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

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 HSP-mediated 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 x 10(7) to 3.0 x 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 x 10(12) VP and transient grade IV thrombocytopenia at the dose of 3.0 x 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.