T Cell Memory After Immunization with a HER2 DNA Vaccine

描述(申请人提供)：晚期乳腺癌和卵巢癌患者治疗中的一个主要临床问题是复发的风险。大多数被诊断为高风险或更晚期癌症的患者，尽管通过手术和化疗等标准治疗已痊愈，但仍将经历疾病复发。癌症疫苗提供了一种独特的治疗策略，可以防止癌症复发，甚至根除微转移疾病。在过去的十年里，肿瘤免疫学的几个进展重新引起了人们对癌症疫苗的兴趣；特定肿瘤抗原的定义，对乳腺癌和卵巢癌等具有免疫原性的癌症的理解，以及能够有效地使患者对“自身”肿瘤抗原产生免疫的技术的发展。我们小组一直在开发基于质粒的DNA疫苗，作为一种可能有效地免疫患者对抗肿瘤中表达的多种抗原的方法。将肿瘤抗原编码的质粒与可溶的细胞因子一起皮下传递，以增强局部皮肤树突状细胞的募集，从而显著提高该方法的免疫原性，导致针对HER2过表达的乳腺癌和卵巢癌患者的针对HER-2/neu(HER2)癌基因蛋白的质粒基疫苗的I期临床研究。这项临床研究旨在确定DNA免疫的安全性和免疫原性。这项提案中概述的实验将确定主动免疫后是否可以产生针对HER2抗原的免疫记忆。癌症疫苗的几项临床试验表明，癌症患者可以通过免疫来产生可检测到的免疫力。我的目标是，免疫是否导致了针对肿瘤特异性蛋白的T细胞记忆反应的发展。从理论上讲，一种有效的癌症疫苗将导致免疫记忆的产生，这种记忆T细胞反应如果有效，将有可能防止疾病复发。这项建议的具体目的是：(1)评估基于HER2 ICD质粒的DNA疫苗在晚期HER2过表达乳腺癌和卵巢癌患者中的安全性和免疫原性程度；(2)确定HER2特异性T细胞记忆在HER2 ICD质粒疫苗主动免疫后是否发生；以及(3)确定局部抗原表达延长是否与免疫后HER2特异性记忆T细胞反应的发展有关。

DESCRIPTION (provided by applicant): A major clinical problem in the treatment of patients with advanced stage breast and ovarian cancer is the risk of relapse. The majority of patients diagnosed with high risk or more advanced stage cancers, although rendered disease free with standard treatments such as surgery and chemotherapy will undergo disease reoccurrence. Cancer vaccines offer a unique therapeutic strategy that may prevent cancer relapse or even eradicate micrometastatic disease. Several advances in tumor immunology in the last decade have resulted in renewed interest in cancer vaccines; the definition of specific tumor antigens, the understanding that cancers such as breast and ovarian are immunogenic, and the development of techniques that can result in immunizing patients effectively to "self" tumor antigens. Our group has been developing plasmid based DNA vaccines as a method that may be effective in immunizing patients against multiple antigens expressed in their tumors. Delivering tumor antigen encoding plasmids interdermally with soluble cytokines that enhance local skin dendritic cell recruitment, thus, markedly improving the immunogenicity of the approach has resulted in the development of a Phase I clinical study of a plasmid based vaccine targeting the HER-2/neu (HER2) oncogenic protein in patients with HER2 overexpressing breast and ovarian cancers. The clinical study is designed to determine the safety and immunogenicity of DNA immunization. Experiments outlined in this proposal will determine whether immunologic memory against the HER2 antigen can be generated after active immunization. Several clinical trials of cancer vaccines have demonstrated that cancer patients can be immunized to develop detectable immunity. My goal will be whether immunization has resulted in the development of a T cell memory response directed against tumor specific proteins. Theoretically an effective cancer vaccine will result in the generation of immunologic memory and this memory T cell response, if effective, would potentially be able to prevent disease relapse. The specific aims of this proposal are to: (1) evaluate the safety and measure the extent of immunogenicity of HER2 ICD plasmid based DNA vaccination in patients with advanced stage HER2 overexpressing breast and ovarian cancer, (2) determine whether HER2 specific T cell memory occurs after active immunization with a HER2 ICD plasmid based vaccine, and (3) determine if prolonged local antigen expression is associated with the development of HER2 specific memory T cell response after immunization.