ANTIBODY MEDIATED T CELL RECOGNITION FOR CANCER THERAPY

描述：(申请人摘要)本申请的主要目的是 开发新的免疫治疗策略以加强免疫破坏 并确定这些免疫反应的作用机制。这个 申请者将专注于耐受性对调节 针对肿瘤抗原的免疫系统。他的目标是描述T细胞的特征 耐受宿主中自身抗原的抗肿瘤反应性谱系 激活这种免疫T细胞库，以诱导肿瘤被根除。 为此，他将使用Her-2/neu转基因小鼠(MMTV-neu) 对neu抗原有耐受性。由于这种耐受性，这些小鼠的 亲和力T细胞对抗Neu抗原的谱系。此外，MMTV-neu小鼠 发展为自发性乳腺肿瘤。在本申请的目标1中，申请人 将研究激活MMTV-neu小鼠免疫系统的策略 用于清除乳腺肿瘤。这些研究包括使用 抗HER-2/neu IL-2和抗HER-2/neu-GM-CSF融合蛋白激活和 增强低亲和力T细胞对抗neu抗原的效应功能。 在目标2中，申请者将评估容忍对 肿瘤清除多肽疫苗的发展及克服途径 宽容。为此，他将使用A2/neu小鼠并检查 A2-HER-2/neu限制性多肽可以防止这些动物的肿瘤生长。在……里面 此外，他将评估多肽疫苗接种是否可以通过 抗HER-2/neu-IL-2融合蛋白。在《目标3》中，他将考察 自我耐受可能会消除或阻止T细胞成为记忆性T细胞。 申请者将评估在进行免疫干预后 抗HER-2/neu-IL-2加抗HER-2/neu-GM-CSF或多肽疫苗加 抗HER-2/neu-IL-2可产生记忆性T细胞反应 能够防止MMTV-neu小鼠复发肿瘤的生长。总的来说， 此应用程序旨在了解启动的要求和 在耐受性宿主中保持有效的抗肿瘤反应。成功 这些研究的完成将为理解 针对自身肿瘤抗原的免疫反应以及如何最好地 使用免疫治疗策略来治疗癌症 抗原。

DESCRIPTION: (Applicant's Abstract) The major objective of this application is to develop novel immunotherapeutic strategies to augment the immune destruction of tumors and to define the mechanism of action of these immune responses. The applicant will focus on the impact that tolerance has on modulation of the immune system against tumor antigens. His goal is to characterize the T cell repertoire with antitumor reactivity for self-antigens in a tolerant host and to activate this immune T cell repertoire to induce the eradication of tumors. Toward this end, he will use Her-2/neu transgenic mice (MMTV-neu) that are tolerant to neu antigens. As result of this tolerance these mice have a low avidity T cell repertoire against neu antigens. In addition, the MMTV-neu mice develop spontaneous mammary tumors. In Aim 1 of this application, the applicant will examine strategies to activate the immune repertoire of the MMTV-neu mice for elimination of the mammary tumors. These studies include the use of anti-Her-2/neu IL-2 and anti-Her-2/neu-GM-CSF fusion proteins to activate and augment the effector function of the low avidity T cells against neu antigens. In Aim 2, the applicant will evaluate the impact that tolerance has on the development of peptide-vaccines for tumor elimination and how to overcome such tolerance. To this end, he will use the A2/neu mice and examine whether A2-Her-2/neu-restricted peptides can prevent tumor growth in these animals. In addition he will evaluate whether peptide-vaccination can be boosted with anti-Her-2/neu-IL-2 fusion protein. In Aim 3, he will examine whether self-tolerance may eliminate or prevent T cells from becoming memory T cells. The applicant will assess whether following immunointervention with anti-Her-2/neu-IL-2 plus anti-Her-2/neu-GM-CSF or peptide vaccines plus anti-Her-2/neu-IL-2 would be possible to generate a memory T cell response capable of preventing the growth of recurring tumors in MMTV-neu mice. Overall, this application intends to learn about the requirements for initiation and perpetuation of an effective antitumor response in tolerized hosts. Successful completion of these studies will add new information for understanding of immunological responses involved against self-tumor antigens and how best to use immunotherapeutic strategies for the treatment of cancer against such antigens.