A phase I study of OncoVEXGM-CSF, a second-generation oncolytic herpes simplex virus expressing granulocyte macrophage colony-stimulating factor
Autor: | Ceri J. Davis, Nicholas D. James, Nicola J. Graham, Iain A. McNeish, Colin Love, Natasha Groves, Hardev Pandha, Agnieszka Michael, Jan Steiner, Neil Steven, R. Charles Coombes, Kevin J. Harrington, Peter J. Guest, Christopher M. Nutting, Robert S. Coffin, Julie Simpson, Dennis Wright, Jennifer C.C. Hu, Claire A. Shorrock, Louise C. Medley |
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Rok vydání: | 2006 |
Předmět: |
Adult
Male Cancer Research Skin Neoplasms viruses Biopsy Breast Neoplasms medicine.disease_cause Virus Herpesviridae Neoplasms Medicine Humans Simplexvirus Melanoma Aged Aged 80 and over Oncolytic Virotherapy business.industry Carcinoma Granulocyte-Macrophage Colony-Stimulating Factor Middle Aged medicine.disease Recombinant Proteins Oncolytic virus Oncolytic Viruses Herpes simplex virus Granulocyte macrophage colony-stimulating factor Treatment Outcome Oncology Head and Neck Neoplasms Antibodies Antinuclear Immunology Cytokines Tumor necrosis factor alpha Female business Talimogene laherparepvec Colorectal Neoplasms medicine.drug |
Zdroj: | Clinical cancer research : an official journal of the American Association for Cancer Research. 12(22) |
ISSN: | 1078-0432 |
Popis: | Purpose: To conduct a phase I clinical trial with a second-generation oncolytic herpes simplex virus (HSV) expressing granulocyte macrophage colony-stimulating factor (Onco VEXGM-CSF) to determine the safety profile of the virus, look for evidence of biological activity, and identify a dosing schedule for later studies. Experimental Design: The virus was administered by intratumoral injection in patients with cutaneous or s.c. deposits of breast, head and neck and gastrointestinal cancers, and malignant melanoma who had failed prior therapy. Thirteen patients were in a single-dose group, where doses of 106, 107, and 108 plaque-forming units (pfu)/mL were tested, and 17 patients were in a multidose group testing a number of dose regimens. Results: The virus was generally well tolerated with local inflammation, erythema, and febrile responses being the main side effects. The local reaction to injection was dose limiting in HSV-seronegative patients at 107 pfu/mL. The multidosing phase thus tested seroconverting HSV-seronegative patients with 106 pfu/mL followed by multiple higher doses (up to 108 pfu/mL), which was well tolerated by all patients. Biological activity (virus replication, local reactions, granulocyte macrophage colony-stimulating factor expression, and HSV antigen-associated tumor necrosis), was observed. The duration of local reactions and virus replication suggested that dosing every 2 to 3 weeks was appropriate. Nineteen of 26 patient posttreatment biopsies contained residual tumor of which 14 showed tumor necrosis, which in some cases was extensive, or apoptosis. In all cases, areas of necrosis also strongly stained for HSV. The overall responses to treatment were that three patients had stable disease, six patients had tumors flattened (injected and/or uninjected lesions), and four patients showed inflammation of uninjected as well as the injected tumor, which, in nearly all cases, became inflamed. Conclusions: Onco VEXGM-CSF is well tolerated and can be safely administered using the multidosing protocol described. Evidence of an antitumor effect was seen. |
Databáze: | OpenAIRE |
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