Four areas of research are being investigated in our laboratory:
1) Identification of T-cell epitopes at the peptide level from known tumor-associated antigens; 2) overcoming immunological tolerance to self, non-mutated tumor-associated antigens, as a way of eliciting strong and effective anti-cancer immunity; 3) regulation of T-cell responses to tumor cells by lymphokines and costimulatory signals; and 4) the role of helper T cells in the regulation of cytotoxic T cell responses to tumor antigens.
Our goal is to define the capacity of synthetic peptides to induce cytotoxic T lymphocyte (CTL) responses to tumor-associated antigens as a means of developing specific immunotherapy for various types of malignancies including breast, colon, lung, prostate and skin cancer. CTL recognize antigenic peptides (epitopes) derived from "processed" proteins and bound to major histocompatibility complex (MHC) class I molecules. We aim to identify CTL epitopes in various types of tumor-associated antigens (TAA), which are expressed preferentially in tumor cells. Potential CTL epitopes have been selected from peptide sequences of tissue specific proteins, oncogene products and developmental antigens by screening for specific anchor binding motifs for MHC molecules and performing quantitative binding assays. The synthetic peptides from TAA that bind with sufficient affinity to purified MHC molecules, are tested in vitro for their ability to induce tumor-specific CTL responses using human blood lymphocytes.
Because most of the known TAA are expressed in normal cells in lower quantities, we are devoting a significant amount of our efforts to the study of potential immune tolerance to these TAA. We wish to formulate possible approaches to overcome/minimize CTL tolerance in order to develop effective immunotherapy for cancer. To address immune tolerance to TAA we utilize transgenic mouse models, which will enable us to quantify and clinically evaluate immune responses induced by various modes of vaccination, to CTL epitopes expressed in tumor cells and in some normal tissues. Identification of epitopes recognized by tumor-reactive CTL will allow the development of therapeutic vaccines to treat early disease to prevent the establishment of metastatic disease and tumor recurrences. Furthermore, these studies will also lead to the development of adoptive cell-based therapies for the advanced metastatic state.