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This article reviews progress made in the design and development of recombinant poxviral-based vaccines that express transgenes for tumor-associated antigens (TAAs) and human T-cell co-stimulatory molecules (designated TRICOM). The TRICOM vaccine platform consists of priming with a recombinant vaccinia (rV-) vector and multiple boosts with a replication defective fowlpox (rF-) vector. The rV, rF-PSA-TRICOM (PROSTVAC) has demonstrated survival benefit in randomized trials. rV, rF-CEA-MUC1-TRICOM (PANVAC) has demonstrated evidence of benefit in patients with colorectal, breast and ovarian cancers. Preclinical studies with TRICOM-based vaccines have demonstrated their ability to be used in combination with anti-CTLA4 monoclonal antibody, radiation, chemotherapeutics, and small molecule targeted therapies to enhance vaccine-mediated immune responses and antitumor activity. Randomized clinical studies have been completed, are ongoing, and are planned employing several of these TRICOM vaccine combination therapies. The importance of trial design in terms of patient population and clinical trial endpoint has been demonstrated in these studies.