ATLR 9 AGONIST, COMBINED WITH LOCAL RADIATION IN RECURRENT LOW-GRADE LYMPHOMAS

ATLR 9 激动剂结合局部放射治疗复发性低度淋巴瘤

• 批准号: 7605212
• 负责人: Ronald Levy
• 金额: $ 4.45万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-02-15 至 2007-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7605212
• 关键词: Agonist; Animals; Antigen Presentation; Apoptosis; Bacterial DNA; Binding; Cell physiology; Clinical; Clinical Trials; Collection; Combined Modality Therapy; Computer Retrieval of Information on Scientific Projects Database; DNA Vaccines; Data; Dendritic Cell Vaccine; Dendritic Cells; Dose; Event; Funding; Grant; Human; Immune; Immune response; Inflammation; Inflammatory Response; Injection of therapeutic agent; Institution; Laboratories; Low Dose Radiation; Lymphoma; Malignant Neoplasms; Malignant neoplasm of prostate; Modality; Modeling; Mus; Necrosis; Oligonucleotides; Patients; Phase; Process; Property; Proteins; Radiation; Radiation therapy; Recruitment Activity; Recurrence; Research; Research Personnel; Resources; Series; Signal Transduction; Site; Source; Subcutaneous Injections; Treatment Protocols; Tumor Antigens; United States National Institutes of Health; base; lymph nodes; melanoma; neoplastic cell; novel strategies; preclinical study; tumor

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Lymphomas, particularly low-grade lymphomas, are among the most immune-responsive of all human cancers. Besides protein and DNA vaccines, another approach proved to be effective is to employ dendritic cells. Clinical trials with dendritic cell vaccines yielded promising results in patients with lymphoma, melanoma and prostate cancer. However, dendritic cell vaccines require collection and ex vivo manipulation of dendritic cells, which are expensive and cumbersome. To circumvent the need for collecting and processing dendritic cells ex vivo, we developed a novel approach to combine low-dose radiation with intratumoral injection of CpG-oligonucleotides (a bacterial DNA motif which binds to TLR9) to elicit immune response to the tumor. The rationale is that radiotherapy triggers tumor necrosis, apoptosis and inflammatory responses. These events, in turn, act as "danger signals" that recruit dendritic cells to sites of inflammation. At the site of inflammation, dendritic cells process tumor-associated antigens (provided by necrosis/apoptosis of tumor cells), undergo maturation and migrate to draining lymph nodes, where they elicit immune response to tumor-antigens. Intrarumoral injection of CpG-oligonucleotides will augment the immune response by recruiting dendritic cells to the tumor site. Furthermore, CpG-oligonucleotides enhance the antigen presentation property of dendritic cells. This new combination approach has been validated in a murine lymphoma model in our laboratory, where tumor-bearing animals were treated with radiation plus intratumoral injection of CpG. Our results showed that this regimen was effective in eradicating established tumor in tumor-bearing mice. Furthermore, the combination therapy was more efficacious than either modality alone. The results of our exciting pre-clinical studies formed the basis of the current clinical investigation. Low-dose radiotherapy has been routinely used in treatment of low-grade lymphoma. Subcutaneous injections of CpG are well tolerated as demonstrated in a series of clinical trails. Based on these data, we propose a Phase I/II study combining local radiation with intratumoral injection of CpG in recurrent low-grade lymphomas. Our primary objective is to evaluate the feasibility of the combination therapy; and secondary objectives are to evaluate the anti-lymphoma effect of this regimen and to evaluate tumor-specific immune response of patients treated with this regimen.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 淋巴瘤，特别是低度淋巴瘤，是所有人类癌症中免疫反应性最强的一种。 除了蛋白质和 DNA 疫苗外，另一种被证明有效的方法是使用树突状细胞。 树突状细胞疫苗的临床试验在淋巴瘤、黑色素瘤和前列腺癌患者中取得了有希望的结果。 然而，树突状细胞疫苗需要收集和离体操作树突状细胞，这是昂贵且繁琐的。 为了避免离体收集和处理树突状细胞的需要，我们开发了一种新方法，将低剂量辐射与瘤内注射 CpG 寡核苷酸（一种与 TLR9 结合的细菌 DNA 基序）相结合，以引发对肿瘤的免疫反应。 其基本原理是放疗会引发肿瘤坏死、细胞凋亡和炎症反应。 这些事件反过来又充当“危险信号”，将树突状细胞招募到炎症部位。 在炎症部位，树突状​​细胞处理肿瘤相关抗原（由肿瘤细胞坏死/凋亡提供），成熟并迁移到引流淋巴结，在那里引发针对肿瘤抗原的免疫反应。 瘤内注射 CpG 寡核苷酸将通过将树突状细胞募集到肿瘤部位来增强免疫反应。 此外，CpG-寡核苷酸增强树突状细胞的抗原呈递特性。 这种新的组合方法已在我们实验室的小鼠淋巴瘤模型中得到验证，其中荷瘤动物接受放射加 CpG 瘤内注射治疗。 我们的结果表明，该方案可有效根除荷瘤小鼠体内已形成的肿瘤。 此外，联合疗法比单独使用任何一种疗法都更有效。 我们令人兴奋的临床前研究结果构成了当前临床研究的基础。 低剂量放射治疗已常规用于治疗低度恶性淋巴瘤。 一系列临床试验证明，皮下注射 CpG 具有良好的耐受性。 基于这些数据，我们提出了一项 I/II 期研究，将局部放疗与 CpG 瘤内注射相结合，治疗复发性低级别淋巴瘤。 我们的主要目标是评估联合疗法的可行性；次要目标是评估该方案的抗淋巴瘤效果以及评估接受该方案治疗的患者的肿瘤特异性免疫反应。