IMMUNE BASED THERAPEUTIC APPROACH FOR PROSTATE CANCER

由于免疫系统具有识别并在许多情况下破坏肿瘤细胞的能力，因此正在致力于开发基于免疫的癌症疗法。细胞毒性T淋巴细胞（CTL）和辅助性T淋巴细胞（Th）都显示出与肿瘤细胞表达的抗原反应，并因此产生保护和治疗作用。由于CTL和Th以与主要组织相容性复合体（MHC）表面分子的肽复合物的形式识别抗原，因此有必要鉴定可以引发能够抑制肿瘤细胞生长的T细胞应答的肿瘤衍生肽的化学性质。 拟议的研究的总体目标是确定来自几个已知的前列腺相关抗原（PAA）的序列，将能够刺激CTL和Th对前列腺肿瘤细胞的肽。我们已经选择了几个PAA的前列腺上皮来源的细胞，包括转化细胞优先表达。 这些PAA的氨基酸序列已被筛选含有MHC结合基序的肽的存在。将合成显示出与MHC分子结合的高度可能性的那些肽，并测试它们在体外引发对天然加工的PAA的T细胞应答的能力，作为它们确实代表T细胞表位的最终证据。 我们工作的最终目标是利用这些肿瘤反应性T细胞表位来开发治疗前列腺癌的免疫方法。 为了实现这一目标，我们提出了以下具体目标：从前列腺癌上表达的PAA中鉴定MHC I类限制性CTL表位。2.-从前列腺癌中常见的PAA中识别MHC II类限制性辅助T细胞表位。3.-通过表位重组增加对PAA的CTL和T辅助免疫应答。这些目标的完成将促进开发新的广泛适用的基于T细胞的免疫疗法，例如分别用于治疗早期和晚期前列腺癌的基于表位的疫苗和过继性T细胞疗法。

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 (Th) have been shown to react with antigens expressed by tumor cells and as a result, establish protective and therapeutic effects. Since CTL and Th 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 Th 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.- Identify MHC class I-restricted CTL epitopes from PAA expressed on prostate cancers. 2.- Identify MHC class II-restricted helper T-cell epitopes from PAA commonly found on prostate cancers. 3.- Increase CTL and T helper immune responses to PAA's by epitope re-engineering. 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 for the treatment of early and advanced prostate cancer respectively.