Synergy of vaccine strategies to amplify antigen-specific immune responsesand antitumor effects

Several different vaccine strategies have been evaluated and combined in an attempt to amplify T-cell responses toward induction of antitumor immunity . The model tumor antigen used was carcinoembryonic antigen (CEA), While in itial T-cell activation studies were conducted in conventional mice, combin ed vaccine strategy studies and antitumor studies were conducted in transge nic mice in which CEA is expressed in normal gastrointestinal tissue and CE A protein is found in sera. The studies reported here demonstrate: (a) A re combinant avipox (fowlpox, rF) vector expressing the signal 1 (CEA) and the B7-1 costimulatory molecule transgenes (designated rF-CEA/B7-1) is more po tent in inducing CEA-specific T-cell responses than rF-CEA; one administrat ion of recombinant fowlpox vector expressing CEA and three different costim ulatory molecule transgenes (B7-1, ICAM-1, LFA-3, designated rF-CEA/TRICOM) was more potent in inducing CEA-specific T-cell responses than four vaccin ations with rF-CEA or two vaccinations with rF-CEA/B7-1, Moreover, up to fo ur vaccinations with rF-CEA/TRICOM induced greater CEA-specific T-cell resp onses with each vaccination. (b) A diversified prime and boost strategy usi ng a prime with a recombinant vaccinia vector expressing CEA and the triad of costimulatory molecules (designated rV-CEA/TRICOM) and a boost with rP-C EA/TRICOM was more potent in inducing CEA-specific T-cell responses than th e repeated use of rF-CEA/TRICOM alone. (c) The addition of granulocyte macr ophage colony-stimulating factor (GM-CSF) to the rF-CEA or rF-CEA/TRICOM va ccinations via the simultaneous administration of a rF-GM-CSF vector enhanc ed CEA-specific T-cell responses, These strategics (TRICOM/diversified prim e and boost/GM-CSF) were combined to treat CEA-expressing carcinoma Liver m etastases in CEA-transgenic mice; vaccination was initiated 14 days posttum or transplant. Antitumor effects in terms of survival and CD8(+) and CD4(+) responses specific for CEA were also observed in this CEA-transgenic mouse model. These studies demonstrate that the use of cytokines and diversified prime and boost regimens can be combined with the use of recombinant vecto rs expressing signal 1 and multiple costimulatory molecules to further ampl ify T-cell responses toward more effective vaccine strategies.