Studies on human prostate-specific antigen as a tumor antigen for the immunotherapy of prostate cancer in a mouse model

Tumor immunotherapy, in which the immune system is directed to respond to malignant cells, is currently being investigated for a variety of cancers. Prostate-specific antigen (PSA), a protein expressed by prostate epithelium and prostatic carcinomas, may provide a useful tumor antigen for immunotherapy. Two critical issues that must be addressed regarding the use of PSA as a tumor antigen are the ability to induce potent anti-PSA cytotoxic T lymphocyte (CTL) responses that are capable of eradicating tumor cells, and the circumvention of immune tolerance mechanisms that may prevent autoimmune responses to PSA, a self-antigen.; To address the first issue, two viral vectors have been constructed for the generation of PSA-specific CTL. The first is a recombinant vaccinia virus that expresses PSA. This work has generated results that underscore the importance of immunodominance as a consideration for the construction of viral vectors and design of immunization strategies. As an alternative method, HSV-1 amplicon vectors expressing PSA have been constructed. These are plasmid-based viral vectors that are packaged into HSV-1 capsids, but lack viral coding sequences. Immunization with HSV-PSA elicits a specific CTL response, and protects mice from challenge with tumors that express PSA.; To address the issue of immune tolerance, transgenic mice that express human PSA in a similar manner to humans provide a model for prostate cancer immunotherapy where the limits of self-tolerance can be tested in a way relevant to potential therapies. These mice have been immunized with PSA either in the form of a tumor antigen or in a strong adjuvant, and the PSA-specific immune response has been analyzed. A qualitatively different antibody response is observed depending on the form of immunization, and possible mechanisms for this conditional B cell non-responsiveness are discussed.; The work in this thesis has resulted in the generation of two viral vector systems to elicit PSA-specific immunity, which in combination with other approaches should be capable of inducing CTL in PSA-expressing mice or humans. Further, the helper T cell and antibody response has been analyzed in PSA-expressing transgenic mice, and has provided invaluable information relevant to the design of immunotherapeutic strategies.