Recombinant Cancer Vaccines: Design and Development
Laboratory of Tumor Immunology and Biology, Center for Cancer Research, Director, Laboratory of Tumor Immunology and Biology, Chief, Laboratory of Tumor Immunology and Biology, National Cancer Institute, National Institutes of Health, MSC, Bethesda, Moldova, Republic Of
Aim: Tumor-associated antigens (TAAs) are by definition either weakly immunogenic or functionally nonimmunogenic in the immune competent host. Thus, if cancer vaccines are to be effective in either preventing or eliminating tumors, vaccines and vaccine strategies must be developed to present antigens to the immune system in a way that makes them more immunogenic. Methods: We have developed and employed five strategies to enhance T-cell responses directed against tumor-associated antigens (TAA). These are: (a) the use of viral vectors to deliver both TAA and immunostimulatory molecule gene products; (b) diversified prime and boost vaccination regimens employing recombinant vaccinia as a primary vaccination followed by multiple boosting vaccinations with replication defective avipox vaccine; (c) the use of viral vectors containing transgenes for a triad of T-cell costimulatory molecules (B7.1, ICAM-1, LFA-3; designated TRICOM) along with the transgene for TAAs; (d) altering the amino acid sequence of the TAA to enhance its immunogenicity; and (e) the use of GM-CSF at the vaccination site, delivered as a recombinant protein or, more efficiently, via an avipox vector, to enhance recruitment of dendritic cells. Results: Clinical trials are ongoing directed against the carcinoma-associated antigens CEA, MUC-1 and PSA employing these vaccines and vaccine strategies. Preclinical studies have emphasized the use of transgenic (Tg) mice. In one such model, the human CEA transgene is expressed as a “self” antigen in fetal tissue and adult GI tissue in a manner similar to humans. The vaccination of these mice with CEA-TRICOM vectors induces higher levels of anti-tumor activity and T-cell responses directed against CEA than the use of vaccines containing one or no costimulatory molecules. In a double Tg model (APC min x CEA Tg) in which mice develop spontaneous CEA-expressing tumors (colonic polyps), CEA-TRICOM vaccine was shown to vastly reduce the development of spontaneous tumors. Moreover, the combined use of a COX-2 inhibitor plus vaccine was shown to further inhibit tumor development. In this model, and in the therapy model of established tumors, no autoimmunity was observed. Conclusions: Phase I/II trials in patients with advanced CEA-expressing tumors, employing either viral vector-based vaccines or agonist peptide-pulsed dendritic cell vaccines, have demonstrated objective clinical responses, drops in serum markers, and T-cell responses specific for CEA. Moreover, preliminary data indicate a correlation between increased survival and the generation of CEA-specific T-cell responses. More comprehensive clinical studies are required and are currently ongoing or planned. These studies thus form a rational basis for the combinatorial use of recombinant vaccines with other forms of anti-cancer therapy.
Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Nice, France; February 7 - 10, 2004; in plenary session 903 (Cancer immunity).