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.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 淋巴瘤，尤其是低度淋巴瘤，是所有人类癌症中最免疫反应的之一。 除了蛋白质和DNA疫苗外，另一种被证明是有效的方法是采用树突状细胞。 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产生了有希望的结果。 但是，树突状细胞疫苗需要对树突状细胞的收集和离体操纵，这些树突状细胞昂贵且繁琐。 为了避免在体内收集和加工树突状细胞的需要，我们开发了一种新型方法，将低剂量辐射与肿瘤内注射CpG-寡核苷酸肽（一种与TLR9结合的细菌DNA基序）结合起来，以引起对肿瘤的免疫反应。 理由是放射疗法会触发肿瘤坏死，凋亡和炎症反应。 这些事件反过来充当“危险信号”，将树突状细胞募集到炎症部位。 在炎症部位，树突状​​细胞会处理肿瘤相关的抗原（由肿瘤细胞的坏死/凋亡提供），经历成熟并迁移至排出淋巴结，在那里它们对肿瘤抗原产生免疫反应。 CpG-寡核苷酸的肿瘤内注射将通过募集树枝状细胞对肿瘤部位来增强免疫反应。 此外，CpG-寡核苷酸增强了树突状细胞的抗原表现特性。 这种新的组合方法已在我们的实验室的鼠淋巴瘤模型中得到了验证，在我们的实验室中，用辐射和肿瘤内注射CpG处理了肿瘤动物。 我们的结果表明，该方案有效地消除了肿瘤小鼠中既定的肿瘤。 此外，组合疗法比单独的模式更有效。 我们令人兴奋的临床前研究的结果构成了当前临床研究的基础。 低剂量放射疗法通常用于治疗低度淋巴瘤。 如在一系列临床踪迹中所证明的，对CpG的皮下注射良好。 基于这些数据，我们提出了一项I/II期研究，该研究将局部辐射与肿瘤内注射CpG在复发性低级淋巴瘤中。 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作用，并评估用该方案治疗的患者的肿瘤特异性免疫反应。