PEPTIDE VACCINES FOR BREAST AND OVARIAN CANCER

尽管目前基于放射和化疗的积极治疗方案，大多数被诊断为转移性乳腺癌或卵巢癌的女性最终死亡。这项建议的目的是将T细胞免疫生物学和合成多肽化学技术结合在一个抗原发现策略中，以确定最终用于设计转移性乳腺癌和卵巢癌免疫治疗疫苗的单个候选多肽序列。对乳腺和/或卵巢肿瘤细胞具有相关裂解特异性的单个人细胞毒性T淋巴细胞(CTL)克隆将被用来筛选非常大的组合肽库，以寻找最能刺激这些CTL克隆的增殖、细胞因子释放或裂解反应的肽序列。从每个克隆扫描中推导出的候选序列将被合成，并且每个候选序列将被单独地评估在所选择的克隆上的活性。然后，最有效的多肽序列将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，这些文库扫描识别的多肽比用于产生特定T细胞克隆的天然多肽配体高出几个数量级，并且这些优化的超级激动剂多肽作为疫苗有效，激发T细胞介导的针对天然多肽配体的免疫反应。拟议的商业应用：在接受放射和化疗药物治疗后，被诊断为转移性乳腺癌或卵巢癌的妇女的存活率统计数据远远不能令人满意。候选肿瘤抗原的缺乏，以及识别和优化它们以提高疫苗效力的困难，阻碍了替代免疫治疗方法的发展。概述了一种抗原发现策略，该策略可以显著增加候选肿瘤抗原作为免疫治疗性疫苗用于临床试验的可用性。

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.