CHEMOKINE ENHANCED IMMUNE THERAPY OF LYMPHOMA

趋化因子增强淋巴瘤的免疫治疗

• 批准号: 6514721
• 负责人: Joseph David Rosenblatt
• 金额: $ 31.24万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-05-01 至 2004-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6514721
• 关键词: Alphaherpesvirinae; B cell lymphoma; CD40 molecule; T lymphocyte; chemokine; genetically modified animals; immune tolerance /unresponsiveness; laboratory mouse; neoplasm /cancer immunotherapy; transfection /expression vector

Immunotherapy of hematologic malignancies is a rapidly evolving approach to eradication of residual disease following chemotherapy and/or radiation. Aberrant expression of normal proteins, fusion proteins and numerous point mutations have been identified in association with hematologic malignancies suggesting a variety of potential immmunotherapeutic targets. However, many human malignancies are believed to induce a state of immunological "tolerance" which renders immune approaches ineffective. In prior studies we have used the combined approach of effector cell recruitment using chemokines, in tandem with specific T-cell activation using costimulatory ligands to successfully eradicate pre-existing T-cell lymphoma in a mouse model. We aim to further develop this strategy using a less immunogenic B-cell lymphoma model, in which the development of tolerance poses a major barrier to immune based therapies. We will explore the utility of recruitment using three constitutively expressed chemokines, specifically, SDF-1beta, DC-CK1, and SLC, to preferentially recruit naive T-cells, which have not been rendered anergic through prior exposure to tumor associated antigens. The chemokines will be studied alone or when used in combination with the CD40L costimulatory molecule. We will attempt to overcome T- cell anergy induced by exposure to tumor cells in the absence of co-stimulatory signals through recruitment of an expanded repertoire of naive T-cells, followed by exposure of the recruited T-cells to tumor cells which express the CD40L costimulatory molecule. We will use Herpes Simplex amplicon vectors, which have been extensively used in our laboratory and which are highly efficient for purposes of gene transfer and expression in vivo. We will study the composition and evolution of immune infiltrates resulting from chemokine transduction and the antitumor activity of the chemokines when used alone and/or in combination with CD40L in the A20 murine B-cell lymphoma model. Using transgenic T-cells with specificity for the influenza Hemagglutinin antigen (HA) and a model system in which HA antigens are presented via A20 B-cells, (A20-HA) we will formally test whether immunologic tolerance to the HA target antigen can be overcome through selective recruitment and costimulation of a naive T-cell population. Optimal dosage and temporal sequencing of chemokine administration will be ascertained in preparation for potential Phase I trials.

血液系统恶性肿瘤的免疫疗法是一种迅速发展的方法，可以消除化学疗法和/或放射后残留疾病。 正常蛋白，融合蛋白和许多点突变的异常表达与血液学恶性肿瘤有关，表明各种潜在的免疫疗法靶标。但是，人们认为许多人类恶性肿瘤会引起免疫“耐受性”状态，从而使免疫方法无效。在先前的研究中，我们使用趋化因子使用了效应细胞募集的组合方法，并使用共刺激配体进行特定的T细胞激活，以成功地消除小鼠模型中预先存在的T细胞淋巴瘤。 我们旨在使用不太免疫原性的B细胞淋巴瘤模型进一步制定这种策略，在这种模型中，耐受性的发展为免疫疗法带来了主要障碍。 我们将使用三种组成型表达的趋化因子，特别是SDF-1BETA，DC-CK1和SLC探索募集的实用性，以优先募集幼稚的T细胞，这些T细胞尚未通过事先暴露于肿瘤相关的抗原的事先暴露而厌食。 趋化因子将单独研究或与CD40L共刺激分子结合使用时。 我们将尝试通过募集扩大的幼稚T细胞的曲目，然后将招募的T细胞暴露于表达CD40L costimulatory Molecule的肿瘤细胞中，然后将肿瘤细胞暴露在没有共刺激信号的情况下，以克服暴露于肿瘤细胞引起的T细胞消极。 我们将使用单纯疱疹扩增子向量，这些载体已在我们的实验室中广泛使用，并且在体内基因转移和表达的目的高度有效。我们将研究由趋化因子转导引起的免疫浸润的组成和演变，以及单独使用和/或与CD40L在A20鼠B细胞淋巴瘤模型中使用时趋化因子的抗肿瘤活性。 使用具有特异性的转基因T细胞对流感血凝素抗原（HA）和模型系统，并通过A20 B细胞（A20-HA）呈现HA抗原的模型系统，我们将正式测试是否可以通过选择性的招募和成本率对HA目标抗原的免疫学耐受性来胜过HA目标抗原。 为潜在的I期试验做准备，将确定趋化因子给药的最佳剂量和时间测序。