Efficacy of the therapeutic HPV vaccine in patients with cervical intraepithelial neoplasia 3: phase 2 clinical trial

Objective: Cervical intraepithelial neoplasia (CIN) 3 is a pre-malignant lesion that may progress to cervical cancer. This phase 2 clinical trial was designed to determine the efficacy of the therapeutic DNA vaccine GX-188E for inducing regression of HPV type 16/18-associated CIN3. Methods: We conducted a prospective, randomized, multicenter, open-label, phase 2 clinical trial of GX-188E in CIN3 patients positive for HPV type 16/18. The therapeutic vaccine was administered as an intramuscular injection by electroporation. Patients were randomly assigned to receive either 1-mg or 4-mg doses of GX-188E. The primary endpoint was to determine the histopathological regression to ＜CIN1 at visit 7 (V7; 20 weeks after the first GX-188E injection), and an extension study was pursued until visit 8 (V8; 36 weeks after the first GX-188E injection). HPV sequencing analysis and an ex vivo IFN-γ ELISPOT assay were performed using the collected cervical biopsy and blood samples from patients, respectively. Results: In total, 72 patients were enrolled and underwent randomization. Among them, 52% (33/64) at V7 and 67% (35/52) of patients at V8 presented histopathological regression after receiving the GX-188E injection. We found that 73% (24/33) of the patients at V7 and 77% (27/35) of the patients at V8 showed histopathological regression with HPV clearance. HPV clearance and histopathological regression were significantly associated at V7 (odds ratio=13.867, 95% CI: 4.070-47.249, p＜0.001) and at V8 (odds ratio=25.313, 95% CI: 4.750- 14.883, p＜0.001). Compared to the measurements at V1 (baseline), the patients at V8 with HPV clearance showed significantly higher fold-changes in their IFN-γ ELISPOT responses compared to those without HPV clearance (t-test, p=0.002). The HPV sequence analysis revealed that the HPV type 16 E6/E7 variants D25E (T178G), V83L (G350T), and N29S (A647G) were associated with histopathological regression at V8. Conclusions: GX-188E is the first therapeutic vaccine to show greater than 50% efficacy against a cohort containing only CIN3 patients with HPV type 16/18 in a phase 2 clinical trial. Thus, this vaccine may be a clinically feasible, non-surgical therapy for treating cervical pre-malignancy in the near future.