PLGA-hTERT CTL表位多抗原肽(MAP)纳米颗粒疫苗的构建及其抗肿瘤效应研究

Previous study has demonstrated that human telomerase reverse transcriptase (hTERT) was considered to be an ideal candidate for a universal TAA used in tumor immunotherapy. Our previous study which supported by grants from the National Nature Science Foundation of China indicated that multiple antigen peptide (MAP) based on CTL epitopes of hTERT could could trigger stronger hTERT-specific CTL responses than their corresponding linear peptide against tumor cells expressing hTERT and HLA-A2 in vitro and ex vivo. These hTERT-specific CTLs could not kill autologous lymphocytes and DCs with low telomerase activity. Although peptide vaccines have the advantage of easy synthesis and safe application, their small molecular weight and short half-life make them easily degradable, and their structure makes them uneasy to be captured by antigen presenting cell (APC), which results in weak immunogenicity and poor immune responses. It has been reported that the nanometer adjuvants could promote antigen peptide being captured by APC. Based on the above analysis, in this study, we prepare PLGA nanoparticle capsulating hTERT CTL epitope MAP to prevent such MAP from being degradated before uptaked by APC, and then test its antitumor efficacy in vitro and in vivo.At the same time, we will test the toxicity effect of PLGA nanoparticle containing hTERT CTL epitope MAP on autologous lymphocytes and dendritic cells. The aim of the study is to provide evidences for clinical use of PLGA nanoparticle with hTERT CTL epitope MAP.

文献及我们的研究表明人端粒酶逆转录酶（hTERT）是一种理想的肿瘤共有抗原，可作为肿瘤免疫治疗的靶标。课题组前期在国家自然科学基金资助下，设计了基于hTERT CTL表位多抗原肽（MAP）疫苗，发现hTERT MAP疫苗体内外可诱导hTERT特异性抗肿瘤免疫效应，且这种免疫杀伤效应较hTERT线性肽明显增高。多肽疫苗具有安全性高、合成方便等优点，但由于其分子量小、易降解，不易被APC捕获。文献报道纳米佐剂可以明显促进抗原被APC摄取，增强在体的免疫应答。本研究拟在前期实验基础上，将hTERT表位MAP疫苗用PLGA纳米颗粒包裹，制备PLGA-hTERT CTL表位MAP纳米颗粒疫苗，以避免hTERT表位肽疫苗在被APC捕获之前被降解，并进一步研究纳米多肽疫苗体内外抗肿瘤免疫效应及其毒副作用，为PLGA-hTERT CTL表位 MAP纳米疫苗的临床应用提供理论依据。

文献及我们的研究表明人端粒酶逆转录酶（hTERT）是一种理想的肿瘤共有抗原，可作为.肿瘤免疫治疗的靶标。课题组前期在国家自然科学基金资助下，设计了基于hTERT CTL表.位多抗原肽（MAP）疫苗，发现hTERT MAP疫苗体内外可诱导hTERT特异性抗肿瘤免疫效应.，且这种免疫杀伤效应较hTERT线性肽明显增高。多肽疫苗具有安全性高、合成方便等优.点，但由于其分子量小、易降解，不易被APC捕获。文献报道纳米佐剂可以明显促进抗原.被APC摄取，增强在体的免疫应答。本研究拟在前期实验基础上，将hTERT表位MAP疫苗用P.LGA纳米颗粒包裹，制备PLGA-hTERT CTL表位MAP纳米颗粒疫苗，以避免hTERT表位肽疫苗.在被APC捕获之前被降解，并进一步研究纳米多肽疫苗体内外抗肿瘤免疫效应及其毒副作.用，为PLGA-hTERT CTL表位 MAP纳米疫苗的临床应用提供理论依据。