TUMOR THERAPY WITH ADOPTIVELY TRANSFERRED CD4 CELLS

描述：（申请人摘要） 免疫致敏的T淋巴细胞可以根除已建立的 恶性肿瘤的动物模型。 然而，不一致的结果一直是 在过继性免疫治疗的临床试验中取得的成果。 申请人已经 专注于从携带肿瘤的宿主中分离治疗性T细胞， 因为这与过继免疫疗法的翻译直接相关， 人体临床试验 T细胞可以从引流淋巴结中分离出来， 能够介导肿瘤消退的进行性生长肿瘤 收养转移。 最近，他发现了一群CD 4 T细胞， 可以介导已建立的MHC II类消退的细胞 阴性肿瘤 这些CD 4 T细胞在每个细胞的基础上更有效， 比以前分离的肿瘤反应性T细胞的肿瘤根除。 的 假设CD 4 T细胞是有效的抗肿瘤效应细胞。 这是 通过研究开发，治疗反应性和效应器来探索 肿瘤反应性CD 4 T细胞的机制，因为这一知识可以提供 人类过继免疫疗法的改进。 具体目标1研究 CD 4 L-选择素- T细胞对脑、肺和 皮下肿瘤，并研究了CD 28和CD 40 L相互作用在肿瘤中的作用。 这些CD 4 T细胞的发展。 CD 4 L-选择素-T细胞可以 消除肿瘤刺激后分泌的IL-2、IFN-g和IL-10， 因此可能不是完全分化的（Th 0），或者可能是 Th 1和Th 2型细胞的混合物。 因此，具体目标2调查 细胞因子分化的CD 4 T细胞和CD 4 T细胞克隆 根除肿瘤，以进一步确定T细胞是负责肿瘤 淘汰 在大量培养的淋巴结T细胞中，IFN-g是 消除肺部肿瘤，而穿孔素是必要的， 消除皮下肿瘤。 CD 4 T细胞所使用的效应分子 细胞消除肿瘤的作用尚未阐明， 穿孔素、IFN-γ和FASL通过适应性转移的CD 4根除肿瘤 在特定目标3中研究了T细胞。

DESCRIPTION: (Applicant's abstract) The adoptive transfer of immunologically sensitized T lymphocytes can eradicate established malignancy in animal models. However, inconsistent results have been achieved in clinical trials of adoptive immunotherapy. The applicant has focused on the isolation of therapeutic T cells from the tumor-bearing host, as this has direct relevance for translation of adoptive immunotherapy to human clinical trials. T cells can be isolated from lymph nodes draining a progressively growing tumor that are able to mediate the regression of tumor upon adoptive transfer. Recently he has identified a population of CD4 T cells that can mediate the regression of an established MHC class II negative tumor. These CD4 T cells are more potent on a per cell basis at tumor eradication than previously isolated tumor-reactive T cells. The hypothesis is that CD4 T cells are potent antitumor effector cells. This is explored by studying the development, therapeutic reactivity, and effector mechanisms of tumor-reactive CD4 T cells, as this knowledge may provide for improvements in human adoptive immunotherapy. Specific Aim 1 studies the therapeutic reactivity of CD4 L-selectin- T cells against brain, lung, and subcutaneous tumors, and studies the role of CD28 and CD40L interactions in the development of these CD4 T cells. The CD4 L-selectin-T cells that can eliminate tumor secrete IL-2, IFN-g, and IL-10 upon stimulation with tumor, and therefore may either not be fully differentiated (Th0), or may be a mixture of Thl and Th2 type cells. Therefore, Specific Aim 2 investigates the ability of cytokine differentiated CD4 T cells and CD4 T cell clones to eradicate tumor, to further define the T cell that is responsible for tumor elimination. In bulk cultured lymph node T cells, IFN-g is required for elimination of tumor in the lungs, while perforin is required for the elimination of subcutaneous tumor. The effector molecules used by CD4 T cells to eliminate tumor have not been elucidated, and the contribution of perforin, IFN-g, and FASL to tumor eradication by adaptively transferred CD4 T cells is investigated in Specific Aim 3.