Background: Idiotypic determinants of the surface immunoglobulin (Ig) associated with a given pt’s B-cell lymphoma are unique to that tumor, and thus are a tumor-specific marker. This study aims to use an idiotype DNA vaccine to lengthen the smoldering phase of WM without inducing cross-resistance to available therapies. Administered vaccine used recombinant plasmid DNA encoding a fusion protein, consisting of autologous lymphoma scFv (pt-specific idiotype) and human CCL20 (macrophage inflammatory protein-3 alpha - MIP-3α) chemokine. Targeted delivery of this fusion protein to APCs, and subsequent processing and presentation, is hypothesized to break tolerance and generate an immune response against the idiotype, promoting eradication of antigen-expressing B-cell lymphoma cells. Methods: Pts with sWM received 3 i.d. vaccinations of pt-specific DNA vaccine at 4-week (wk) intervals (wks 0, 4 and 8). Two dose levels (500µg; 2500µg) were evaluated in a 3+3 design. Primary objective: to evaluate the vaccine’s safety and identify it’s MTD. Secondary objectives: 1) to assess immunogenicity of the vaccine 2) to determine time to symptomatic WM. Results: Between 1/2016 - 1/2019, 9 pts (7 men) were treated (500 µg: n = 3; 2500µg: n = 6). Median age at enrollment was 67 yrs (range 56-78); median time from diagnosis to 1^st vaccination was 26.5 mos (8.8-120.9). MYD88 L265P + (6 pts). CXCR4 WHIM + (1 pt). With median follow up of 26.5 months (range: 8-36.4), all pts remain alive. Seven have stable disease; 2 progressed to symptomatic WM (8 mos. (1pt) and 26 mos. (1pt) from 1^st vaccination). All pts completed planned therapy. No DLTs or Grade 4 AEs occurred. Ten mos. after the 3^rd vaccination, 1 pt had a grade 3 pleural effusion and leukopenia with an increase in rheumatoid factor (23.1 IU/mL [normal range 0.0-15.9]) and ANA titer of 1:80; all resolved within 2 mos. Grade 1-2 AEs ( > 3pts): leukopenia (6), nausea (5), anemia (4), increased creatinine (4), fatigue (4). Conclusions: Idiotype (scFv-CCL20) DNA vaccine therapy appears to be safe in pts with sWM. Results of immunogenicity assays are underway, and will inform whether tumor specific immune responses are induced. Additional follow up is required to determine time to symptomatic WM. Clinical trial information: NCT01209871