IMMUNOTHERAPY OF BREAST CANCER WITH TUMOR ANTIGEN SPECIFIC CYTOTOXIC T CELLS

这一提议是基于这样一个前提，即一个有效的细胞 对“非免疫原性”自发性乳房的免疫应答 肿瘤相关抗原(TAA)的激活可诱发肿瘤 特异性细胞毒性T淋巴细胞(CTL)。我们已经在体外证明了 我们可以从浸润性淋巴细胞中激活和扩增TAA特异性CTL 人类乳腺癌。过继免疫治疗的实用方面 如果CTL前体(CTLp)能够 从患者外周血单个核细胞(PBMC)中提取 而不是肿瘤浸润性淋巴细胞(TIL)，因为可获得性有限 后者。为了将这种治疗方式应用于人类使用，我们有 使用一种新的基因传递系统开发的方法，允许 自体TAA特异性CTL的激活和体外扩增 刺激细胞。初步研究将检查PBMC群体中的 存在抗HBR2/neu和抗MAGE-I CTL。基于相对的 用极限稀释法测定这些TAA特异性CTL的频率 (LDA)存在于PBMC中，第二系列实验将寻求 通过特定细胞提高整体外周CTL反应性 表达HER2/neu或MAGE-L的金丝雀痘构建体免疫小鼠 I期临床试验的背景。这项提案的总体目标是 是开发和执行免疫疗法的I期临床研究 体外激活和扩增自体TAA特异性CTL的研究 并提供了TAA的有效性分析 用客观的免疫表型和功能标志物检测特异性CTL 反应性。然后，我们建议在#年开展II期临床试验。 大剂量细胞减量治疗后肿瘤负担最小的患者 化疗和自体骨髓移植(ABMT) 来自第一阶段研究的临床和生物学数据。建议的临床 试验由杜克多学科乳房诊所 杜克大学骨髓移植计划和杜克大学肿瘤学联盟 旨在实施新疗法的临床试验 策略和确保有足够数量的病人 乳腺癌符合这项研究的条件。

This proposal is based upon the premise that an effective cell mediated immune response against "non-immunogenic" spontaneously arising breast tumors can be elicited by activation of tumor associated antigen (TAA) specific cytotoxic T lymphocytes (CTL). We have demonstrated in vitro that we can activate and expand TAA specific CTL from lymphocytes infiltrating human breast carcinomas. The practical aspects of adoptive immunotherapy with CTL would be greatly enhanced if CTL precursors (CTLp) could be harvested from patient peripheral blood mononuclear cells (PBMC) rather than tumor infiltrating lymphocytes (TIL) due to the limited availability of the latter. To apply this therapeutic modality to human use, we have developed methods using a novel gene delivery system that allows for activation and ex vivo expansion of TAA specific CTL using autologous stimulator cells. Initial studies will examine PBMC populations for the presence of anti-HBR2/neu and anti-MAGE-I CTL. Based on the relative frequency of these TAA specific CTL quantitated by limit dilution analysis (LDA) present in PBMC, the second series of experiments will seek to increase overall peripheral CTL reactivity by specific cellular immunization with canary pox constructs expressing HER2/neu or MAGE-l in the context of a phase I clinical trial. The overall goal of this proposal is to develop and perform phase I clinical studies of immunotherapy with ex vivo activated and expanded autologous TAA specific CTL in patients with breast cancer and provide an analysis of the effectiveness of TAA specific CTL using objective phenotypic and functional markers of immune reactivity. We then propose to develop phase II clinical trials in patients with minimal tumor burden following high dose cytoreductive chemotherapy and autologous bone marrow transplant (ABMT) based on the clinical and biologic data from the phase I study. The proposed clinical trials are facilitated by the Duke Multidisciplinary Breast Clinic, the Duke Bone Marrow Transplant Program and the Duke Oncology Consortium, which are designed to implement clinical trials of novel therapeutic strategies and insures the availability of an adequate number of patients with breast cancer eligible for this study.