RECOMBINANT VACCINES FOR ACTIVE SPECIFIC IMMUNOTHERAPY OF HUMAN CARCINOMA

某些肿瘤相关抗原（TAAs）是潜在的靶点

Certain tumor associated antigens (TAAs) represent potential targets for active specific immunotherapy. Studies are ongoing to evaluate the immunogenicity, safety, and toxicity of recombinant vaccinia viruses expressing human tumor associated antigens, as immunogens for the treatment of human carcinomas. We have constructed, characterized and determined the safety and immunogenicity of two recombinant vaccinia viruses in both a murine tumor model as well as rhesus monkeys. The first recombinant vaccinia virus contained the gene for the human carcinoembryonic antigen and was designated rV-CEA; and the second vaccinia virus, designated rV-PSA, expressed human prostate specific antigen. CEA is a 18OKd glycoprotein which is overexpressed in human colorectal, gastric, pancreatic, breast and non small cell carcinoma, while PSA is a 30-33 Kd glycoprotein overexpressed in prostatic carcinoma. It is unclear whether these TAAs are immunogenic in humans; cell mediated responses to these tumor antigens have not been documented in normal or cancer patients. Anti-tumor activity was demonstrated in an animal tumor model by immunization of mice with rV- CEA. This recombinant immunogen was also shown to induce both cell- mediated and humoral CEA specific immune responses in both mice and non-human primates. Other immunogens such as a polynucliotide vaccine expressing human CEA were also shown to elicit antitumor and CEA specific cell mediated immune responses in mice. The rV-CEA immunogen has been evaluated in Phase I clinical trials, where several patients were shown to elicit specific T-cell responses to CEA following immunization. rV-PSA has also been evaluated for its safety and immunogenicity in both mice and rhesus monkeys. Southern blot analyses have demonstrated that the rhesus monkey contains genes highly related to human PSA and thus represents a relevant model for the ability of rV-PSA to elicit a cellular immune response. rV-PSA was shown to have no toxicity in these animal models. Rhesus monkeys were able to elicit PSA specific humoral as well a T-cell lymphoproliferative responses after immunization with rV-PSA. Recombinant vaccinia virus expressing the costimulatory molecules B7-1 and B7-2 were constructed, characterized, and analyzed for their ability to enhance CEA specific cellular immune responses in a murine tumor model. rV-B7-1 was shown to enhance CEA specific immune responses when co-administered with rV-CEA. Infection of tumor cells with rV-B7-1 enhanced the immunogenicity of tumors in mice and this immunogenicity had long term memory. Direct infection of tumor cells with rV-B7-1 and immunization of patients with these tumor cells may open a new route of immunotherapy. Infection of tumor cells with rV- B7 can be accomplished faster and more efficiently than gene therapy protocols using retroviral vectors and appears to elicit the correct antitumor responses. Other approaches to enhance rV-CEA and rV-PSA specific immunogenicity following primarily immunization are being developed using purified recombinant proteins, peptides, and polynucleotide vaccines. Recombinant vaccinia viruses containing the c-erb/B2 and breast mucin muc-1 genes, respectively, have also been designed and constructed.