Preclinical evaluation of DISC-GMCSF for the treatment of breast carcinoma.
BACKGROUND
DISC-hGMCSF is a gH-deleted HSV-2 based vector expressing human GM-CSF that has entered clinical trials for the therapy of metastatic melanoma. To determine whether this product also has potential to treat breast carcinoma, a series of in vitro and in vivo studies were made.


METHODS
Breast carcinoma cell lines and primary cultures of breast carcinoma cells were infected with DISC-GFP or DISC-human-GMCSF (DISC-hGMCSF) and the number of GFP-positive cells and GM-CSF yields were determined. In vivo efficacy of DISC-murine-GMCSF (DISC-mGMCSF) in combination with systemic chemotherapy was assessed in the murine 4T1 breast carcinoma model by direct injection into subcutaneous tumours.


RESULTS
DISC-hGMCSF was able to infect all breast carcinoma cell lines and the majority of primary breast carcinoma cultures with high efficiency, although culture-to-culture variability in infectability was noted in the latter. In the MCF-7 breast carcinoma cell line, expression of hGMCSF was found to peak over the first 24 h post-infection and drop to background levels by 7 to 14 days. In the 4T1 murine breast tumour model, injection of subcutaneous tumours led to a delay in tumour growth and, in rare cases, complete regression of visible tumour. DISC-mGMCSF and DISC-LacZ showed similar levels of efficacy. When mice were given simultaneous 5FU chemotherapy the effectiveness of DISC-mGMCSF treatment was undiminished, and up to three out of ten mice showed complete absence of visible tumour.


CONCLUSIONS
DISC-hGMCSF is able to infect human breast carcinoma cells at high efficiency and express GM-CSF. DISC-mGMCSF demonstrated efficacy in the murine 4T1 model, even during concomitant chemotherapy. Taken together these results indicate that DISC-hGMCSF may have potential for the treatment of breast carcinoma.
Loudon
Peter T
PT
Xenova Group plc, 310 Cambridge Science Park, UK. Peter_Loudon@xenova.co.uk
McLean
Cornelia S
CS
Martin
Gilly
G
Curry
Jayne
J
Leigh Shaw
M
M
Hoogstraten
Conny
C
Verdegaal
Els
E
Osanto
Susanne
S
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D001943:Breast Neoplasms / Q000235:genetics / Q000628:therapy*; D045744:Cell Line, Tumor; D002469:Cell Separation; D002498:Centrifugation; D005260:Female; D005434:Flow Cytometry; D005472:Fluorouracil / Q000494:pharmacology; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics*; D049452:Green Fluorescent Proteins; D018258:Herpesvirus 2, Human / Q000235:genetics*; D006801:Humans; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D015674:Mammary Neoplasms, Animal / Q000235:genetics / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D010641:Phenotype; D013997:Time Factors
D000964:Antimetabolites, Antineoplastic; D008164:Luminescent Proteins; D049452:Green Fluorescent Proteins; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D005472:Fluorouracil