Abstract Prior studies have shown preliminary clinical efficacy in combining CPG-ODN with radiation therapy (XRT) to patients with indolent B-cell lymphoma. We report Phase 1 data of combination XRT and SD-101, a synthetic class C CPG-ODN, selected for strong induction of type I interferon. Methods: This dose-escalation Phase I trial (3+3 design) enrolled patients with untreated indolent B-cell lymphoma. The primary endpoints were safety and alpha-interferon-gene induction. Secondary endpoints included efficacy assessment using Cheson (1999) criteria and quantification of changes in tumor-infiltrating lymphocytes. Patients had a single lesion treated with XRT (2 Gy daily X 2 days) followed by weekly intratumoral SD-101 × 5 doses. Pharmacodynamic assessment included flow cytometry assessment of T-cell infiltrates in a FNA sample of the treated tumor and RT-PCR RNA assay of whole blood to assess induction of alpha-interferon genes. Efficacy assessment included imaging (CT at 3, 6, and every 6 months thereafter). Results: As of 23 Dec 2015, 13 patients total were enrolled and treated with SD-101 doses of 1, 2, 4 or 8 mg/dose. There were no dose limiting toxicities. Twelve patients received all planned doses of XRT and SD-101. One patient (8 mg) withdrew consent for treatment after receiving 1 SD-101 dose due to Grade 2 confusion and flu-like symptoms. The most common adverse events (AEs) (decreasing frequency) were chills, malaise, myalgia, fatigue, headache, pyrexia, and nausea, typically resolving within 48 hours. One serious AE occurred (Grade 3 Pulmonary Embolism (4 mg)) which was incidental and asymptomatic. There were 2 dose delays due to an AE (Grade 3 neutropenia) in the same patient (8 mg) that resolved without treatment. The other AE was Grade 3 malaise reported in 2 patients (8 mg). At study Day 90, a reduction of the product of diameters in treated tumors occurred in 12 patients (median -45.3%; range [-87, +100]) and in non-treated tumors occurred in 11 patients (median -8.1%; range [-48, +45]). An induction of alpha-interferon genes occurred at all dose levels with similar level of induction. At the treated site, regulatory T-cells (T Regs) were reduced in 8 of 10 patients (average decrease 22.3 + 9.5%) at Day 8. There was an average reduction of 83.3 + 9.9% in follicular T helper cells (Tfh) at Day 8 (n = 9 with baseline Tfh). Conclusions: SD-101 combined with radiation therapy showed preliminary abscopal anti-tumor activity and was well tolerated. A maximum tolerated dose has not yet been reached at the doses explored. Target engagement of the TLR-9 receptor (induction of interferon-alpha genes) was observed across all dose groups. A decrease in the proportion of T Regs and Tfh cells suggests modulation of their inhibitory effects and tumor growth promoting effects, respectively. The study is currently enrolling 2 expansion cohorts at 1 mg and 8 mg. Citation Format: Ronald Levy, Nancy Bartlett, Jonathan Friedberg, Patrick Reagan, Leo Gordon, Craig Bergman, Robert Coffman, Robert Janssen, Albert Candia, Michael Khodadoust, Matthew Frank, Steven Long, Debra Czerwinski, Michael Chu, Holbrook Kohrt. SD-101, a novel intratumoral class C CpG-ODN, given with low-dose radiation in patients with untreated low-grade B-cell lymphoma: interim results of a phase I trial. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT047.