PEPTIDE VACCINES FOR BREAST AND OVARIAN CANCER

尽管目前积极的治疗方案的基础上放疗和化疗，大多数妇女诊断为转移性乳腺癌或卵巢癌最终死亡。本提案的目的是在抗原发现策略中结合T细胞免疫生物学和合成肽化学技术，以鉴定最终用于转移性乳腺癌和卵巢癌免疫抑制疫苗设计的单个候选肽序列。对乳腺和/或卵巢肿瘤细胞具有相关裂解特异性的人细胞毒性T淋巴细胞（CTL）的单个克隆将用于筛选非常大的组合肽文库，以获得最佳刺激这些CTL克隆的增殖、细胞因子释放或裂解应答的肽序列。将合成从每个克隆扫描推导出的候选序列，并单独评估每个序列对选择克隆的活性。然后，最有效的肽序列将可用于其他必要的临床前评估和I/II期毒性/疗效临床试验。初步研究表明，这些文库扫描鉴定出比用于产生特定T细胞克隆的天然肽配体更有效几个数量级的肽，并且这些优化的超激动剂肽作为疫苗是有效的，激发针对天然肽配体的T细胞介导的免疫应答。拟议的商业应用：经诊断患有转移性乳腺癌或卵巢癌的妇女在接受放射治疗和化疗药物治疗后的存活率统计数字远不能令人满意。由于缺乏候选肿瘤抗原，以及难以识别和优化它们以提高其作为疫苗的有效性，替代免疫方法受到阻碍。抗原发现的战略概述，可能会大大增加候选肿瘤抗原作为免疫疫苗的临床试验的可用性。

Despite current aggressive treatment protocols based on irradiation and chemotherapy, the majority of women diagnosed with metastatic breast or ovarian cancer ultimately die. The objective of this proposal combines the technologies Of T cell immunobiology and synthetic peptide chemistry in a strategy of antigen discovery to identify individual candidate peptide sequences for ultimate use in the design of immunotherapeutic vaccines for metastatic breast and ovarian cancer. Individual clones of human cytotoxic T lymphocytes (CTL) having relevant lytic specificity for breast and/or ovarian tumor cells will be used to screen very large combinatorial peptide libraries for peptide sequences that best stimulate proliferative, cytokine release, or lytic responses by these CTL clones. Candidate sequences deduced from each clonal scan will be synthesized and each individually assessed for activity on the selecting clone. The most effective peptide sequences will then be made available for other necessary preclinical assessments and for phase I/II toxicity/efficacy clinical trials. Preliminary studies indicate that these library scans identify peptides several orders of magnitude more effective than native peptide ligands used to generate a particular T cell clone, and that these optimized superagonist peptides are effective as vaccines, provoking T cell mediated immune responses against native peptide ligands. PROPOSED COMMERCIAL APPLICATIONS: The survival statistics for women diagnosed with metastatic breast or ovarian cancer, following treatment with irradiation and chemotherapeutic drugs, are far from satisfactory. Alternative immunotherapeutic approaches have been hampered by the paucity of candidate tumor antigens, as well as the difficulties in identifying and optimizing them to enhance their effectiveness as vaccines. A strategy for antigen discovery is outlined that may substantially increase the availability of candidate tumor antigens for clinical tests as immunotherapeutic vaccines.