The cytotoxic T lymphocytes (CTL) appear to be among the most direct and effective elements of the immune system that are capable of generating anti-tumor immune responses. A fast growing number of reports demonstrate the presence of anti-tumor CTL in peripheral blood from patients with cancer. Recently, a novel gene, named survivin, that is highly expressed in many types of cancer has been identified. Survivin may be an ideal target for immunotherapy of many human tumors because of its strong expression in cancer, little or no expression in adult tissues, and its essential role for the survival of the tumor cells. In the current proposal we plan to identify immunogenic survivin-derived peptides. We will also focus on the further development of optimized synthetic vaccines for cancer based on this antigen. The goals of this study are to design optimized synthetic vaccines based on several class I restricted, survivin-derived peptides. We will utilize several modern approaches for vaccine design, including terminal modifications to inhibit proteolytic degradation of the peptides, amino acid substitutions to enhance the MHC binding affinity and the T cell receptor binding affinity of these peptides, and endoplasmic reticulum insertion signal sequences to enhance their antigen presentation. We will then use these vaccines to generate in vitro antigen-specific CTL lines and clones from healthy volunteers and from patients with cancer. We will test the ability of these antigen-specific CTL to kill cancer cells in a class I-restricted and antigen-dependent fashion. In some of the experiments we will use human dendritic cells to induce antigen-specific CTL in vitro. We will also analyze carefully all data for statistical significance. The design of optimized vaccines based on survivin-derived peptides will undoubtedly contribute to the development of more efficient approaches for treatment of cancer. These vaccines might be used directly to immunize patients with cancer. Dendritic cells loaded with these vaccines can also be used to elicit powerful anti-tumor immune responses. In addition, antigen-specific CTL might be extremely useful for cellular immunotherapy of cancer. Therefore, the findings of this study will be used in translational and clinical programs that will benefit patients with many types of cancer expressing survivin.
| Zhang, Menghua; Dias, Peter; Minev, Boris et al. (2010) Induction characterization and targeting of human hematopoietic cancer stem cells. J Stem Cells 5:1-7 |
