T-Cell Independent Antitumor Mechanisms of CD40 Ligation

CD40 连接的 T 细胞非依赖性抗肿瘤机制

• 批准号: 6773145
• 负责人: PAUL M SONDEL
• 金额: $ 25.9万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-01 至 2006-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6773145
• 关键词: CD40 molecule; Listeria; MHC class I antigen; T lymphocyte; adenocarcinoma; antigen presenting cell; antitumor antibody; cytokine receptors; dendritic cells; gene targeting; genetically modified animals; immunocytochemistry; laboratory mouse; leukocyte activation /transformation; macrophage; melanoma; monoclonal antibody; natural killer cells; neoplasm /cancer immunology; neoplasm /cancer immunotherapy; neoplasm /cancer vaccine; neoplastic cell; neutralizing antibody; nitric oxide; nonhuman therapy evaluation; tumor antigens

Stimulation of antigen-presenting cells through their CD40 receptors can induce antitumor T cell responses in some murine tumor models. We have recently shown that an agonistic anti-CD40 mAb can also induce antitumor effects via activation of natural killer (NK) cells, even in the absence of T cells. Our preliminary results suggest that macrophages activated via CD40 ligation may also kill tumor cells in vivo. We also hypothesize that the T cells or NK cells activated by CD40 ligation will cause augmented antitumor destruction when combined with immunotherapeutic reagents designed to activate antitumor T cells (tumor vaccines) or NK cells (immunocytokine fusion proteins), respectively. The purpose of this project is to determine the mechanisms inducing T cell dependent or T cell independent antitumor effects in response to anti-CD40 mAb treatment, identify the specific cells and cytokines involved in these responses, and evaluate the adjuvant antitumor efficacy of anti- CD40 mAb when combined with other forms of immunotherapy. Specifically, we will accomplish this through the following 3 aims: 1. Determine the mechanisms accounting for preferential activation of T cells or NK cells in response to anti-CD40 mAb. 2. Evaluate NK cell and macrophage-mediated mechanisms of antitumor effects induced by anti-CD40 mAb. 3. Determine the role of anti-CD40 mAb in augmenting effects of immunotherapies against poorly immunogenic tumors. Together, these studies will characterize the novel, T cell-independent mechanisms of the antitumor effects induced by anti-CD40 mAb. Furthermore, they will determine how anti-CD40 mAb-activated cells may be used to further augment the antitumor effects of tumor vaccines and mAb-IL2 fusion proteins. These results may be directly implemented into the design of clinical trials potentially combining CD40 ligation with different forms of immunotherapy.

通过 CD40 受体刺激抗原呈递细胞可以在一些小鼠肿瘤模型中诱导抗肿瘤 T 细胞反应。 我们最近发现，即使在没有 T 细胞的情况下，激动性抗 CD40 mAb 也可以通过激活自然杀伤 (NK) 细胞来诱导抗肿瘤作用。 我们的初步结果表明，通过 CD40 连接激活的巨噬细胞也可能在体内杀死肿瘤细胞。 我们还假设，当分别与旨在激活抗肿瘤 T 细胞（肿瘤疫苗）或 NK 细胞（免疫细胞因子融合蛋白）的免疫治疗试剂结合时，通过 CD40 连接激活的 T 细胞或 NK 细胞将导致增强的抗肿瘤破坏。 该项目的目的是确定抗 CD40 mAb 治疗诱导 T 细胞依赖性或 T 细胞非依赖性抗肿瘤作用的机制，识别参与这些反应的特定细胞和细胞因子，并评估抗 CD40 mAb 的辅助抗肿瘤功效mAb 与其他形式的免疫疗法联合使用。具体来说，我们将通过以下 3 个目标来实现这一目标： 1. 确定 T 细胞或 NK 细胞响应抗 CD40 mAb 优先激活的机制。 2. 评估抗CD40 mAb 诱导的NK 细胞和巨噬细胞介导的抗肿瘤作用机制。 3. 确定抗 CD40 mAb 在增强针对免疫原性较差的肿瘤的免疫疗法中的作用。 这些研究将共同​​描述抗 CD40 mAb 诱导的抗肿瘤作用的新型、独立于 T 细胞的机制。此外，他们还将确定如何使用抗 CD40 mAb 激活细胞进一步增强肿瘤疫苗和 mAb-IL2 融合蛋白的抗肿瘤效果。 这些结果可以直接应用到可能将 CD40 连接与不同形式的免疫疗法相结合的临床试验的设计中。