A Novel Therapeutic DNA Vaccine Elicits Reduction of Tumor Clones and Favorable Perturbations in the Immune Microenvironment in Patients (pts) with Untreated Smoldering Waldenström Macroglobulinemia (sWM)

Background: Idiotypic determinants of the surface immunoglobulin (Ig) associated with a given pt's B-cell lymphoma are unique to that tumor, and can thus serve as 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 antigen-presenting cells, 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 intradermal vaccinations of pt-specific DNA vaccine at 4-week (wk) intervals (wks 0, 4 and 8). Two dose levels (500 µg; 2500 µg) were evaluated in a 3+3 design. The primary objective was to evaluate the vaccine's safety and identify the maximum tolerated dose. Secondary objectives were to assess immunogenicity of the vaccine to generate tumor-specific cellular immune responses.

Results: Between 1/2016 - 1/2019, 9 pts (7 men) were treated (500 µg: n = 3; 2500 µg: 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 38 months (range: 8.8-51), 8 pts are known alive; 1 has been lost to follow up. Six have maintained stable disease; 3 have progressed to symptomatic WM at 8, 25, and 28 months respectively, 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 observed in > 3pts include: leukopenia (6), nausea (5), anemia (4), increased creatinine (4), fatigue (4).

Immune correlatives have now been completed in all 9 patients. Analysis is ongoing, and complete data will be presented at the meeting. Serial pre- and post- vaccine samples analyzed by single-cell RNA seq from 3 representative patients (LPL 005, LPL 007, LPL 008) treated at the 2500 mg dose are shown in the Figure. DNA vaccine treatment significantly reduced the number of clonal B-cells in the bone marrow compartment of the 2 patients who have maintained SD (LPL 007 and LPL 008). DNA vaccine treatment also induced increases in monocytes in the tumor microenvironment of these 2 patients. In addition, T-cell receptor (TCR) sequence analysis revealed clear increases in TCR clonal expansions, consistent with a vaccine effect. In contrast, LPL 005, who had the earliest progression to symptomatic phase WM, had an increase in tumor B cells on post vaccine samples, and TCR clonotypes showed no changes. Similar changes were observed with serial bone marrow samples from the remaining patients treated on the trial, correlating with clinical outcome.

Conclusions: Idiotype (scFv-CCL20) DNA vaccine therapy appears to be safe in pts with sWM. Preliminary results of serial single cell RNAseq analysis suggest that the tumor immune microenvironment is favorably altered after chemokine-tumor antigen DNA vaccine treatment and these vaccine-induced changes may correlate with clinical outcome. The immunologic changes observed suggest response to this vaccine, and warrant further investigation in a Phase II trial, possibly in combination with immune checkpoint blockade.

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