Ex vivo expansion of HER-2/neu specific T helper cells

描述（由申请人提供）：在小鼠模型中，已显示出抗肿瘤T细胞疗法可有效根除肿瘤。然而，这种治疗策略尚未成功地转化为临床治疗人类恶性肿瘤。大多数研究集中在输注细胞毒性T淋巴细胞（CTL）的治疗。虽然CTL已经显示在输注后是有功能的，但是由于包括寿命短的许多原因，它们根除肿瘤的能力降低。辅助性T细胞（Th）的伴随激活是CTL持续存在所必需的。事实上，Th细胞输注单独可以激活内源性CTL免疫。Th细胞的2种主要亚型是Thl和Th 2。Th 1细胞引起CTL免疫，Th 2细胞引起B细胞免疫。目前赫赛汀的临床应用证明了体液免疫对癌症的重要性。基于这些观察，假设Th的过继性T细胞疗法可以是治疗HER-2/neu过表达的人乳腺恶性肿瘤的有效疗法。然而，Th过继性T细胞治疗的许多原理仍然未知。临床相关的小鼠模型（neu转基因小鼠）可用于确定这些原则。此外，最近的研究表明，肿瘤特异性Th细胞可以从HER-2/neu过表达癌症患者体内扩增。 该提案概述了建立Th 1和Th 2 T辅助细胞输注在鼠模型中根除neu过表达肿瘤中的作用所需的临床前研究，并将鉴定在扩增HER 2特异性Th细胞同时保留抗原特异性功能最有效的培养条件。这项建议的具体目标是：（1）为了检测过继转移的Th 1和Th 2 CD 4 T细胞对neu转基因小鼠中neu介导的肿瘤的治疗功效，和（2）为了确定用于从HER 2-T患者的血液中优先扩增抗原特异性Th 1 T细胞或Th 2 T细胞的最佳培养条件，过表达癌症所提出的研究的结果将导致HER 2特异性过继免疫疗法用于治疗晚期HER 2过表达恶性肿瘤的I期试验。

DESCRIPTION (provided by applicant): Adoptive T cell therapy has been shown to be effective at eradicating tumors in murine models. Yet, this therapeutic strategy has not been successfully translated to the clinic to treat human malignancy. Most studies have focused on therapy with infusion of cytotoxic T lymphocytes (CTL). While CTL have been shown to be functional following infusion, their capabilities of eradicating tumor are diminished due to a number of reasons including a short life span. Concomitant activation of the T helper cell (Th) is necessary for a CTL persistence. In fact, Th cell infusions alone can activate endogenous CTL immunity. The 2 predominant subtypes of Th cells are Thl and Th2. Thl cells elicit CTL immunity and Th2 cells elicit B cell immunity. The importance of humoral immunity against cancer is evident by the current clinical use of Herceptin. Based on these observations, it is hypothesized that adoptive T cell therapy of Th can be an effective therapy for the treatment of HER-2/neu-overexpressing human breast malignancies. Yet many of the principles of adoptive T cell therapy with Th remain unknown. A clinically relevant mouse model (neu-transgenic mouse) is available to identify these principles. Furthermore, studies have recently demonstrated that tumor-specific Th cells can be expanded ex vivo from patients with HER-2/neu-overexpressing cancers. This proposal outlines the pre-clinical studies needed to establish the role of Thl and Th2 T helper cell infusion in the eradication of neu-overexpressing tumors in a murine model and will identify the culture conditions most effective in expanding HER2-specific Th cells while retaining antigen-specific function. The specific aims of this proposal are: (1) To examine the therapeutic efficacy of adoptively transferred Thl and Th2 CD4 T cells against neu-mediated tumors in the neu-transgenic mouse, and (2) To determine optimal culture conditions for preferential expansion of antigen-specific Thl T cells or Th2 T cells from the blood of patients with HER2-overexpressing cancers Results from the proposed studies will lead to a Phase I trial of HER2-specific adoptive immunotherapy for the treatment of advanced stage HER2 overexpressing malignancies.