Methods and compositions for constructing and producing recombinant adenovirus-based vector vaccines are provided. In particular aspects, there are be provided compositions and methods involving adenovirus vectors comprising genes for target antigens, such as pro state-specific antigen (PSA), pro state-specific membrane antigen (PSMA), MUC1, CEA, and/or Brachyury, and costimulatory molecules for use in treatment methods that generate highly reactive anti-tumor immune responses and that allows for multiple vaccinations in individuals with preexisting immunity to adenovirus.