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。肿瘤相关抗原衍生的大量T细胞表位的成功鉴定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构成了用于诱导抗肿瘤免疫应答的有吸引力的方法，因为它们容易制造，它们易于表征，它们相对稳定，并且最重要的是，与其他类型的疫苗相比，它们是极其成本有效的。然而，基于肽的疫苗不是非常免疫原性的，并且迄今为止临床上的结果有些令人失望。我们假设肽疫苗不能诱导获得抗肿瘤效果所需的强大的T细胞应答，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）应答，我们认为这是在肿瘤部位持续抗肿瘤CTL功能所必需的（次要假设）。为了解决这些问题，我们提出在动物肿瘤模型系统中探索以下具体目标：1）评估各种疫苗制剂和佐剂诱导针对肽免疫原的CTL和HTL应答的能力; 2）评估通过破坏淋巴细胞稳态来增强由肽疫苗接种诱导的抗肿瘤T细胞应答的可能性;（3）研究抗原特异性HTL在效应性和记忆性CTL抗肿瘤反应的存活和增殖能力中的作用。为了实现这些目标，我们选择了可以以方便的方式应用于人体试验的化合物和实验方法。这些研究的完成将显著促进有效肽疫苗向临床的转化。

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.