Optimization of Peptide Based Vaccines for Cancer

描述（由申请人提供）：基于肽的癌症疫苗的优化。成功鉴定来自肿瘤相关抗原的众多T细胞表位，为开发用于治疗和预防癌症的亚单位疫苗打开了大门。由代表这些T细胞表位的合成肽制备的疫苗是诱导抗肿瘤免疫反应的一种有吸引力的方法，因为它们易于制造，易于表征，相对稳定，最重要的是，与其他类型的疫苗相比，它们具有极高的成本效益。然而，肽基疫苗的免疫原性不强，到目前为止，临床结果有些令人失望。我们假设肽疫苗无法诱导获得抗肿瘤效果所需的强大T细胞反应，因为它们缺乏唤醒免疫系统所必需的“危险信号”。此外，迄今为止测试的大多数肽疫苗都被设计为刺激细胞毒性T淋巴细胞（CTL），而忽略了触发抗肿瘤辅助T淋巴细胞（HTL）反应，我们认为这是肿瘤部位抗肿瘤CTL功能持续存在所必需的（次要假设）。为了解决这些问题，我们建议在动物肿瘤模型系统中进行以下具体目标的探索：1)评估各种疫苗配方和佐剂对肽免疫原诱导CTL和HTL反应的能力；2)通过破坏淋巴细胞稳态，评估多肽疫苗增强抗肿瘤T细胞反应的可能性；3)研究抗原特异性CTL在肿瘤效应CTL和记忆CTL的生存和增殖能力中的作用。为了实现这些目标，我们选择了一些化合物和实验方法，这些方法可以以一种权宜的方式应用于人体试验。这些研究的完成将显著促进有效肽疫苗的临床应用。

DESCRIPTION (provided by applicant): Optimization of Peptide Based Vaccines for Cancer. The successful identification of numerous T cell epitopes derived from tumor-associated antigens has opened the doors to the development of subunit vaccines for the treatment and prevention of cancer. Vaccines prepared from synthetic peptides representing these T cell epitopes constitute an attractive approach for the induction of anti-tumor immune responses because they are easily manufactured, they are simple to characterize, they are relatively stable and most importantly, they are extremely cost effective as compared to other types of vaccines. However, peptide based vaccines are not very immunogenic and so far the results in the clinic have been somewhat disappointing. We hypothesize that peptide vaccines fail to induce the robust T cell responses that are required to attain anti-tumor effects, because they lack the "danger signals" necessary that awaken the immune system. Moreover, most peptide vaccines tested so far have been designed to stimulate cytotoxic T lymphocytes (CTL) and have overlooked to trigger anti-tumor helper T lymphocyte (HTL) responses, which we believe are necessary for the persistence of anti-tumor CTL function at the tumor site (secondary hypothesis). In order to address these issues we propose to explore in an animal tumor model system the following specific aims: 1) To evaluate various vaccine formulations and adjuvants for their capacity to elicit CTL and HTL responses against peptide immunogens; 2) To assess the possibility of enhancing anti-tumor T cell responses induced by peptide vaccination, by disrupting lymphocyte homeostasis; and 3) To study the role of antigen-specific HTL in the survival and proliferative capacity of effector and memory CTL responses against tumors. To accomplish these aims we have selected compounds and experimental approaches that could be applied to human trials in an expedient manner. The completion of these studies should markedly facilitate the translation of effective peptide vaccines into the clinic.