ANTIBODY MEDIATED T CELL RECOGNITION FOR CANCER THERAPY

本申请的主要目的是 开发新的免疫策略来增强免疫破坏 并确定这些免疫反应的作用机制。的 本申请人将关注耐受性对细胞的调节的影响， 免疫系统对抗肿瘤抗原。他的目标是描述T细胞 在耐受宿主中对自身抗原具有抗肿瘤反应性的库， 来激活免疫T细胞库以诱导肿瘤的根除。 为此，他将使用Her-2/neu转基因小鼠（MMTV-neu）， 对neu抗原耐受。由于这种耐受性，这些小鼠具有低的 T细胞对neu抗原的亲和力。此外，MMTV-neu小鼠 患上自发性乳腺肿瘤在本申请的目的1中，申请人 将研究激活MMTV-neu小鼠免疫系统的策略 来消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融合蛋白以激活和 增强低亲合力T细胞对neu抗原的效应子功能。 在目标2中，申请人将评估耐受性对 用于肿瘤消除的肽疫苗的开发以及如何克服这种困难 宽容为此，他将使用A2/neu小鼠并检查是否 A2-Her-2/neu限制性肽可以防止这些动物中的肿瘤生长。在 此外，他还将评估肽疫苗接种是否可以用 抗Her-2/neu-IL-2融合蛋白。在目标3中，他将研究 自身耐受可以消除或阻止T细胞成为记忆T细胞。 申请方将评估免疫干预后， 抗Her-2/neu-IL-2加抗Her-2/neu-GM-CSF或肽疫苗加 抗-Her-2/neu-IL-2有可能产生记忆T细胞应答 能够防止MMTV-neu小鼠中复发肿瘤的生长。总的来说， 此应用程序旨在了解启动的要求， 在耐受的宿主中保持有效的抗肿瘤应答。成功 这些研究的完成将为了解 涉及自身肿瘤抗原的免疫反应，以及如何最好地 使用免疫策略来治疗癌症， 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.