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，过继T细胞疗法已被证明在根除肿瘤方面有效。然而，这种治疗策略还没有成功地转化到临床上来治疗人类恶性肿瘤。大多数研究都集中在细胞毒性T淋巴细胞(CTL)输注治疗上。虽然CTL在输注后被证明是有功能的，但由于许多原因，包括生命周期短，它们根除肿瘤的能力会减弱。伴随的T辅助细胞(Th)的激活对于CTL的持久性是必要的。事实上，单是Th细胞输注就可以激活内源性CTL免疫。Th细胞的两个主要亚型是Th1和Th2。Th1细胞诱导CTL免疫，Th2细胞诱导B细胞免疫。目前赫赛汀的临床应用证明了抗癌体液免疫的重要性。基于这些观察，我们推测Th过继T细胞疗法可能是治疗HER-2/neu过表达的乳腺癌的一种有效方法。然而，Th过继T细胞治疗的许多原则仍不清楚。一种临床相关的小鼠模型(neu转基因小鼠)可以用来确定这些原理。此外，最近的研究表明，HER-2/neu过表达的癌症患者的肿瘤特异性Th细胞可以在体外扩增。 这项建议概述了在小鼠模型中建立Th1和Th2T辅助细胞输注在根除neu过度表达肿瘤中的作用所需的临床前研究，并将确定在保留抗原特异性功能的同时扩增HER2特异性Th细胞的最有效的培养条件。这项建议的具体目的是：(1)检测过继转移的Th1和Th2 CD4 T细胞对neu转基因小鼠neu介导肿瘤的治疗效果，以及(2)确定从HER2过表达癌症患者的血液中优先扩增抗原特异性Th1 T细胞或Th2 T细胞的最佳培养条件。

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.