexpressing HSP70 in advanced solid tumor patients

Abstract

Our pre-clinical studies demonstrated that intratumoral vaccination with a recombinant oncolytic type 2 adenovirus overexpressing the heat shock protein (HSP)70 protein, designated as H103, can inhibit primary and metastatic tumors through enhanced oncolytic activity and HSPmediated immune responses against shared and mutated tumor antigens. In the pre-clinical studies of local H103 administration, no significant toxicity was observed in the animal trials with mice, cavy or rhesus monkeys. A phase I clinical trial of intratumoral injection of H103 was conducted in the patients with advanced solid tumors. A total of 27 patients were injected intratumorally with H103 in a dose-escalation study from a dose of 2.5 Â 10 7 to 3.0 Â 10 12 viral particles (VPs). The maximum tolerated dose of H103 was not defined. Two patients developed dose-limiting toxicities of grade III fever at the dose of 1.5 Â 10 12 VP and transient grade IV thrombocytopenia at the dose of 3.0 Â 10 12 VP. The common adverse events were mainly mild to moderate (grade I/II) in nature, including fever, mild injection-site reaction, leucopenia, lymphopenia, thrombocytopenia and hypochromia. The objective response (complete response+partial response) to H103-injected tumors was 11.1% (3/27), and the clinical benefit rate (complete response+partial response+minor response+stable disease) was 48.1%. Interestingly, transient and partial regression of distant, uninjected tumors was observed in three patients. The numbers of immune cells (CD4 + and CD8 + T cells, and natural killer cells) were elevated after H103 administration, but without statistical significance. This phase I trial demonstrates that intratumoral administration of H103 can be safely applied to cancer patients and shows promising clinical antitumor activity, warranting a further clinical investigation.

Enhanced Safety Profiles of the Telomerase-Specific Replication-Competent Adenovirus by Incorporation of Normal Cell-Specific microRNA-Targeted Sequences

“…Several clinical trials using oncolytic Ads have been carried out, and promising results have been reported (3)(4)(5). Various types of oncolytic Ads have been developed, and can be mainly classified into 2 groups.…”

Clinical development directions in oncolytic viral therapy

“…55 Two follow-up products have been introduced, H102, currently in pre-clinical testing, and H103, an oncolytic type 2 adenovirus overexpressing the heat shock protein HSP 70 , recently tested as a intratumoral vaccination in a completed phase I clinical trial in patients with advanced solid tumors. 56 Transient and partial regression of distant, un-injected tumors was observed in three patients during this study, and because of promising clinical antitumor activity and positive safety outcome further studies are being pursued.…”

Official Medications for Anti-Tumor Gene Therapy

“…III фаза клинических испытаний препарата Oncorine™ была проведена в сочетании с химиотерапией препара-тами цисплатин и 5-фторурацил [56]. Больные получали интратуморальные инъекции препарата Oncorine™ еже-дневно в течение 5 дней, цикл введения повторяли каж-дые 3 недели.…”