Phase I and II randomized clinical trial of an oral therapeutic vaccine targeting human papillomavirus for treatment of cervical intraepithelial neoplasia 2 and 3

Abstract

Background: Although many human papillomavirus (HPV)-targeted therapeutic vaccines have been examined for efficacy in clinical trials, none have been translated into clinical use. These previous agents were mostly administered by intramuscular or subcutaneous injection to induce systemic immunity. We investigated the safety and therapeutic efficacy of an HPV-16 E7-expressing lacticaseibacillus-based oral vaccine.

Methods: In a double-blind, placebo-controlled, randomized trial, a total of 165 patients with HPV-16-positive high-grade cervical intraepithelial neoplasia 2 and 3 were assigned to orally administered placebo or low, intermediate, or high doses of IGMKK16E7 (lacticaseibacillus paracasei expressing cell surface, full-length HPV-16 E7). In the 4 groups, IGMKK16E7 or placebo was administered orally at weeks 1, 2, 4, and 8 postenrollment. The primary outcomes included histopathological regression and IGMKK16E7 safety.

Results: In per-protocol analyses, histopathological regression to normal (complete response) occurred in 13 (31.7%) of 41 high-dose recipients and in 5 (12.5%) of 40 placebo recipients (rate difference = 19.2, 95% confidence interval [CI] = 0.5 to 37.8). In patients positive for HPV-16 only, the clinical response rate was 40.0% (12 of 30) in high-dose recipients and 11.5% (3 of 26) in recipients of placebo (rate difference = 28.5, 95% CI = 4.3 to 50.0). There was no difference in adverse events that occurred in the high-dose and placebo groups (P = .83). The number of HPV-16 E7-specific interferon-γ producing cells within peripheral blood increased with level of response (stable disease, partial, and complete responses; P = .004). The regression to normal (complete response) rates among recipients with high levels of immune response were increased in a dose-dependent manner.

Conclusion: This trial demonstrates safety of IGMKK16E7 and its efficacy against HPV-16-positive cervical intraepithelial neoplasia 2 and 3. IGMKK16E7 is the first oral immunotherapeutic vaccine to show antineoplastic effects.

Trial registration: jRCT2031190034.

Figure 1.

Patients’ enrollment and random assignment. Screening exclusions at registration included women who were human papillomavirus-16 negative and those not diagnosed with cervical intraepithelial neoplasia 2 or 3 by central pathology (*). The remaining 165 patients were enrolled and participated in a double-blind random assignment. A total of 165 patients were assigned to all groups, and 3 patients were discontinued from the study.

Figure 2.

Rate of regression to normal (complete response). A) The regression to normal (complete response) rates at 16 weeks after the first dose for each treatment group is shown for all participants (full analysis set, per-protocol set) and subgroups of patients with human papillomavirus (HPV)-16–only positive results and cervical intraepithelial neoplasia (CIN) 3. B) The complete response rates at 24 weeks after the first dose for each treatment group are shown. A linear dose response in complete response rates is indicated using P values, with a linear dose response observed in patients with HPV-16 subtype only or with CIN 3 at baseline. FAS = full analysis set; PPS = per-protocol set.

Figure 3.

Forest plots of differences in complete response rates for vaccine compared with placebo treatments in various subgroups. Rate differences and their 95% confidence intervals are shown in forest plots for complete response rate comparisons of various treatment vs placebo groups 24 weeks after the first vaccine dose. Patients with human papillomavirus (HPV)-16 and other HPV subtypes or cervical intraepithelial neoplasia 2 were small in number (approximately 10 patients), and complete response rates did not differ between treatment groups. CI = confidence interval; CIN = cervical intraepithelial neoplasia; FAS = full analysis set; HPV = human papillomavirus; PPS = per-protocol set; RD = rate difference. Bold means statistical difference.

Figure 4.

Immunological responses and clinical efficacy. To evaluate the magnitude of human papillomavirus (HPV)-16 E7–specific Th1 immune response, the numbers of HPV-16 E7–specific interferon-γ–producing cells in peripheral blood were obtained by enzyme-linked immunosorbent spot assay. The spot-forming cell numbers (spot-forming cells per 10^6 peripheral blood monocytes) for each patient were plotted on the y axis. A) Comparisons of spot-forming cells at the study endpoint among regression to normal, regression to cervical intraepithelial neoplasia (CIN) 1, and stable disease (CIN 2-3) groups. B) Change in spot-forming cells for each patient, grouped by treatment type and dose. Red dots depict patients with complete response, and the dotted line represents the median of spot-forming cell change among the full analysis set. ANOVA = analysis of variance; CR = complete response; IFN = interferon.