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Clinical Trial
. 2019 Nov;30(6):e88.
doi: 10.3802/jgo.2019.30.e88.

A phase 1/2a, dose-escalation, safety and preliminary efficacy study of oral therapeutic vaccine in subjects with cervical intraepithelial neoplasia 3

Young Chul Park  1 , Yung Taek Ouh  2 , Moon Hee Sung  1   3 , Hong Gyu Park  1 , Tae Jin Kim  4 , Chi Heum Cho  5 , Jong Sup Park  6 , Jae Kwan Lee  7
Affiliations
Clinical Trial

A phase 1/2a, dose-escalation, safety and preliminary efficacy study of oral therapeutic vaccine in subjects with cervical intraepithelial neoplasia 3

Young Chul Park et al. J Gynecol Oncol. 2019 Nov.

Abstract

Objective: Persistent infection of HPV increases the chance of carcinoma in situ of cervix through stages of cervical intraepithelial neoplasia (CIN) 1, 2, and 3, and finally progresses into cervical cancer. We aimed to explore the safety and efficacy of BLS-M07 which is orally administered agent expressing human papillomavirus (HPV) 16 E7 antigen on the surface of Lactobacillus casei in patients with CIN 3.

Methods: Patients with CIN 3 were recruited in our clinical trial. Reid Colposcopic Index (RCI) grading and serum HPV16 E7 specific antibody production were used to evaluate efficacy of BLS-M07. In phase 1, BLS-M07 was administered orally, 5 times a week, on weeks 1, 2, 4, and 8 with dosages of 500 mg, 1,000 mg, and 1,500 mg. In phase 2a, patients were treated with 1,000 mg. The primary endpoints were the safety and the pathologic regression on colposcopic biopsy.

Results: Nineteen patients were enrolled in the CIN 3 cohort. In phase 1, no patients experienced dose limiting toxicity. No grade 3 or 4 treatment-related adverse events or deaths were observed. At 16 weeks after treatment, RCI grading was improved and serum HPV16 E7 specific antibody production increased (p<0.05). Six of 8 (75%) patients with CIN 3 were cured in phase 2a.

Conclusions: Oral immunization with BLS-M07 increases production of serum HPV16 E7 specific antibody which induces protective humoral immunity. The safety of this oral vaccine was proved and could be a competitive non-surgical therapeutic agent of CIN 3.

Trial registration: ClinicalTrials.gov Identifier: NCT02195089.

Keywords: Cervical Intraepithelial Neoplasia; Papillomavirus E7 Proteins; Papillomavirus Vaccines.

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Conflict of interest statement

Young-Chul Park, Moon-Hee Sung, Hong-Gyu Park from BioLeaders, Corp. are employees of and/or shareholders of the company, which is developing BLS-M07 vaccine. The remaining authors declare no competing financial interests.

Figures

Fig. 1
Fig. 1. Scheme of the phase I/IIa clinical trial. In the phase I trial, DLT and MTD were assessed after the first dose of treatment and each subsequent cohort was enrolled once each subject had completed the first dose of treatment. In the phase II trial, efficacy was assessed based on CIN by colposcopic biopsy.
CIN, cervical intraepithelial neoplasia; DLT, dose-limiting toxicity; HPV, human papillomavirus; IgG, immunoglobulin G; MTD, maximum tolerated dose.
Fig. 2
Fig. 2. Treatment of CIN 3 with oral vaccination BLS-M07. The effect of BLS-M07 was evaluated by RCI on colposcopic finding. The RCI score at 16 weeks after initial treatment (visit 6) was significantly decreased compared to initial assessment.
CIN, cervical intraepithelial neoplasia; RCI, Reid Colposcopic Index. *p<0.05.
Fig. 3
Fig. 3. The effect of oral vaccination of BLS-M07 on HPV16 E7-specific IgG. IgG titers were assessed using a log-based slope equation where the OD = 0.2. The titers of HPV16 E7-specific IgG titers at initial visit (visit 1), at completion of treatment (visit 4 at 9 week) and follow up at 16 week (visit 6). Antibody titers were increased significantly at 16 week (visit 6).
HPV, human papillomavirus; IgG, immunoglobulin G; OD, optical density.
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