Clinical study of a survivin long peptide vaccine (SurVaxM) in patients with recurrent malignant glioma.

Survivin is an anti-apoptotic protein that is highly expressed in many cancers, including malignant gliomas. Preclinical studies established that the conjugated survivin peptide mimic SurVaxM (SVN53-67/M57-KLH) could stimulate an anti-tumor immune response against murine glioma in vivo, as well as human glioma cells ex vivo. The current clinical study was conducted to test safety, immunogenicity and clinical effects of the vaccine. Recurrent malignant glioma patients whose tumors were survivin-positive, and who had either HLA-A*02 or HLA-A*03 MHC class I allele-positivity, were given subcutaneous injections of SurVaxM (500 µg) in Montanide ISA 51 with sargramostim (100 µg) at 2-week intervals. SurVaxM was well tolerated with mostly grade one adverse events (AE) and no serious adverse events (SAE) attributable to the study drug. Six patients experienced local injection site reactions; three patients reported fatigue (grades 1 and 2), and 2 patients experienced myalgia (grade 1). Six of eight immunologically evaluable patients developed both cellular and humoral immune responses to vaccine. The vaccine also stimulated HLA-A*02, HLA-A*03 and HLA-A*24 restricted T cell responses. Three patients maintained a partial clinical response or stable disease for more than 6 months. Median progression-free survival was 17.6 weeks, and median overall survival was 86.6 weeks from study entry with seven of nine patients surviving more than 12 months.

The mechanism of methylselenocysteine and docetaxel synergistic activity in prostate cancer cells.

The study was designed to evaluate the combination treatment of methylselenocysteine (MSeC) and docetaxel and to delineate the underlying mechanism associated with observed in vitro synergy between MSeC and docetaxel in prostate cancer cells. Cells were treated with different concentrations and schedules (concurrent or sequential) of MSeC and docetaxel alone or in combination. Cell growth/death was assessed with sulforhodamine B assay, trypan blue assay, and time-lapse video. Loewe synergism/antagonism model was used to determine whether the combination effect was additive, synergistic, or antagonistic. Apoptosis and caspase-3 activity were evaluated with cell death ELISA assay and caspase activity assay, respectively. Synergy between MSeC and docetaxel was further assessed in the presence and absence of z-VAD-fmk, a pan-caspase inhibitor. Effect of MSeC and docetaxel alone or in combination on the cellular expression of the antiapoptotic protein survivin was measured with Western blot analyses. Pretreatment with MSeC was crucial to enhance docetaxel antitumor activity. The enhanced antitumor activity of the sequential combination treatment of MSeC and docetaxel (MSeC/docetaxel) was highly synergistic. Apoptosis increased after MSeC/docetaxel, compared with each drug alone or concurrent treatment. Pretreatment with z-VAD-fmk converted the synergy into antagonism, suggesting that the synergy is caspase-dependent apoptosis. The survivin level was down-regulated following MSeC/docetaxel treatment when compared with each drug alone. In conclusion, pretreatment with MSeC was essential to markedly sensitize cells to docetaxel. The synergy between MSeC and docetaxel in C2G prostate cancer cells is associated with increased level of caspase-dependent apoptosis and decreased level of survivin.

Silencing survivin results in synergy between methylseleninic acid and paclitaxel against skov3 ovarian cancer cells.

This study evaluates methylseleninic acid (MSeA) improvement of paclitaxel efficacy against human ovarian cancer (skov3) with regard to survivin expression. MSeA and paclitaxel alone and in concurrent or sequential combination treatments were tested. Cell growth/death was evaluated using SRB, trypan blue, colony formation and ELISA assays. Cells were transfected with survivin shRNA and survivin's expression was measured using RT-PCR and Western blots. Drugs interaction was further evaluated using isobologram analyses. Different treatments with MSeA did not enhance paclitaxel's efficacy in the wild type skov3. Silencing survivin had no effect on MSeA or paclitaxel efficacy when used alone or in concurrent combination. After sequential combination treatment, synergy and significant induction of apoptosis were observed in cells transfected with survivin shRNA. However, antagonism and minimal induction of apoptosis were observed in empty or scramble survivin shRNA transfected cells. In conclusion, these data suggest that synergy between MSeA and paclitaxel in skov3 is associated with silencing survivin expression.