The recent discovery of tumor-associated antigens (TAA) in certain human malignancies has prompted renewed efforts to develop antigen- specific immunotherapy of cancer. However, most TAA described thus far are expressed in one or a few tumor types, and among patients with these types of tumors, TAA expression is not universal. For this project, it was hypothesized that the telomerase catalytic subunit (hTERT) might function as a nearly universal tumor antigen. More than 85% of human cancers exhibit strong telomerase activity whereas normal adult tissues with few exceptions do not. In a human system, preliminary work has demonstrated that a peptide derived from hTERT is capable of triggering cytotoxic T lymphocytes (CTL) that lyse hTERT+ tumors in a MHC Class I-restricted fashion. Further investigation of hTERT as a widely expressed tumor antigen is the focus of this project. The proposed experimental approach is based on the hypothesis that epitopes recognized by cytotoxic T lymphocytes can be deduced from genes selectively expressed in tumors and subsequently tested by evaluating CTL reactivity against antigen-positive tumor cells. The ultimate goal is the identification of multiple hTERT epitopes that would be useful in the design of hTERT-directed immunotherapies. Specifically, the project aims to: (1) Identify multiple cytotoxic T lymphocyte epitopes derived from hTERT and restricted to the most common MHC Class I alleles, (2) Compare the generation of hTERT-specific CTL from the peripheral blood of cancer patients and the generation of such CTL from normal donors, and (3) Evaluate hTERT-specific CTL for cytotoxicity against primary tumors and normal cells that express telomerase. The applicant is an M.D. who will have completed his clinical fellowship training in hematology-oncology prior to the proposed starting date. The research will be performed in a laboratory at the Dana-Farber Cancer Institute under the sponsorship of Dr. Lee M. Nadler, a recognized leader in the field of tumor immunology with a strong track record for fostering the career development of physician-scientists.
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