Tumor cells can be killed in the test tube and in mice by antibody or T cell mediated mechanisms. We focus on optimizing the vaccines for each separately, since the optimal vaccines are quite different. Because of the greater ease of testing antibody responses, these studies are most advanced.
Vaccines that Induce Antibodies
A large-scale immunohistology screen was performed to identify the dominant cell surface antigens expressed by common human cancers; and a series of studies were conducted in mice and in patients to identify the most potent vaccines for inducing antibodies against these antigens. In every case, the best antibody response was induced by covalently linking antigen to the large carrier molecule keyhole limpet hemocyanin (KLH), which is obtained from the keyhole limpet,a mollusc. The optimal adjuvants in each case were purified saponin fractions or semisynthetic saponins, all derived from the bark of a South American tree.
These vaccines have induced consistent antibodies against a series of 10 cell surface carbohydrate and protein antigens. Recently, the individual monovalent vaccines have been combined in polyvalent vaccines containing 3 to 7 different conjugates. A series a Phase II trials in patients with melanoma, neuroblastoma, small-cell lung cancer, ovarian cancer and breast cancer are planned to determine whether vaccine-induced antibodies against multiple cell surface antigens are able to prolong disease-free survival and overall survival after surgical resection of all known disease. These are scheduled to begin in 2007.
Projects
The class, subclass, and functional characteristics of polyvalent vaccine-induced antibodies over time with repeated vaccinations and correlation of these responses to clinical outcome.
Vaccines that Induce T-cell Immunity
CA-125 (MUC16) and PSMA are the major cell surface glycoproteins of ovarian cancers and prostate cancer (respectively). These were initially cloned at this Center. We are exploring a variety of approaches in the mouse to increasing the antibody, CD8 and CD4 T cell responses to these glycoproteins. These include comparing the impact of peptides and proteins mixed with different adjuvants or conjugated to different carrier proteins and DNA vaccines. DNA vaccine followed by protein vaccine prime/boost combinations will be tested. The antibody response is measured in ELISA, FACS, and cytotoxicity assays. T cell responses are tested in ELISPOT and intracellular cytokine assays. Clinical trials should commence late in 2007.
Projects
Impact of different adjuvant combinations or conjugation to carrier proteins on immune response to MUC16 and PSMA peptide and protein vaccines.
Impact of hybridization with different carrier proteins or electroporation on response to DNA vaccines.
Impact of different prime/boost combinations on antibody and T cell responses.
