A double-blind randomized, placebo-controlled trial of oral administration with human papillomavirus (HPV) type 16 E7-expressing Lactobacillus-based vaccine, BLS-ILB-E710c, for the treatment of cervical intraepithelial neoplasia (CIN2/3)

Background - Despite preventive HPV vaccines is implemented worldwide, current treatments for high grade cervical intraepithelial neoplasia are ablative, and no pharmacological treatments are available. Here we evaluated safety of BLS-ILB-E710c, HPV 16 E7-expressing Lactobacillus-based vaccine, and explored its efficacy for histopathological regression in women with CIN2/3. Methods - Safety and efficacy of BLS-ILB-E710c were assessed in CIN2/3 associated with HPV16 and its related HPV types in a randomized, double-blind, placebo-controlled phase 2b study. Total of 116 patients was recruited from fourteen hospitals in South Korea, and were randomized (2:1) to receive 1000 mg BLS-ILB-E710c or placebo for 5 days at 1, 2, 4, and 8 weeks. The primary endpoint was histopathological regression to CIN1 or normal pathology at 16 weeks after the first dose. Full analysis set (FAS) and Per-protocol set (PPS) analyses were based on patients receiving at least one oral vaccination, and on patients receiving four rounds of oral vaccination without protocol violations, respectively. The safety population included all patients who enrolled. The trial is registered at clinicaltrials.gov (number NCT03274206). Findings - Total of 116 patients were randomized, and 113 received either BLS-ILB-E710c (n=75) or placebo (n=38). The oral vaccination was well tolerated and no serious vaccine-related AEs occurred. No differences were showed between the BLS-ILB-E710c and placebo groups for patient background and adverse events. In the full analysis set (FAS) no statistically significant difference was noted between the two groups of histopathological regression at 16 weeks. However, the distribution by Bethesda system (for cervical cytology) in CIN2 patients showed significant differences between two groups (P=0.0304), which can affect histopathological regression. Sub-group analysis in FAS is performed to reduce the bias; histopathological classification (CIN2, CIN3) and cytological classification (≤ASCUS, LSIL, HISL). Therefore, in CIN3 sub-group, BLS-ILB-E710c recipients showed 13.33% of higher histopathological regression at 32 weeks than placebo recipients, and interestingly represented the statistically significant difference when histopathological regression at 32 weeks compared with 16 weeks (percentage point difference 34.87 [95% CI 7.78–61.96]; P=0.0216). In BLS-ILB-E710c recipients of CIN3 sub-group with histopathological regression, E7-specific CD8+ T lymphocyte immune responses were induced at 32 weeks (P= 0.0323). In addition, in HSIL sub-group, BLS-ILB-E710c recipients showed higher histopathological regression at 32 weeks than placebo recipients in similar with CIN3 sub-group analysis. Interpretation – Based on the finding this study, BLS-ILB-E710c could induce the local immune response by recruiting HPV16 E7-specific CD8+ T cells to cervical lesions, leading to histologic regression. To assess the efficacy of BLS-ILB-E710c as a novel Lactobacillus-based oral vaccine, it is necessary to define the population and time frame for phase 3 trial. Citation Format: Jae Kwan Lee, Seung Hun Song, Young Tae Kim, Chi-Heum Cho, Chan Joo Kim, Young-Chul Park. A double-blind randomized, placebo-controlled trial of oral administration with human papillomavirus (HPV) type 16 E7-expressing Lactobacillus-based vaccine, BLS-ILB-E710c, for the treatment of cervical intraepithelial neoplasia (CIN2/3) [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P043.