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

描述（由申请人提供）：过继T细胞疗法已被证明在小鼠模型中有效根除肿瘤。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。大多数研究都集中在输注细胞毒性T淋巴细胞（CTL）的治疗上。虽然CTL已被证明在输注后具有功能，但由于许多原因，包括寿命短，它们根除肿瘤的能力减弱。辅助性T细胞（Th）的同时激活对于CTL的持久性是必要的。事实上，单独输注Th细胞可以激活内源性CTL免疫。Th细胞的两种主要亚型是Thl和Th2。Thl细胞引起CTL免疫，Th2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，我们假设过继T细胞治疗Th可能是治疗HER-2/ new过表达的人类乳腺恶性肿瘤的有效疗法。然而，Th的过继性T细胞疗法的许多原理仍然未知。临床相关的小鼠模型（新转基因小鼠）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/ new -过表达的癌症患者体内扩增。

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.