title: 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 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.
authors.affiliation: Department of Medical Oncology, Chinese Academy of Medical Sciences, Cancer Hospital, Peking, PR China.
authors.forename: J-L
authors.initials: JL
authors.lastname: Li
authors.forename: H-L
authors.initials: HL
authors.lastname: Liu
authors.forename: X-R
authors.initials: XR
authors.lastname: Zhang
authors.forename: J-P
authors.initials: JP
authors.lastname: Xu
authors.forename: W-K
authors.initials: WK
authors.lastname: Hu
authors.forename: M
authors.initials: M
authors.lastname: Liang
authors.forename: S-Y
authors.initials: SY
authors.lastname: Chen
authors.forename: F
authors.initials: F
authors.lastname: Hu
authors.forename: D-T
authors.initials: DT
authors.lastname: Chu
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000328:Adult; D000368:Aged; D000912:Antibodies, Neoplasm / Q000096:biosynthesis; D005260:Female; D018840:HSP70 Heat-Shock Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D006801:Humans; D015552:Injections, Intralesional; D007958:Leukocyte Count; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D050130:Oncolytic Virotherapy / Q000009:adverse effects / Q000379:methods*; D050504:Oncolytic Viruses / Q000235:genetics; D016896:Treatment Outcome
chemical_list: D000912:Antibodies, Neoplasm; D018840:HSP70 Heat-Shock Proteins