Optimization of Peptide Based Vaccines for Cancer

基于肽的癌症疫苗的优化。成功识别大量T细胞 来自肿瘤相关抗原的表位为亚单位的发展打开了大门， 用于治疗和预防癌症的疫苗。由合成肽制备的疫苗 这些T细胞表位构成了诱导抗肿瘤免疫应答的有吸引力的方法 因为它们易于制造、易于表征、相对稳定且最 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- 基于疫苗的免疫原性不是很强，到目前为止， 失望我们假设肽疫苗不能诱导强烈的T细胞应答， 因为它们缺乏必要的“危险信号”， 免疫系统此外，迄今为止测试的大多数肽疫苗被设计为刺激细胞毒性T细胞， 淋巴细胞（CTL），并忽略了触发抗肿瘤辅助T淋巴细胞（HTL）反应， 我们认为，这些抗体对于肿瘤部位抗肿瘤CTL功能的持久性（继发性）是必需的。 假设）。为了解决这些问题，我们建议在动物肿瘤模型系统中探索 1）评价各种疫苗制剂和佐剂的能力， 研究多肽免疫原诱导的CTL和HTL反应; 2）探讨增强多肽免疫原抗肿瘤活性的可能性 通过破坏淋巴细胞稳态，由肽疫苗接种诱导的T细胞应答;和3）研究 抗原特异性HTL在效应和记忆CTL应答的存活和增殖能力中的作用 对抗肿瘤为了实现这些目标，我们选择了化合物和实验方法， 可以以一种方便的方式应用于人体试验。这些研究的完成应明显 有助于将有效的肽疫苗转化为临床。

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 representinc 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.