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

该子项目是利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH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 中心，不一定是研究者的机构。 淋巴瘤，特别是低度淋巴瘤，是所有人类癌症中最具免疫应答性的。 除了蛋白质和DNA疫苗之外，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身上取得了可喜的成果。 然而，树突状细胞疫苗需要树突状细胞的收集和离体操作，这是昂贵且麻烦的。 为了避免需要收集和处理树突状细胞离体，我们开发了一种新的方法，结合联合收割机低剂量辐射与肿瘤内注射CpG-寡核苷酸（一种细菌DNA基序，结合TLR 9），以引发对肿瘤的免疫反应。 其基本原理是放疗引发肿瘤坏死、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应答。 肿瘤内注射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应答。 此外，CpG-寡核苷酸增强树突状细胞的抗原呈递性质。 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验证，其中荷瘤动物接受放射治疗加瘤内注射CpG。 我们的结果表明，这种方案是有效的根除已建立的肿瘤在荷瘤小鼠。 此外，联合治疗比单独使用任何一种方式更有效。 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。 低剂量放射治疗已被常规用于治疗低度恶性淋巴瘤。 如一系列临床试验所证明的，CpG的皮下注射耐受性良好。 基于这些数据，我们提出了一个I/II期研究结合局部放疗与肿瘤内注射CpG复发性低级别淋巴瘤。 我们的主要目的是评估联合治疗的可行性;次要目的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应答。

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.