T Cell Memory After Immunization with a HER2 DNA Vaccine

描述（由申请人提供）：治疗晚期乳腺癌和卵巢癌患者的一个主要临床问题是复发风险。 大多数被诊断为高风险或更晚期癌症的患者，尽管通过标准治疗如手术和化疗使疾病消失，但仍会复发。 癌症疫苗提供了一种独特的治疗策略，可以预防癌症复发，甚至根除微转移性疾病。 在过去的十年中，肿瘤免疫学的一些进展导致了对癌症疫苗的重新关注;特异性肿瘤抗原的定义，对乳腺癌和卵巢癌等癌症具有免疫原性的理解，以及可以使患者有效地对“自身”肿瘤抗原免疫的技术的发展。 我们的小组一直在开发基于质粒的DNA疫苗，作为一种方法，可能是有效的免疫患者对多种抗原表达在他们的肿瘤。 将编码肿瘤抗原的质粒与增强局部皮肤树突细胞募集的可溶性细胞因子一起皮内递送，从而显著改善该方法的免疫原性，这导致在HER 2过表达乳腺癌和卵巢癌患者中开发了靶向HER-2/neu（HER 2）致癌蛋白的基于质粒的疫苗的I期临床研究。 本临床研究旨在确定DNA免疫的安全性和免疫原性。 本提案中概述的实验将确定是否可以在主动免疫后产生针对HER 2抗原的免疫记忆。 癌症疫苗的几项临床试验已经证明，癌症患者可以免疫以产生可检测的免疫力。 我的目标将是免疫是否导致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，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。 这项建议的具体目标是：（1）评估基于HER 2 ICD质粒的DNA疫苗接种在患有晚期HER 2过表达乳腺癌和卵巢癌的患者中的安全性并测量其免疫原性程度，（2）确定在用基于HER 2 ICD质粒的疫苗主动免疫后是否发生HER 2特异性T细胞记忆，和（3）确定延长的局部抗原表达是否与免疫后HER 2特异性记忆T细胞应答的发展相关。

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.