GVAX was then re-engineered to secrete 5- to 10-fold higher levels of GM-CSF in an attempt to improve responses. A phase III trial (VITAL-1) was scheduled to randomize 600 metastatic CRPC patients without pain to GVAX or docetaxel/prednisone, and another phase III trial (VITAL-2) was designed to evaluate GVAX plus docetaxel compared with docetaxel/prednisone in metastatic CRPC patients with pain

(Table 1). Disappointingly, preliminary analysis of the VITAL-2 trial demonstrated a survival advantage for docetaxel/prednisone over GVAX/docetaxel.25 The Inhibitors,research,lifescience,medical study was prematurely terminated after accrual of 408 patients due to an imbalance in deaths, with 67 deaths in the GVAX/docetaxel and 47 deaths in the standard arm. Overall survival was shorter in the GVAX-containing arm with median survival of 12.2 Wnt inhibitor months versus 14.1 months (P Inhibitors,research,lifescience,medical = .0076). An unplanned futility analysis of the VITAL-1 trial was conducted by the Independent Data Monitoring Committee (IDMC) following the termination of VITAL-2, which indicated that the trial had less than a 30% chance of meeting its predefined primary endpoint of an improvement in survival.26 Therefore, this trial, which was fully enrolled in 2007 with 626 patients, was also terminated. In another recent trial, Inhibitors,research,lifescience,medical GVAX demonstrated activity in hormone-naive patients with PSA relapse.27 Novel combination approaches with other immunotherapeutic agents,

for example, GVAX plus ipilimumab, a monoclonal antibody (mAb) that targets CTLA-4, demonstrated activity, although endocrinopathy with hypophysitis was observed at larger doses.28 However, Inhibitors,research,lifescience,medical further directions for the clinical development of GVAX PCa remain unclear owing to the negative results from the large phase III trials. Inhibitors,research,lifescience,medical Poxvirus Vaccines The use of viral vaccines offers several potential advantages, including the inherent immunogenicity of the virus and high levels of gene expression. The poxviruses represent a family of related double-stranded DNA viruses distinguished by their host specificity and have been extensively studied as vaccines in preclinical

models.29 Similar to other poxviruses, however the vaccinia virus replicates within the cytoplasm of infected cells and induces cell lysis, releasing new virion capable of infecting surrounding cells. The host immune response to vaccinia virus, including foreign transgenes expressed by recombinant vectors, includes strong neutralizing antibody titers and a significant cell-mediated T-cell response. The ability to express large eukaryotic genes, induce potent immunity, and lack of nuclear integration suggested that recombinant poxviruses could be useful for vaccines targeting highly specific antigens. The rapid appearance of strong neutralizing antibodies against the vaccinia vector itself appeared to inhibit the ability to boost immunity against weak foreign transgenes expressed by recombinant vectors.