Because the immune system has the capacity to recognize and in many cases destroy tumor cells, significant efforts are being devoted to the development of immune-based therapies for cancer. Both cytotoxic T lymphocytes (CTL) and helper T lymphocytes (HTL) have been shown to react with antigens expressed by tumor cells and as a result, establish protective and therapeutic effects. Since CTL and HTL recognize antigens in the form of peptide complexes with major histocompatibility complex (MHC) surface molecules, it is necessary to identify the chemical nature of tumor-derived peptides that can elicit T-cell responses capable of inhibiting tumor-cell growth. The overall objective of the proposed study is to identify peptides derived from sequences of several known prostatic-associated antigens (PAA) that will be capable of stimulating CTL and HTL against prostate tumor cells. We have selected several PAA which are preferentially expressed on cells of prostatic epithelial origin including transformed cells. The amino acid sequences of these PAA have been screened for the presence of peptides containing MHC binding motifs. Those peptides that display a high degree of probability of binding to MHC molecules will be synthesized and tested for their capacity to elicit in vitro T-cell responses to naturally processed PAA as final proof that they indeed represent T-cell epitopes. The ultimate goal of our work is to utilize these tumor-reactive T-cell epitopes to develop immunotherapeutic approaches to treat prostatic cancers. To accomplish this goal, we propose the following specific aims: 1. To identify MHC class I-restricted CTL epitopes from PAA expressed on prostate cancers. 2. To identify MHC class II-restricted helper T-cell epitopes from PAA commonly found on prostate cancers. 3. To increase CTL and T helper immune responses to PAA by epitope re-engineering. 4. To vaccinate prostate cancer patients with dendritic cells pulsed with CTL and HTL peptide epitopes. The completion of these aims should facilitate the development of novel broadly applicable T-cell based immune therapies such as epitope-based vaccines and adoptive T-cell therapy.
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