PHASE I-II STUDY OF COMBINATION IMMUNOTHERAPY FOR HER-2/NEU CYTOTOXIC T CELLS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 来自肿瘤疫苗研究的数据现在表明，接受过肿瘤抗原特异性疫苗接种的患者可能会有生存优势。我们小组已经证明，在用标准治疗获得最大反应或完全缓解后，使用基于HER2多肽的疫苗免疫的晚期乳腺癌患者具有潜在的生存优势。最近的研究表明，在体外用曲妥珠单抗对HER2过度表达的肿瘤细胞进行增敏，将增强针对HER2的CTL的功能。理论上，曲妥珠单抗增强HER2特异性CTL反应的机制可能是HER2受体内化，HER2蛋白降解，MHC多肽递呈增加，导致CD8+HER2特异性CTL功能增强。因此，曲妥珠单抗与基于HER2多肽的疫苗相结合，旨在在人类白细胞抗原A2的背景下诱导CTL，甚至可能进一步增强HER2特异性CTL反应的产生，并在佐剂环境中使用时潜在地转化为改善晚期乳腺癌患者的生存。这是一项临床试验，旨在利用曲妥珠单抗和基于HER2 CTL生成肽的疫苗(HER2 CTL疫苗)之间的潜在协同效应，以增加针对HER2特异性表位的CTL前体频率。晚期乳腺癌患者将接受治疗，直到他们的疾病通过化疗和曲妥珠单抗稳定下来，而曲妥珠单抗在维持期间接受HER2 CTL疫苗接种。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Data from tumor vaccine studies now indicate there might be survival advantages for patients who have received tumor-antigen specific vaccinations. Our group has demonstrated a potential survival advantage for patients with advanced stage HER2 overexpressing breast cancer immunized with a HER2 peptide based vaccine after being treated to maximal response or complete remission with standard therapy. Recent studies have demonstrated that "sensitization" of HER2 overexpressing tumor cells with trastuzumab, in vitro, will enhance the function of CTL specific for HER2. Theoretically, the mechanism of trastuzumab's enhancement of a HER2 specific CTL response might be the internalization of the HER2 receptor, degradation of the HER2 protein, and increased MHC-peptide presentation with a resultant increase in CD8+ HER2 specific CTL function. Thus, combination of trastuzumab with HER2 peptide based vaccine designed to elicit CTL in the context of HLA-A2 may even further enhance the generation of a HER2 specific CTL response and potentially translate into improved survival for advanced stage breast cancer patients when used in the adjuvant setting. This is a clinical trial designed to utilize the potential synergistic effect between trastuzumab and a HER2 CTL generating peptide based vaccine (HER2 CTL vaccine) in order to increase CTL precursor frequencies that target HER2 specific epitopes. Patients with advanced stage breast cancer will be treated until their disease stabilizes with chemotherapy and trastuzumab and while on maintenance trastuzumab receive vaccinations with a HER2 CTL vaccine.