Preclinical evaluation of DISC-GMCSF for the treatment of breast carcinoma.

Abstract

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. 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. 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. 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.