Radioimmunotherapy (RIT) for relapsed indolent non-Hodgkin lymphoma makes overall response prices (ORR) of 80% with mostly partial remissions. length of time of response (DR) of 35 months (4.6-76+). Correlative studies demonstrated a decrease in IL10 and TNFα and an increase in IL1β ARN-509 in response to therapy. CpG 7909 at a dose of 0.48 mg/kg is safe with standard RIT and produces a high CR rate and long DR; these results warrant confirmation. Keywords: lymphoma radioimmunotherapy rituximab ibritumomab tiuxetan CpG 7909 Introduction Radioimmunoconjugates utilize the selectivity of a monoclonal antibody to target radiation to tumor cells using radionuclides with high-energy delivered over a short path length to avoid damage to the surrounding normal tissues. In patients with relapsed NHL single doses of RIT have an ORR of 80% with 30% CR a median time to progression (TTP) of 1-1.5 years with 20% of patients achieving long-term remissions [1-3]. Similar to chemotherapy results in indolent NHL the best predictor of a long-term response to RIT is the achievement of a CR [1 3 Based on these results the US FDA has approved 90Y-ibritumomab tiuxetan (Zevalin? Spectrum Pharmaceuticals) for the treatment of relapsed low grade and follicular B-cell NHL and as consolidation after induction chemotherapy; 131I-tositumomab (Bexxar? GlaxoSmithKline) is approved for relapsed low grade follicular and transformed NHL. Several strategies are being tested to improve RIT results. These include moving RIT upfront as a single agent  consolidation after chemotherapy [5 6 adding a radiosensitizer such as the porphyrin derivative motexafin gadolinium  and combining RIT with stem cell support where the myelosuppression is overcome with the use of autologous stem cells using standard [8 9 and dose-escalated [10-14] approaches. Each of these has shown promise in early phase clinical trials. CpG 7909 is a 24 mer oligodeoxynucleotide (ODN) synthesized on a nuclease-resistant phosphorothioate backbone that contains ARN-509 four CG sequences and is designed to activate the immune system through the Toll-like receptor 9 (TLR 9). CpG 7909 has direct effects on human malignant B cells and plasmacytic dendritic cells [15 16 It can increase CD20 expression on malignant B cells induce a type 1 T helper cell (TH1) adaptive immune response and be safely administered to patients with B cell malignancies as a single-agent [17 18 or in combination with rituximab . Early phase clinical evaluation indicates CpG 7909 can enhance the development of an immune response to B cell lymphoma following exposure to radiation . Thus combining CpG 7909 with RIT could enhance clinical response to RIT by either increasing delivery of radiation to the cancer cell due to enhanced expression of the target antigen or facilitating development of an active anti-lymphoma immune response. ARN-509 In this study we combined intravenous (IV) CpG 7909 with standard dose RIT using 90Y-ibritumomab tiuxetan. We selected the IV rather than the subcutaneous (SC) route that has been used in prior studies [17 18 because the IV CpG 7909 has virtually no side effects and is more likely to reach the tumor ARN-509 and induce direct effects on the B cell lymphoma that express the TLR9 receptor [17 18 The goal was to determine the maximum tolerated doses (MTD) of IV CpG 7909 that can be delivered in four doses (two prior and two after RIT) for patients with relapsed NHL. Secondary goals were to learn the ORR DR and TTP with this regimen. Translational research goals were to study the effects of CpG 7909 RASGRP on 90Y-ibritumomab tiuxetan biodistribution learn the effect of CpG 7909 in vitro on gene expression and determine if CpG 7909 produced detectable immunological effects in the blood in this treatment setting. Patients and Methods Patient Eligibility Trial LS0382 (NCT00438880) was conducted by the University of Iowa/Mayo Clinic Lymphoma SPORE and was approved by the Institutional Review Boards of each site. Patients ≥18 years with biopsy-proven relapsed/refractory CD20+ B-cell NHL of the following types were eligible: small lymphocytic (SLL) lymphoplasmacytoid follicular grades 1-3 marginal zone and diffuse large. Patients were required to have measurable disease (≥1 lesion ≥2.