Objectives We conducted a prospective, randomized, phase 2 clinical trial of GX-188E, a therapeutic HPV vaccine in combination with Imiquimod (IMQ) or IL-7-hyFc for HPV-16 or -18 related CIN 3. The primary endpoint was to determine the histopathological regression to <CIN1 assessed at week 20 (W20), and at week 36 (W36). In addition, viral clearance, HPV E6/E7 specific T-cell response and Flt-3L concentration were also assessed.

Methods Hypothesis was that combination of GX-188E with IMQ or IL-7-hyFc could result in synergistic improvement of immune-mediated tumor clearance compared to GX-188E alone.

Results In total, 51 patients were randomized, and 1 dropout occurred due to pregnancy. Among 25 patients receiving GX-188E plus IMQ, 16 (64%) and 18 patients (72%) at W20 and W36 demonstrated histopathological regression, respectively. HPV clearance was observed in 13 (52%) and 15 patients (60%) at W20 and W36, respectively. On the other hand, in patients receiving GX-188E plus IL-7-hyFc, 4 (16%) and 11 out of 25 patients (44%) showed histopathological regression at W20 and W36, respectively.

The lower efficacy obtained in GX-188E plus IL-7-hyFc may be attributed to insufficient local delivery of IL-7-hyFc via transcytosis across mucosal layer due to its liquid formulation. Considering vaginal fluid may also disturb mucosal delivery pathway, development of appropriate formulation is necessary.

Conclusions To better understand the mechanism of systemic and local HPV-specific T cell responses induced by GX-188E, immunological analysis including intracellular cytokine staining PBMC, analysis of tumor infiltrating CD4/CD8 T cells and levels of CD69, CD103, and foxp3 are needed.