Targeting Early Activated T cells for Adoptive Therapy

针对早期激活的 T 细胞进行过继治疗

• 批准号: 7729347
• 负责人: DAVID J COLE
• 金额: $ 25.93万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-07-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7729347
• 关键词: Address; Affect; Antigen Presentation; Antigen-Presenting Cells; Antigens; Avidity; CD8B1 gene; Cell Communication; Cell Survival; Cells; Clinical; Cyclophosphamide; Dendritic Cells; Development; Effectiveness; Environment; Frequencies; Funding Mechanisms; Generations; Goals; Immunotherapy; In Vitro; Interleukin-12; Length; Lymphocyte Homing Receptors; Lymphoid; Lymphopenia; MAP Kinase Signaling Pathways; Memory; Modeling; Patients; Phagocytosis; Phase; Phenotype; Protocols documentation; Signal Transduction; Staging; T memory cell; T-Lymphocyte; Telomerase; Testing; Titrations; Tumor Immunity; Vaccines; base; cancer therapy; conditioning; design; early experience; experience; in vivo; insight; interest; lymph nodes; melanoma; novel; peripheral blood; preconditioning; response; trafficking; tumor

Effective anti-tumor immunity requires the generation and persistence of functional, high avidity tumor-specific effector and memory T cells. Among the critical factors that often control this response is the activation/differentiation state of the relevant effector T-cells. We have made the singular observation that IL- 12 conditioning during in vitro priming is able to promote the acquisition of a central memory (Tcm) like phenotype in antigen-specific T cells. These “early activated” T (TEA) cells are characterized by increased expression of lymph node (LN) homing receptors, robust proliferation in vitro, an augmented survival, and increased anti-tumor activity in vivo. We have also recently observed that cyclophosphamide (CTX) preconditioning induces expansion of immature DCs mainly in the peripheral blood during the rebound phase which is associated with highly effective anti-tumor responses in vivo. With an interest in capitalizing on the combined potential of these observations, we hypothesize that the enhanced survival and function of IL- 12 pre-conditioned TEA cells will result in the generation of more effective anti-tumor immunity when combined with a surging frequency of circulating DCs. To test this hypothesis we propose to define how IL-12 pre-conditioning enhances T-cell survival and function (looking at co-stimulation signature, survival signaling, and impact on functional avidity) and define the TEA cell response to antigen presentation in a DC rich environment (looking specifically at the contribution of secondary lymphoid compartments. The ability to understand and harness the combined potential of early activated T cell generation and robust circulating DC induction could serve to synergistically augment in the generation of an effective anti-tumor response in vivo. The two year ARRA funding mechanism will allow us to address the first aspect of this goal by defining how IL-12 conditioning enhances antigen experienced T-cell survival and function.

有效的抗肿瘤免疫需要功能性、高亲和力肿瘤特异性效应和记忆T细胞的产生和持续存在。通常控制这种应答的关键因素是相关效应T细胞的活化/分化状态。我们已经进行了独特的观察，即在体外引发期间IL- 12调节能够促进抗原特异性T细胞中的中枢记忆（Tcm）样表型的获得。这些“早期活化的”T（TEA）细胞的特征在于淋巴结（LN）归巢受体的表达增加、体外稳健增殖、存活增加和体内抗肿瘤活性增加。我们最近还观察到，环磷酰胺（CTX）预处理诱导扩增的未成熟的DC主要在外周血中的反弹阶段，这是与高效的抗肿瘤反应在体内。有兴趣利用这些观察结果的组合潜力，我们假设IL- 12预处理的TEA细胞的增强的存活和功能将导致在与循环DC的激增频率组合时产生更有效的抗肿瘤免疫。为了验证这一假设，我们提出定义IL-12预处理如何增强T细胞存活和功能（观察共刺激信号、存活信号传导和对功能亲合力的影响），并定义TEA细胞对富含DC的环境中抗原呈递的应答（特别观察次级淋巴区室的贡献）。理解和利用早期活化T细胞产生和稳健循环DC诱导的组合潜力的能力可以协同增强体内有效抗肿瘤应答的产生。为期两年的ARRA资助机制将使我们能够通过定义IL-12调节如何增强抗原经历的T细胞存活和功能来解决这一目标的第一个方面。