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

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 淋巴瘤，特别是低级别淋巴瘤，是所有人类癌症中免疫反应性最强的癌症之一。除了蛋白质和DNA疫苗，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产生了令人振奋的结果。然而，树突状细胞疫苗需要收集和体外操作树突状细胞，这是昂贵和繁琐的。为了避免在体外收集和处理树突状细胞的需要，我们开发了一种新的方法，将低剂量辐射与瘤内注射CpG-寡核苷酸(与TLR9结合的细菌DNA基序)相结合，以诱导对肿瘤的免疫反应。其基本原理是放射治疗会引发肿瘤坏死、细胞凋亡和炎症反应。这些事件反过来又扮演着“危险信号”的角色，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(由肿瘤细胞的坏死/凋亡提供)，经历成熟并迁移到引流淋巴结，在那里它们引发对肿瘤抗原的免疫反应。瘤内注射CpG-寡核苷酸将通过向肿瘤部位招募树突状细胞来增强免疫反应。此外，CpG-寡核苷酸增强了树突状细胞的抗原提呈特性。 这种新的组合方法已经在我们实验室的小鼠淋巴瘤模型中得到了验证，在该模型中，荷瘤动物接受了放射加CpG瘤内注射的治疗。结果表明，该方案能有效地根除荷瘤小鼠已建立的肿瘤。此外，联合治疗比单独使用任何一种方法都更有效。 我们激动人心的临床前研究结果构成了当前临床研究的基础。低剂量放射治疗是治疗低度恶性淋巴瘤的常规方法。皮下注射CpG耐受性良好，一系列临床试验证明。基于这些数据，我们提出了一项I/II期研究，结合局部放射和瘤内注射CpG治疗复发的低级别淋巴瘤。我们的主要目的是评估联合治疗的可行性；次要目标是评估该方案的抗淋巴瘤效果，并评估接受该方案治疗的患者的肿瘤特异性免疫反应。

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.