A phase I study of OncoVEXGM-CSF, a second-generation oncolytic herpes simplex virus expressing granulocyte macrophage colony-stimulating factor

被引:429
作者
Hu, Jennifer C. C.
Coffin, Robert S.
Davis, Ceri J.
Graham, Nicola J.
Groves, Natasha
Guest, Peter J.
Harrington, Kevin J.
James, Nicholas D.
Love, Colin A.
McNeish, Iain
Medley, Louise C.
Michael, Agnieszka
Nutting, Christopher M.
Pandha, Hardev S.
Shorrock, Claire A.
Simpson, Julie
Steiner, Jan
Steven, Neil M.
Wright, Dennis
Coombes, R. Charles
机构
[1] Imperial Coll Sch Med, Dept Canc Med, London, England
[2] Royal Marsden Hosp, London SW3 6JJ, England
[3] Univ London St Georges Hosp, Sch Med, Dept Oncol, London SW17 0RE, England
[4] UCL, London, England
[5] Biovex Inc, Cambridge, MA USA
[6] Univ Birmingham, Inst Canc Studies, Birmingham, W Midlands, England
[7] Oxford Therapeut Consulting, Magdalen Ctr, Oxford, England
关键词
D O I
10.1158/1078-0432.CCR-06-0759
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Purpose: To conduct a phase I clinical trial with a second-generation oncolytic herpes simplex virus (HSV) expressing granulocyte macrophage colony-stimulating factor (OncoVEX(GM-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 10(6), 10(7) and 10(8) 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 10(7) pfu/mL. The multidosing phase thus tested seroconverting HSV-seronegative patients with 10(6) pfu/mL followed by multiple higher doses (up to 10(8) 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: OncoVEX(GM-CSF) is well tolerated and can be safely administered using the multidosing protocol described. Evidence of an antitumor effect was seen.
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页码:6737 / 6747
页数:11
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