Advances in cancer vaccines

James W. Hodge, Ph.D., and Jeffrey Schlom, Ph.D.

Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, USA.

AIM Tumor-associated antigens (TAAs) are weakly immunogenic or functionally nonimmunogenic in the tumor-bearing host. Thus, if vaccines are to be effective in cancer therapy, strategies must be developed to present TAAs to the immune system in a way that makes them more immunogenic. METHODS We have developed several approaches to enhance the immunogenicity of TAAs, and have developed animal models to evaluate these strategies. These strategies include a) delivery of the TAA via recombinant poxviral vectors, b) diversified prime and boost vaccination regimens, c) the use of multiple T cell costimulatory molecules, d) design of agonist TAA epitopes, and e) the use of cytokines as biological adjuvants. RESULTS Studies have demonstrated that two types of recombinant poxvirus vectors are very effective in enhancing antigen-specific T-cell responses: the replication-competent vaccinia (rV) and the replication-defective avipox viruses. One of the vaccine targets for these studies is carcinoembryonic antigen (CEA), which is overexpressed in the vast majority of human carcinomas. Phase I clinical trials demonstrated that both rV-CEA (V) and avipox-CEA (A) could elicit CEA-specific T-cell responses in patients with advanced carcinomas. A small randomized Phase II trial was conducted in which patients with advanced CEA-expressing carcinomas, who had failed conventional therapies, received either rV-CEA (V) prime vaccination followed by three monthly avipox-CEA (A) booster vaccinations (i.e., the VAAA regimen), or the reciprocal AAAV regimen. Patients vaccinated with the VAAA regimen demonstrated the generation of significantly higher levels of CEA-specific T cells and longer survival than patients randomized to the AAAV regimen. There was also a correlation between survival at > 2 years post-vaccination and CEA-specific T-cell responses. Studies have also demonstrated that the insertion of a transgene for one of several T-cell costimulatory molecules into poxvirus vectors along with the transgene for a TAA enhanced the potency of the immune response to the TAA. We have demonstrated that the insertion of the transgenes for a TRiad of COstimulatory Molecules (B7-1, ICAM-1 and LFA-3, designated TRICOM) into these vectors, along with the TAA transgene, could markedly enhance T-cell responses to the TAA, and the elimination of well-established tumors in animal models. Ongoing studies also indicate that CEA/TRICOM vectors can be used to treat spontaneously arising CEA positive colon tumors in APC min+ x CEA+ double transgenic mice.Infection of peptide-pulsed dendritic cells with TRICOM vectors greatly enhances the generation of antigen-specific T-cell responses. These studies have led to the recent initiation of a clinical trial in which patients with advanced CEA-expressing carcinomas will be receiving CEA/TRICOM vector vaccines. CONCLUSIONS Collaborative clinical trials in patients with advanced carcinoma have now been initiated with rV-CEA/TRICOM and rF-CEA/TRICOM vectors. These vectors also contain a CEA agonist epitope described previously. Clinical grade rF-TRICOM and rV-TRICOM vectors have also now been developed for intratumoral applications and for peptide-pulsed dendritic cell therapy studies. As part of this program, collaborative clinical trials using the vectors described above as well as recombinant PSA and MUC-1-based recombinant vaccines (in prostate and breast cancer patients, respectively) are ongoing and planned within several cancer centers throughout the U.S.

Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Paris, France; February 9 - 12, 2002; in the section on Molecular Genetics & Therapy - 1.