Integrating Innate & Adaptive Immunity in Cancer Therapy

整合先天

• 批准号: 7227417
• 负责人: NEJAT K EGILMEZ
• 金额: $ 28.66万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-05-21 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7227417
• 关键词: Address; Biodegradable microsphere; Cancer Patient; Cells; Complex; Development; Disease; Event; Granulocyte-Macrophage Colony-Stimulating Factor; Home environment; Immune; Immunity; Immunotherapeutic agent; Individual; Inflammatory; Inflammatory Response; Interleukin-12; Mediating; Microspheres; Modeling; Mus; NK Cell Activation; Natural Killer Cells; Neoplasm Metastasis; Nodule; Primary Neoplasm; Systemic disease; T memory cell; T-Lymphocyte; Testing; Tumor Immunity; base; cancer therapy; cytokine; cytotoxicity; design; insight; killings; response; tumor

DESCRIPTION (provided by applicant): The slow release of IL-12 and GM-CSF from biodegradable microspheres into a single primary tumor nodule promotes the development of potent systemic anti-tumor immunity and the complete eradication of disseminated tumor nodules in a metastatic murine tumor model. The immune mechanisms that mediate the eradication of systemic disease have not yet been defined in this model. Our hypothesis is that the local and sustained release of IL-12 and GM-CSF into the tumor microenvironment promotes the activation of the tumor-associated effector memory T-cells, which then initiate a cascade of local inflammatory events that result in the development of a systemic anti-tumor immunity. To this end, in Aim 1 we will phenotypically and functionally define the T cells that are present in the primary tumor microenvironment and characterize the downstream events that follow their activation. Studies proposed in Aim 2 will address the continuing hypothesis that the induction of inflammatory activity within the primary tumor will prime the development of a long-term systemic anti-tumor T-cell response that effectively infiltrates and suppresses metastatic tumors. Preliminary observations suggest that a systemic NKT/NK cell response is also involved in the suppression of metastatic tumors. In Aim 3 we will test the notion that activation of a systemic but transient NKT/NK response accompanies the early local immune events and that co-induction of innate and adaptive immunity is critical to effective eradication of systemic disease. Finally, in Aim 4 we will test the hypothesis that the intensity of the immediate effector memory T-cell response that is induced within the primary tumor microenvironment determines the efficacy of long-term cure in individual mice. The information derived from these studies is expected to provide valuable insights for the design of an effective, cytokine-based immunotherapeutic strategy for the treatment of cancer patients.

描述（由申请人提供）：IL-12和GM-CSF从可生物降解的微球缓慢释放到单个原发性肿瘤结节中，促进了有效的全身抗肿瘤免疫的发展，并完全根除转移性小鼠肿瘤中的播散性肿瘤结节模型。该模型尚未定义介导根除全身性疾病的免疫机制。我们的假设是，IL-12 和 GM-CSF 局部持续释放到肿瘤微环境中，促进了肿瘤相关效应记忆 T 细胞的激活，然后引发一系列局部炎症事件，导致肿瘤的发展。全身抗肿瘤免疫力。为此，在目标 1 中，我们将从表型和功能上定义原发肿瘤微环境中存在的 T 细胞，并表征其激活后的下游事件。目标 2 中提出的研究将解决一个持续的假设，即原发性肿瘤内炎症活动的诱导将促进长期全身性抗肿瘤 T 细胞反应的发展，从而有效地渗透和抑制转移性肿瘤。 初步观察表明，全身性 NKT/NK 细胞反应也参与了转移性肿瘤的抑制。在目标 3 中，我们将测试这样的概念：系统性但短暂的 NKT/NK 反应的激活伴随着早期局部免疫事件，并且先天性和适应性免疫的共同诱导对于有效根除全身性疾病至关重要。最后，在目标 4 中，我们将检验以下假设：原发性肿瘤微环境中诱导的即时效应记忆 T 细胞反应的强度决定了个体小鼠的长期治愈效果。从这些研究中获得的信息预计将为设计有效的、基于细胞因子的免疫治疗策略来治疗癌症患者提供有价值的见解。