Catalogo Articoli (Spogli Riviste)

OPAC HELP

Titolo:
Preclinical safety testing of DISC-hGMCSF to support phase I clinical trials in cancer patients
Autore:
Loudon, PT; Blakeley, DM; Boursnell, MEG; Day, DA; Duncan, IA; Lowden, RC; McLean, CS; Martin, G; Miller, JC; Shaw, ML;
Indirizzi:
Xenova Grp PLC, Cambridge CB4 0WG, England Xenova Grp PLC Cambridge England CB4 0WG PLC, Cambridge CB4 0WG, England
Titolo Testata:
JOURNAL OF GENE MEDICINE
fascicolo: 5, volume: 3, anno: 2001,
pagine: 458 - 467
SICI:
1099-498X(200109/10)3:5<458:PSTODT>2.0.ZU;2-H
Fonte:
ISI
Lingua:
ENG
Soggetto:
HERPES-SIMPLEX VIRUS; TYPE-1 MUTANT G207; MALIGNANT GLIOMA; REPLICATION; MICE; INFECTION; VECTOR; MOUSE; ENCEPHALITIS; VACCINATION;
Keywords:
HSV vectors; cancer; preclinical safety; toxicology; biodistribution; latency;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
30
Recensione:
Indirizzi per estratti:
Indirizzo: Loudon, PT Xenova Grp PLC, 310 Cambridge Sci Pk, Cambridge CB4 0WG, England Xenova Grp PLC 310 Cambridge Sci Pk Cambridge England CB4 0WG
Citazione:
P.T. Loudon et al., "Preclinical safety testing of DISC-hGMCSF to support phase I clinical trials in cancer patients", J GENE MED, 3(5), 2001, pp. 458-467

Abstract

Background DISC-hGMCSF is a gH-deleted HSV-2 based vector expressing humanGM-CSF that is being developed for cancer immunotherapy. To support first clinical use, a range of preclinical safety studies were performed using DISC-hGMCSF in addition to DISC-murine-GMCSF and the backbone. vector, TA-HSV. Methods The toxicity of the DISC vectors was assessed by repeated dose, neurovirulence and neuroinvasiveness studies in mice, and by safety studies in rabbits, guinea pigs and athymic nude mice. Studies were also conducted to determine whether the vector could establish latency in local ganglia in mice following intradermal injection, and whether it could reactivate from the latent state. The vector biodistribution following intravenous administration was also investigated in mice, using PCR to detect vector DNA. Results The DISC vectors were essentially non-toxic in all the systems studied. No adverse reactions were seen in mice receiving four intravenous doses of DISC-mGMCSF and the results from studies of neurovirulence, neuroinvasiveness, local tolerance in rabbit, general safety in mice and guinea pigsand safety in athymic nude mice were consistent with DISC being unable to replicate and cause disease. The vector could establish latency in local ganglia in mice, but at low efficiency, and could not reactivate infectious virions. Following intravenous administration, vector DNA was widely distributed up to Day 28, but by Day 56 had disappeared from gonads and brain and was only found in blood and liver. Conclusion The panel of safety studies provided evidence that DISC-hGMCSF will be unable to replicate and cause disease, and has low toxicity in man. These data were presented to the Medicines Control Agency and the Gene Therapy Advisory Committee as part of the regulatory submissions for a clinical trial in melanoma patients. These submissions have been approved, and DISC-hGMCSF has now entered a phase I clinical trial in the UK by direct intratumoural injection. Copyright (C) 2001 John Wiley & Sons, Ltd.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 06/04/20 alle ore 02:01:21