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.