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.

恶性血液病的免疫治疗是一种快速发展的根除化疗和/或放疗后残留疾病的方法。正常蛋白、融合蛋白和许多点突变的异常表达已被确定与血液恶性肿瘤相关，这表明有多种潜在的免疫治疗靶点。然而，许多人类恶性肿瘤被认为诱发一种免疫“耐受”状态，使免疫方法无效。在之前的研究中，我们使用了使用趋化因子的效应细胞募集结合使用共刺激配体的特异性t细胞激活的组合方法，成功地根除了小鼠模型中预先存在的t细胞淋巴瘤。我们的目标是使用免疫原性较低的b细胞淋巴瘤模型进一步发展这一策略，其中耐受性的发展是免疫治疗的主要障碍。我们将探索使用三种组成表达的趋化因子，特别是sdf -1 β， DC-CK1和SLC，优先招募未通过先前暴露于肿瘤相关抗原而呈现无能的幼稚t细胞的效用。这些趋化因子将被单独研究或与CD40L共刺激分子联合使用。我们将尝试通过招募更多的初始T细胞，然后将招募的T细胞暴露于表达CD40L共刺激分子的肿瘤细胞，来克服在缺乏共刺激信号的情况下暴露于肿瘤细胞所诱导的T细胞能量。我们将使用单纯疱疹扩增子载体，这种载体在我们的实验室中已经广泛使用，并且在体内基因转移和表达方面效率很高。我们将在A20小鼠b细胞淋巴瘤模型中研究趋化因子转导引起的免疫浸润的组成和进化，以及趋化因子单独使用和/或与CD40L联合使用时的抗肿瘤活性。利用对流感血凝素抗原（HA）具有特异性的转基因t细胞和HA抗原通过A20 b细胞呈递的模型系统（A20-HA），我们将正式测试对HA靶抗原的免疫耐受是否可以通过选择性募集和共同刺激初始t细胞群来克服。趋化因子给药的最佳剂量和时间顺序将在为潜在的I期试验做准备时确定。